Docket No.: 512-53
`
`METHODS OF TREATING ACNE
`
`Inventor:
`
`· Robert A. Ashley
`
`Hoffmann & Baron, L.L.P:
`6900 Jericho Turnpike
`Syosset, New York 11791
`(516) 822-3550
`
`Dr. Reddy's Laboratories, Ltd., et al.
`v.
`Galderma Laboratories, Inc.
`IPR2015-__
`Exhibit 1040
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`Exh. 1040, Page 1 of 93
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`

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`METHODS OF TREATING ACNE
`
`CROSS-REFERENCE TO RELATED APPLICATION
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`5
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`This application claims the benefit of U.S. Provisional Application No.
`
`60/281,916, filed April5, 2001, and U.S. Provisional Application No. 60/325,489,
`
`filed September 26, 2001, both of which are incorporated herein by reference.
`
`BACKGROUND OF THE INVENTION
`
`10
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`Acne is a common disease characterized by various types oflesions. The
`
`areas affected typically are areas of the skin where sebaceous glands are largest, most
`
`iuimerous, and most active. The lesions associated with acne are usually categorized
`
`as either non-inflammatory or inflammatory.
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`Non-inflammatory lesions include comedones. Comedones appear in two
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`15
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`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 (keratinoc)rtes) become unusually cohesive,
`
`forming a microcomedb or a microscopic hyperkeratotic plug in the follicular canal.
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`The progressive acclUTiulation of these microcomedones lead to visible comedones.
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`. 20
`
`In its mildest form, acne is a more or less. superficial disorder characterized by
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`shgiit, spotty skin Imtaflons. In such cases, ordinary skin hygiene is typically a
`satisfactory treatine!lt. In the more 1ni1ammatozy types of acne, however, pustules;
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`infected cysts; and :ln extreme cases, canailzing, inflamed and infected sacs appear.
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`Without effective treatment, these lesions may become extensive and leave
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`25
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`permanent, disfiguring scars.
`
`M~croorg<:-nisms, especially_ P':()p~onibacterium acnes, ate strongly implicated
`
`in the pathogenesis of acne. The microorganisms are thought to release microbial
`
`mediators of inflammation into the dermis or trigger the release of cytokines from
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`ductal keratinocytes.
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`Exh. 1040, Page 2 of 93
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`Accordingly, the efficacy of antibiotics in treating acne is thought to be due, in
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`significant part, to the direct inhibitory effect of the antibiotics on the growth and
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`metabolism of these microorganisms. Systemically-administered tetracycline
`
`antibiotics, especially minocycline hydrochloride, are particularly effective in treating
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`5
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`acne.
`
`The tetracyclines are a class of compounds of which tetracycline is the parent
`
`compound. Tetracycline has the following general structure:
`
`HO
`
`OH 0
`Structure A
`
`10
`
`The numbering system of the multiple ring nucleus is as follows:
`
`Structure B
`
`15
`
`. Tetracycline, as well as the 5-hydroxy (oxytetracycline, e.g. Terramycin) and .
`
`7-chloro (chlorotetracycline, e.g. Aureomyqin) derivatives, exist in natUre, and are all
`·-·
`. -
`well known antibiotics. Semisynthetic derivatives such as 7-
`
`dimethy laminotetracyciine ( minocycline) and 6a-deoxy-5-hydroxytetracycline
`
`(doxycycline) are also known tetracycline antibiotics. Natural tetracyclines may be
`
`20 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 of tetracyclines, further activities of
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`antibiotic tetracyclmes have been investigated for possible therapeutic effects on acne.
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`2
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`Exh. 1040, Page 3 of 93
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`

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`For example, a study by Elewski et al., J Amer. Acad. Dermatol., 8:807-812
`
`(1983) suggests that acne therapy, consisting of orally-administered tetracycline at a
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`total daily dose of 1000 mg, may have therapeutic anti-inflammatory effects in
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`addition to antibiotic effects. In particular, it was found that the anti-inflammatory
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`5
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`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. Dermatol., 101:86-91
`
`(1993), evaluated the effects of oral minocycline or tetracycline therapy on the
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`10
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`cytokine and microflora content of open comedones in acpe patients. The total daily
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`dose of minocycline administered was 100 mg. The total daily dose of tetracycline
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`administered was 1000 mg.
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`I
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`Eady et al. found that the therapies upregulated the production ofbioactive IL-
`lex-like material and immunochemical IL-1/3. IL-l is considered to be a pro(cid:173)
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`15
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`inflammatory cytokine.
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`Accordingly to Eady et al., no overall decrease in the numbers of
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`propionibacteriaimg of comedonal material was fou:zid. It is important to note,
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`20
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`however, that the numbers of propionibacteria/mg of comedonal material are not
`
`expected to decrease in responseJo aJ1tibiotic therapy. Since the bacteria within
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`comedones are encapsulated by the follicle, they are not susceptible to antibiotic
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`treatment.
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`25
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`Another possible activity of tetracyclines in acne therapy was investigated by
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`Bodokh, I., et al., Acta. Derm. Venera!., 77:255-259 (1997). Their study was
`
`designed to evaluate the action of minocycline on seba~eous eJScretion in acne
`patients. A 100 -mg daily dose ofminocyclme was adminiSterecf. A subc-i1mcai
`increase in seborrhoea_ was reported. The authors propose that minocycline induces
`
`30
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`an increase in seborrhoea via a reduction in ductal obstruction. The mechanism by
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`which the ductal obstruction is reduced is proposed to be a reduction in ductal
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`3
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`Exh. 1040, Page 4 of 93
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`

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`irritation. The authors suggest t¥-t the reduction of ductal irritation is due to.
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`minocycline's direct effect on P. acnes, or minocycline's effect on the lipase ·
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`produced by P. acnes.
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`5
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`Bodokh et al. also found that during treatment no correlation exists between
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`seborrhoea intensity and clinical severity of acne. The authors state that the lack of
`
`correlation shows that seborrhoea is pathogenic because it is the "culture 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.
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`10
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`Similarly, in a recent clinical study it was reported that tetrac?'cline in sub(cid:173)
`
`antibiotic do·ses had no clinical effect on acne. (Cunliffe et al., J. Am. A cad.
`
`Dermatol., 16:591-9 (1987).) In particular, a 100mgtotal daily dose ofmmocycline
`and ~tal daily dose of tetracycline were found to be necessary to successfully
`treat acne.
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`15
`
`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.
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`20
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`For example, in conventional acne therapy; tetracycline is administered at an initial
`
`dose of 500 to 2,000 mg/day, foiiowed by a maintenance dose of 250-500 mg/day.
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`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
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`25
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`significant part, to the antibiotic effects of the tetracyclines. In ad~tion to their
`
`~
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`antibiotic effects, it has been proposed that tetracyclines reduce the number of
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`inflammatory lesions (papules, pustules and nodules) by a variety of non-antibiotic
`
`mechanisms. Such mechanisms include interfering with the chemotaxis of
`
`polymorphonuclear leukocytes (P1v1N) into the inflammatory lesion, inhibition of
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`30
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`PMN derived collagenase, and by scavenging reactive oxl.dative species produced by
`
`resident inflammatory cells.
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`4
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`Exh. 1040, Page 5 of 93
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`

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`There is no disclosure in the prior art of using either a sub-antibiotic dose of
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`an antibiotic tetracycline compound, or of using a non-antibiotic tetracycline
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`compound for the treatment of acne.
`
`The use of tetracycline antibiotics, however, can lead to undesirable side
`
`effects. For example, the long term administration of antibiotic tetracyclines can
`
`reduce or eliminate healthy microbial :flora, such as intestinal :flora, and can lead to the
`
`production of antibiotic resistant organisms or the overgrowth ofyeast and fungi.
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`5
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`10
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`Accordingly, there is a need for an effective treatment of acne which causes
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`fewer undesirable side effects produced by the systemically-administered antibiotics
`
`used iii conventional acne therapy.
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`15
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`SUMMARY OF INVENTION
`
`The present invention provides a method of treating acne in a human in need
`
`thereof. The method comprises achninistering systemically to the human a
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`tetracycline compound in an amount that is effective to treat acne but has substantially
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`20
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`no antibiotic activity (i.e. substantially no antimicrobial activity), without
`
`administering a bisphosphonate compound.
`
`Addition'!-lly, the present inyention .provides methods for reducing the number
`
`of comedones, inhibiting oxidation of melanin, and/or inhibiting lipid-associated
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`25
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`abnormal follicular 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, and/or to inhibit lipid-associated abnormal follicular
`
`differentiation, but has substantially no antibiotic activity.
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`30
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`5
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`Exh. 1040, Page 6 of 93
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`

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`BRIEF DESCRIPTION OF THE DRAWINGS
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`5
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`Figure 1 shows the photoirritancy factor (PIF) for some tetracycline
`
`compounds. For structure K, the compounds indicated are as follows:
`
`10
`
`COL
`
`308
`311
`306
`
`R7
`
`hydrogen
`hydrogen
`hydrogen
`
`R8
`
`hydrogen
`hydrogen
`hydrogen
`
`R9
`
`ammo
`palmitamide
`dimethylamino
`
`For structures L, M, Nor 0 the compounds indicated are as follows:
`
`COL
`
`R7
`
`801
`802
`804
`805
`
`hydrogen
`hydrogen
`hydrogen
`hydrogen
`
`R8
`
`hydrogen
`hydrogen
`hydrogen
`hydrogen
`
`R9
`
`acetamido
`dimethylaminoacetamido
`nitro
`amino
`
`For structure P, R8 is hydrogen and R9 is nitro.
`
`DETAILED DESCRIPTION
`
`The present invention provides mef!J.ods of treating acne. As used herein; the
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`15
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`20
`
`25
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`-
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`30
`
`term." acne" is a disorder of the skin characterized by pa:pules, pustules, cysts, nodules,
`comedones, and other blemishes or skin lesions. These blemishes and lesions are
`___ -:,:::-~::·\
`·-
`.
`..
`.
`. .
`-
`often accompanied by inflammation of the skin glands and pilosebaceous follicles, as .1
`
`' -
`
`.
`
`.
`
`..
`
`well as, microbial, especially bacterial, -infection.
`
`Fnr·the-purposes·o-fthis specification; acne includes·alllmown types of-acne.
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`3 5 · · Some types of acne include, for example, acne vulgaris, cystic acne, acne atrophica,
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`bromide acne, chlorine acne, acne conglobata, acne cosmetica, acne detergicans,
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`epidemic acne, acne estivalis, acne fulminans, halogen acne, acne indurata, iodide
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`acne, acne keloid, acne mechanica, acne papulosa, pomade acne, premenstral acne,
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`6
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`Exh. 1040, Page 7 of 93
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`

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`acne pustulosa, acne scorbutica, acne scrofulosorum, acne urticata, acne varioliformis,
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`acne venenata, propionic acne, acne excoriee, gram negative acne, steroid acne,
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`nodulocystic acne and acne rosacea. Acne rosacea is characterized by inflammatory
`
`lesions (erythema) and permanent dilation of blood vessels (telangectasia).
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`5
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`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.
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`10
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`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
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`acne, gram negative folliculitis, sebaceous gland dysfunction, hiddradenitis
`
`suppurativa, pseudo-folliculitis barbae, or folliculitis.
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`15
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`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
`
`antibiotic activity.
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`20
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`The tetracycline compound can be an antibiotic or non-antibiotic compound.
`
`The tetracycline compound has the general tetracycline structure indicated above, or a
`
`derivative thereof.
`
`Some examples of antibiotic (i.e. antimicrobial) tetracycline compounds
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`25
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`include doxycycline, mino<?yciine, tetracycline, oxytetracycline, chlortetracycline,
`
`demeclocycline, lymecycline and their pharmaceutically acceptable salts.
`
`Doxycycline is preferably administered as its hyclate salt or as a hydrate, preferably
`
`monohydrate.
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`30
`
`Non-antibiotic tetracycline compounds are structurally related to the antibiotic
`
`tetracyclines, but have had thei.r antibiotic activity substantially or completely
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`7
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`I
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`Exh. 1040, Page 8 of 93
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`

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`eliminated by chemical modification. For example, non-antibiotic tetracycline
`
`compounds are capable of achieving antibiotic activity comparable to that of
`
`tetracycline or doxycycline at concentrations at least about ten times, preferably at
`
`least about twenty five times, greater than that of tetracycline or doxycycline,
`
`5
`
`respectively.
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`07
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`Examples of chemically modified non-antibiotic tetracyclines (CMTs) include
`
`4-de( dimethylamino )tetracycline (CMT -1 ), tetracyclinonitrile (CMT -2), 6-demethyl-
`
`6-deoxy-4-de( dimethylamino )tetracycline (CMT-3 ), 7 -chloro-4-
`
`10
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`de(dimethy1amino)tetracycline (CMT-4), tetracycline pyrazole (CMT-5), 4-hydtoxy-
`
`4-de( dimethylamino )tetracycline (CMT -6), 4-de( dimethylamino-12a-
`
`, deoxytetracycline (CMT -7); 6-deoxy-5a-hydroxy-4-de( dimethylamino )tetracycline
`
`'(CMT -8), 4'-de( dimethylamino )-12a-deoxyanhydrotetracycline (CMT -9), 4-
`
`, de( dimethylamino )minocyeline (CMT -1 0).
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`15
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`Further examples of chemically modified non-antibiotic tetracyclines include
`
`Structures C-Z. (See Index of Structures.)
`
`Tetracycline derivatives, for purposes of the invention, may be any
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`20
`
`tetracycline derivative, including those compounds disclosed generically or
`
`specifically in co-pending U.S. patent application serial no. 09/573,654 filed on May
`
`18, 2000, which are here:in incorporated by reference.
`
`The minimal amolint of the tetracycline compound administered to a human is
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`25
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`the lowest amount capable of providing effective treatment of acne~ Effective
`
`treatment is a reduction or inllibition of the blemishes and lesions associated with
`
`acne. J_'he amount of the tetracycline compound is such that it does not significantly
`
`prevent the growth-of microbes, e.g. bacteria.
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`30
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`Two ways in which to describe the administered amount of a tetracycline
`
`compound is by daily dose, and by serum level.
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`8
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`I
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`Exh. 1040, Page 9 of 93
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`

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`For example, tetracycline compounds that have significant antibiotic activity
`
`may be administered in a dose (i.e. amount) which is 1 0-80% of the antibiotic dose .
`
`. More preferably, the antibiotic tetracycline compound is administered in a dose which
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`5
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`is 40-70% ofthe antibiotic dose.
`
`Some examples of antibiotic doses of members of the tetracycline family
`
`include 50, 75, and 100 mg/dayof 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
`
`10
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`of oxytetracyclinej 6b0 mg/day of demec1ocycline; and 600 mg/day oflymecycline.
`
`Examples of the maximum non-antibiotic doses of tetracyclines based on
`
`steady-state pharmacokinetics are as follows: 20 tng/twice a day for doxycycline; 3 8
`
`mg of minocycline one, two, three or four times a day; and 60 mg of tetracycline one,
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`15
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`two, three or four times a day.
`
`In a preferred embodiment, to reduce the number of comedones, doxycycline
`
`is administered in a daily amount of from about 30 to about 60 milligrams, but
`
`maintains a concentration in hrip:tan plasma below the threshold for a significant
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`20
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`antibiotic effect.
`
`In an especially preferred ~ml;>odiment, doxycycline hyclate is administered at
`a 20 milligram dose tWice daily. Such a forirtulatiort is sold for the tteatfrieht of
`periodontal disease by CollaGenex Pharmaceuticals, Inc. of Newtown, Pennsylvania
`
`25
`
`under the trademark Periostat ®.
`
`Example 38 below sumniarizes 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 unexpected.
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`30
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`The reduction is particularly unexpected since, as can be seen from the microbiology
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`9
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`I
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`Exh. 1040, Page 10 of 93
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`

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`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
`
`5
`
`levels follows.
`
`An antibiotic tetracycline compound is advantageously administered in an
`
`amount that results in a serum tetracycline concentration which is 10-80% of the
`
`mmimum antibiotic serum concentration. The minimum antibiotic serum
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`10
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`concentration is the lowest concentration known to exert a significant antibiotic effect.
`
`Some examples ofthe approximate antibiotic setum concentrations of
`
`members of the tetracycline family folio\¥.
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`15
`
`For example, a single dose of two 100 mg minocycline HCl tablets
`
`administered to adult humans results in minocycline serum levels ranging from 0. 7 4
`
`to 4.45 flg/ml over a period of an hour. The average level is 2.24 flg/ml.
`
`Two hundred and fifty milligrams of tetracycline HCl administered every six
`
`20
`
`hours over a twenty-four hour period produces a peak plasma concentration of
`
`approximately 3 p,glml. Five hundred milligrams of tetracycline HCl administered
`every six hours over a twenty-four hour period produces a serum concentration level
`of 4 to 5 flg/ml.
`
`25
`
`In one embodiment, the tetracycline compound can be administered in an
`ai.nourit which results in a serum concentration between about 0.1 and 10.0 fLg/ml,
`
`more preferablybetween0.3 and 5.0 11g/ml. For example, doxycyclineis
`admin:lstered in an amount which results J.n a serum concentration between about o. i
`and 0.8 .uglml, more preferably between 0.4 and 0.7 fLg/uM.
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`30
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`10
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`Exh. 1040, Page 11 of 93
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`Some examples of the plasma antibiotic threshold levels of tetracyclines based
`
`on steady-state pharmacokinetics are as follows: 1.0 p.g/ml for doxycycline; 0.8 1-Lg/ml
`
`for minocycline; and 0.5 !-Lg/ml for tetracycline.
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`5
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`Non-antibiotic tetracycline compounds can be used in higher amounts than
`
`antibiotic tetracyclines, while avoiding the indiscriminate killing of microbes, and the
`
`emergence of resistant microbes. For example, 6-demethyl-6-deoxy-
`
`4-de(dimethylamino)tetracycline (CMT-3) may be administered in doses of about 40
`
`to about 200- mg/day, or in amounts that result in serum levels of about 1.55 1-Lg/ml to
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`10
`
`about 1 0 1-Lg/ml.
`
`The actual preferred amounts of tetracycline compounds in a specified case
`will vary according to the particular compositions formulated, the mode of
`
`application, the particular sites of application, and the subject being treated.
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`15
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`The tetracycline compounds can be in the form ofpharmaceutically acceptable
`
`salts of the compounds. The term "pharmaceutically acceptable salt" refers to a salt
`
`prepared from tetracycline compound~ and pharmaceutically acceptable non-toxic
`
`acids or bases. The acids may be inorganic or organic acids oftetracyclihe
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`20
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`compounds. Examples of inorganic acids inClude hydrochloric, hydrobromic,
`
`hydroiodic, sulfuric, and phosphoric acids. Examples o{organic acids include
`
`-
`
`J
`
`carboxylic and sulfonic acids. The radical of the organic acids may be aliphatic or
`
`. aromatic. Some examples of org~nic acids include formic, acetic, phenylacetic,
`
`propionic, succinic, glycolic, glucuronic, maleic, furoic, glutamic, benzoic,
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`25
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`anthranilic, salicylic, phenylacetic, ma:J?-delic, embonic (pamoic ), methanesulfonic,
`
`ethanesulfonic, panthenoic, benzenesulfonic, stearic, sulfanilic, alginic, tartaric, citric, )
`
`gluconic, gulonic, arylsulfonic, and galacturonic acids. Appropriate organic bases
`
`may be selected, for example, from N,N-dibenzylethylenediamine, chloroprocaine,
`
`choline, diethanolamine, ethylenediamine, meglumine (N-methylglucamine), and
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`30
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`procaine.
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`11
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`Exh. 1040, Page 12 of 93
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`The tetracycline compounds mentioned above, especially doxycycline and
`
`minocycline, are unexpectedly effective in reducing the number of comedones when
`
`administered at a dose which has substantially no antibiotic effect .. Preferably the .
`
`reduction is at least about 20% greater than for a placebo control, more preferably at
`
`· 5
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`least about 30% greater than for a placebo control, most preferably at least about 40%
`
`greater than for a placebo control, and optimally at least about 50% greater than for a
`
`placebo control.
`
`The inventors are not certain of, and do not wish to be limited by, any
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`10
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`particular mechanism of action. Nevertheless, it is believed that the ability of
`
`tetracyclines, such as doxycycline, to inhibit oXidation of melanin and to inhibit lipid(cid:173)
`
`associated abnormal folliCular differentiation prevents keratinocytes from becoming
`
`cohesive, thereby inhibiting the formation of comedones.
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`15
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`Preferably, the tetracycline compounds have low phototoxicity, or are
`
`administered in an amount that results in a serum level at which the phototoxicity is
`
`acceptable. Phototoxicity is a chemically-induced photosensitivity. Such
`
`photosensitivity renders skin susceptible to damage, e.g. sunburn, blisters, accelerated
`
`aging, erythemas and eczematoid lesions, upon exposure to light, in particular
`-·
`ultraviolet light. The preferred amount of the tetracycline compound produces no
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`20
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`more phototoxicity than is produced by the administration of a 40 mg total daily dose
`
`of doxycycline.
`
`Phototoxicity can be evaluated in terms of a photoirritancy factor (PIF), as
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`25
`
`described in the examples. A PIF value of about 1.0 indicates that a compound is
`
`considered to have no measurable phototoxicity.
`
`The low phototoxic derivatives preferably have PrF values no greater than
`
`about 5, prefer~bly no greater than about 2, more preferably no greater than about 1.5,
`
`30 most preferably no greater than about 1.2, and optimally about 1.
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`12
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`Exh. 1040, Page 13 of 93
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`Some antibiotic tetracyclines having low phototoxicity include, for example,
`
`minocycline and tetracyline.
`
`Some non-antibiotic tetracyclines having low phototoxicity include, but are
`
`5
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`not limited to, tetracycline compounds having the general formulae:
`
`STRUCTUREK
`
`wherein: R7, R8, and R9 taken together in each case, have the following meanings:
`
`10
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`15
`
`and
`
`R7
`
`hydrogen
`hydrogen·
`hydrogen
`
`R8
`
`hydrogen
`hydrogen
`hydrogen
`
`R9
`
`amino
`palmitamide
`diniethylamino
`
`STRUCTUREL
`STRUCTUREN
`
`STRUCTlTRE M
`STRUCTUREO
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`20
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`25
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`wherein: R7, R8, and R9 taken together in each case, have the following meanings:
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`R7
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`·hydrogen
`hydrogen
`hydrogen
`hydrogen
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`R8
`
`hydrogen
`hydrogen
`hydrogen
`hydii:>gen
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`R9
`
`acetamido
`dimethylaminoacetamido
`nitro
`amino
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`and
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`30
`
`STRUCTUREP
`
`wherein: R8, and R9 taken together are, respectively, hydrogen and nitro.
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`. 35
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`The tetracycline compounds are administered without administering a
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`bisphosphonate compound. Bisphosphonates compounds are related to inorganic
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`13
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`Exh. 1040, Page 14 of 93
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`pyrophosphonic acid. The bisphosphonates include, as non-limiting examples,
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`alendronate ( ( 4-amino-1- hydroxybutylidene) bisphosphoriic acid), clodronate
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`(dichloromethane diphosphonic acid), etidronate ((1-hydroxyethylidene) diphosphanic
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`acid) and pamidronate ((3-amino-1- hydroxypropylidene) bisphosphonic acid); also
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`5
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`risedronate ([ -hydroxy-:2-(3-pyridinyl)ethylidel_le] bisphosphonic acid), tiludronate,
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`i.e., tiludronic acid ([(4-chlorophenyl) thio] methylene] bisphosphonic acid) and
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`zolendronate.
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`The tetracycline compounds may, for example, be administered systemically.
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`10
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`For the purposes of this specification, "systemic administration" means administration
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`to a human by a method that causes the compounds· to be absorbed into the
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`bloodstream.
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`For example, the tetracyclines compounds can be administered orally by any
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`15 · method known in the art. For example, oral administra,tion can be by tablets,.
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`capsules, pills, troches, elixirs, suspensions, syrups, wafers, chewing gum and the
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`like.
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`Additionally, the tetracycline compounds can be administered_ enterally or
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`20
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`parenterally, e.g., intravenously; intramuscularly; subcutaneously, as injectable
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`solutions or suspensions; intraperitoneally; or rectally. Administration can also be
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`intranasa+Jy, in the form of, for example, an intranasal spray; or transdermally, in the
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`form of, for example, a patch.
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`25
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`For the_pharmaceutical purposes described above, the tetracycline compounds
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`of the invention can be formulated per se in pharmaceutical preparations optionally
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`with a suitable pharmaceutical carrier (vehicle) or excipient as understood by
`- - --- -
`-··-
`--- --
`-
`-
`practitioners in the art. These preparations can be made according to conventional
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`chemical methods.
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`30
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`In the case of tablets for oral use, carriers which are commonly used include
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`lactose and com starch, and lubricating agents such as magnesium stearate are
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`14
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`Exh. 1040, Page 15 of 93
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`commonly added. For oral administration in capsule form, useful carriers include
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`lactose and com starch. Further examples of carriers and excipients include milk,
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`sugar, certain types of clay, gelatin, stearic acid or salts thereof, calcium stearate, talc,
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`vegetable fats or oils, gums and glycols.
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`5
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`When aqueous suspensions are used for oral administration, emulsifYing
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`and/or suspending agents are commonly added. In addition, sweetening and/or
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`flavoring agents may be added to the oral compositions.
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`·10
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`For intramuscular, intraperitoneal, subcutaneous and intravenous use, sterile
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`solutions of the tetracycline compounds can be employed, and the pH of the solutions
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`can be suitably adjusted and buffered. For intravenous use, the total concentration of
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`the solute(s) can be controlled in order to render'the preparation isotonic.
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`15
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`The tetracycline compounds of the present invention can further comprise one
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`or more pharmaceutically acceptable additional ingredient(s) such as alum, stabilizers,
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`buffers, coloring agents, flavoring agents, and the like.
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`20
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`The tetracycline compound may be administered intermittently. For example,
`the tetracycline compound m~y be administered 1-6 times a day, preferably 1-4 times
`a day.
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`Alternatively, the tetracycline compound may be administered by sustail;led
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`release. Sustained release administration is a method of drug delivery to achieve a
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`25
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`certain level of the drug over a particular period oftiine. The level. typically is
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`measured by serum concentration. Further description of methods of delivering
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`tetracycline compounds by sustained release can be found in the patent application,
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`"Controlled Delivery of Tetracycline and Tetracycline Derivatives/' filed on Apnl5,
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`2001 and assigned to CollaGenex Pharmaceuticals, Inc. of Newtown, Pennsylvania.
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`30
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`The aforementioned application is incorporated herein by reference in its entirety.
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`15
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`Exh. 1040, Page 16 of 93
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`For example, 40 milligrams of doxycycline may be administered by sustained release
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`over a 24 hour period.
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`In the embodiment in which the tetracycline compound is a non-antibiotic
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`5
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`tetracycline.compound, administration can include topical application. Particular non(cid:173)
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`antibiotic tetracycline compounds have only limited biodistribution, e.g. CMT-5. In
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`such cases, topical application is the preferred method of administration of the
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`compound.
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`10
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`Carrier compositions deemed to be suited for topical use include gels, salves,
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`lotions, creams, ointrrients and the like. The non-antibiotic tetracycline compound can
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`also be incorporated with a support base or matrix or the like which can be directly
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`applied to skin.
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`15
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`Topical application of non-antibiotic tetracycline compounds are effective in
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`treating acne while not inducing significant toxicity in the human. For example,
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`amounts of up to about 25% (w/w) in a vehicle are effective. Amounts of:from about
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`0.1% to about 10% are preferred.
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`20
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`Combined or coordinated topical and systemic administration of the
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`tetracycline compounds is also contemplated tinder the invention. For example, a
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`non-absorbable non-antibiotic tetracycline compound can be administere~ t~pically,
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`. while ~ tetracycline compound_ cap_8:bl~ of substantial absorption and effective
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`systemic distributioh in a human can be admihistered systemically.
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`25
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`The tetracycline compounds are prepared by methods known in the art. For
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`example, natural tetracyclines may be modified without losing their antibiotic
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`properties, although certain elements of the structure must be retained. The
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`modifications that may and may not be made to the basic tetracycline structure have
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`30
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`been reviewed by Mitscher in The Chemistry of Tetracyclines, Chapter 6, Marcel
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`Dekker, Publishers, New York (1978).- According to Mitscher, the substituents at
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`16
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`Exh. 1040, Page 17 of 93
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`positions 5-9 of the tetracycline ring system may be modified without the complete
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`loss o~ antibiotic properties. Changes to the basic ring system or replacement of the
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`· substituents at positions 1-4 and 10-12, however, generally lead to synthetic
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`tetracyclines w:ith substantially less or effectively no antibiotic activity.
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`Further methods of preparing the tetracycline compounds are described in the
`
`examples.
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`EXAMPLES
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`The following examples serve to provide further appreciation of the invention
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`but are not meant in any way to restrict the effective scope of the invention;
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`Preparation of Compounds
`
`EXAMPLE!
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`4-Dedimethy I amino-7 -dimethy1amino-6-demethyl-6-deoxy-9-nitro tetracycline sulfate
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`5
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`10
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`15
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`To a solution of one millimole of 4-dedimethylamino-7-dimethylamino-6-
`demethyl-6-deoxytetracycline in 25 ml of concentrated sulfuric acid at ooc was added
`1.05 mmole of potassium nitrate. The resulting solution was stirred at ice bath
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`20
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`temperature for 15 minutes and poured in one liter of cold ether with stirring. The
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`precipitated solid was allowed to settle and the majority of solvent decanted. The
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`remaining material was filtered through a sintered glass funnel and the collected solid
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`was washed well with cold ether. The product was dried in a vacuum desiccator
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`25
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`overnight.
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`9-amino-4-dedimethylamino-7 -dimethylamino-6-demethyl-6-deoxytetracycline
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`· EXAMPLE2
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`30
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`sulfate
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`17
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`Exh. 1040, Page 18 of 93
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`To a solution of300 mg of the 9.-nitro compound from example I, -in 30 ml of
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`ethanol was added 50 mg of Pt02 . The mixture was hydrogenated at atmospheric
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`pressure until the theoretical amount of hydrogen was absorbed. The system is
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`flushed with nitrogen, the catalyst Pt02 is filtered and the filtrate added dropwise to
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`5
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`300 ml of ether. The product that separates is filtered and dried in a vacuum
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`desiccator.
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`EXAMPLE3
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`9-Acetamido-4-dedimethy lamino-7 -dimethylamino-6-demethyl-6-deoxytetracyc line
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`sulfate
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`IO
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`To a well stirred cold solution of 500 mg of9-amino-4-dedimethylamino-7-
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`dimethylamino-6-demethyl-6-deoxytetracycline sulfate from example 2, in 2.0 ml of
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`1.3-dimethyl-2-imidazolidinone, 500 mg of sodium bicarbonate was added followed
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`by 0.21 ml of acetyl chloride. The mixture is stirred at room temperature for 30
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`15 minutes, filtered and the filtrate was added dropwise to 500 ml of ether. The product
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`that separated was filtered and dried in a vacuum desiccator.
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`4-bedimethylamino-7 -dimethylamino-6-demethy 1-6-deoxy-9-diazoniumtetracycline
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`20
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`sulfate
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`EXA1'\1PLE 4
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`To a solution of 0.5 g of 9-amino-4-dedimethy lamino-7 -dimethylamino-6-
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`demethyl-6-deoxytetracycline sulfate, ·from example 2, in I 0 ml.of 0. IN hydrochloric
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`acid in methanol cooled in an ice bath, 0.5 ml ofn-butyl nitrite was added. The
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`25
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`solution was stirred at ice bath temperature for 30 minutes and then poured into 250
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`ml of ether. The product that ·sepanited was ·filtered, washed with ether and dried in a·
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`vacuum desicca