Trials@uspto.gov
`Tel: 571-272-7822
`
`Paper 12
`Entered: February 16, 2016
`
`/
`
`UNITED STATES PATENT AND TRADEMARK OFFICE
`
`BEFORE THE PATENT TRIAL AND APPEAL BOARD
`
`DR. REDDY’S LABORATORIES, LTD. and
`DR. REDDY’S LABORATORIES, INC.,
`Petitioner,
`
`V.
`
`GALDERMA LABORATORIES,INC.,
`Patent Owner.
`
`Case IPR2015-01777
`Patent 8,603,506 B2
`
`Before ERICA A. FRANKLIN, ZHENYU YANG,and
`ROBERTA. POLLOCK,Administrative Patent Judges.
`
`POLLOCK, Administrative Patent Judge.
`
`DECISION
`DenyingInstitution of Inter Partes Review
`37 C.F-R. § 42.108
`
`
`Tel: 571-272-7822
`
`Paper 12
`Entered: February 16, 2016
`
`/
`
`UNITED STATES PATENT AND TRADEMARK OFFICE
`
`BEFORE THE PATENT TRIAL AND APPEAL BOARD
`
`DR. REDDY’S LABORATORIES, LTD. and
`DR. REDDY’S LABORATORIES, INC.,
`Petitioner,
`
`V.
`
`GALDERMA LABORATORIES,INC.,
`Patent Owner.
`
`Case IPR2015-01777
`Patent 8,603,506 B2
`
`Before ERICA A. FRANKLIN, ZHENYU YANG,and
`ROBERTA. POLLOCK,Administrative Patent Judges.
`
`POLLOCK, Administrative Patent Judge.
`
`DECISION
`DenyingInstitution of Inter Partes Review
`37 C.F-R. § 42.108
`
`
`
`IPR2015-01777
`Patent 8,603,506 B2
`
`INTRODUCTION
`Dr. Reddy’s Laboratories, Ltd. and Dr. Reddy’s Laboratories, Inc.
`(collectively, “Petitioner’) filed a Petition (Paper 1; “Pet.’”’)to institute an
`interpartes review ofclaims1, 7, 8, 14, 15, and 20 ofUS 8,603,506 B2 (Ex.
`1001; “the ’506 patent”). Galderma Laboratories Inc. (“Patent Owner”)!
`
`filed a Patent Owner Preliminary Response. Paper9 (“Prelim. Resp.”). We
`have jurisdiction under 35 U.S.C. § 314.
`For the reasons provided below, we determine Petitioner has not
`established a reasonable likelihood that it would prevail in showing the
`
`unpatentability of at least one challenged claim of the ’506 patent. See
`
`35 U.S.C. § 314(a). We, therefore, deny the Petition for an inter partes
`
`review.
`
`Related Proceedings
`a.
`Petitioner indicates that the °506 patent has been asserted in the
`
`United States District Court for the District of Delaware (Civil Action No.
`15-670). Pet. 2; Paper6, 2.
`
`In addition to the case before us, Petitioner has requested inter partes
`
`review ofclaims1, 7, 8, 14, 15, and 20 of US 8,603,506 B2 on other
`
`grounds in Case Nos. IPR2015-01778 and IPR2015-01782.
`
`' Petitioner further indicates that the Complaint in Civil Action No. 15-670
`states that Nestlé Skin Health S.A. is now the ownerofthe ‘506 patent. Pet.
`2n.1. Although Patent Owner does not directly address this assertion in the
`Preliminary Response, the USPTO Assignment Database indicates that
`patent is assigned to Galderma Laboratories, Inc. Absent additional
`information, we refer to Galderma Laboratories, Inc. as the Patent Owner.
`
`
`
`Case IPR2015-01777
`Patent 8,603,506 B2
`
`—
`The ’506 Patent
`b.
`The *506 patent is directed to the treatmentof“all known types of
`
`acne,” broadly defined as “a disorder of the skin characterized by papules,
`
`pustules, cysts, nodules, comedones, and other blemishes or skin lesions.”
`
`Ex. 1001, 4:23-32. The genus “acne”is expressly defined as encompassing
`acne rosacea (“rosacea”),” a skin disorder “characterized by inflammatory
`
`lesions (erythema) and permanentdilation of blood vessels (telangectasia).”
`
`Id. at 4:31-43. The specification further states the “[t]he present inventionis
`
`particularly effective in treating comedones.” /d. at 4:23-433
`
`By way of background, the ’506 patent discloses that the efficacy of
`systemically-administered tetracycline compoundsin the treatment of acne
`is commonly believed to be due,“in significant part, to the direct inhibitory
`
`effect of the antibiotics on the growth and metabolism of[] microorganisms”
`
`that “reléase microbial mediators of inflammation into the dermisortrigger
`
`the release of cytokines from ductal keratinocytes.” Ex. 1001, 1:42—50. In
`
`addition to these antibiotic effects, the specification also notes that
`
`tetracyclines may have therapeutic anti-inflammatory effects due to, for
`
`example, the “inhibition of neutrophil chemotaxis induced by bacterial
`
`chemotactic factors,”the “inhibition of [polymorphonuclear leukocyte]
`
`derived collagenase, and by scavenging reactive oxidative species produced
`
`by resident inflammatory cells.” Jd. at 2:21-32, 3:14—25.
`
`* The parties agree that the term “acne rosacea”in the specification refers to
`rosacea. Pet. 30-31; Prelim. Resp. 15-16.
`3 Petitioner asserts, and Patent Ownerdoesnot contest, that comedonesare
`not a feature of rosacea. Pet. 9, 25; see Prelim. Resp. 23-24; Ex. 1004 7 13.
`
`3
`
`
`
`Case IPR2015-01777
`Patent 8,603,506 B2
`
`The °506 patent teaches that although tetracyclines are administered in
`
`conventional antibiotic therapy, antibiotic doses of thesecompounds can
`result in undesirable side effects such as the reduction or elimination of
`
`healthy microbial flora and the production ofantibiotic resistant
`
`microorganisms. /d. at 3:7-17, 3:31-36. To address the needforeffective
`treatments that minimize these side effects, the °506 patent disclosesthat “all
`
`knowntypes of acne” may be treated by administering a tetracycline
`
`compoundin an amount having “substantially no antibiotic activity (i.e.
`
`substantially no antimicrobial activity)” and, thus, “does not significantly
`
`prevent the growth of ... bacteria.” Jd. at 3:37-50; 4:31-32; 5:31-35. The
`
`°506 patent defines “effective treatment” as “a reduction or inhibition of the
`blemishes and lesions associated with acne” (id 5:31~33), which may be
`achieved by administering non-antibiotic tetracycline compounds(i.e., those
`
`lacking substantial antibiotic activity) or by using sub-antibiotic doses of
`
`_ tetracycline compoundshaving knownantibiotic effects (see, e.g., id. at
`
`3:26-29, 4:58-61, 5:1-9, 5:35-42). With respect to the latter, the
`
`specification indicates that a sub-antibiotic dose may comprise “10-80% of
`
`the antibiotic dose,” or “an amountthat results in a serum tetracycline
`
`concentration which is 10-80% of the minimum antibiotic concentration.”
`
`Id. at 5:36-42; 6:7-12.
`
`The specification teaches that, whereas exemplary antibiotic doses of
`tetracycline compoundsinclude 50, 75, and 100 milligrams per day of
`
`doxycycline, in an especially preferred embodiment, doxycycline (as
`
`doxycycline hyclate) is administered as a 20 milligram dose, twice daily,
`
`i.e., 40 milligrams per day. Id. at 5:43-45; 5:59-63. The specification
`
`teaches that this 40 milligram daily dose provides the maximum non-
`
`
`
`Case IPR2015-01777
`Patent 8,603,506 B2
`
`antibiotic (i.e., sub-antibiotic) of doxycycline based on steady-state
`
`pharmacokinetics. Jd. at 5:49-52. In terms of serum concentration,
`
`doxycycline mayalso be administered in an amountthat results in a serum
`
`concentration between about 0.1 and 0.8 pg/ml. Jd. at 6:29-32.
`
`Example 38 of the ’506 patent discloses that in a six-month, placebo-
`
`controlledtrial for the treatment of acne* using 20 mg doxycycline hyclate,
`
`twice daily, doxycycline-treated patients showeda statistically significant
`
`reduction in both comedonesandinflammatory lesions (defined as “papules
`
`and pustules, less than or equal to 5 nodules”) as compared to placebo. Jd. at
`
`19:54—55; 20:24-32. The six-month doxycycline treatment “resulted in no
`
`reduction in skin microflora .
`
`.
`
`. nor an increase in resistance counts when
`
`compared with placebo.” Jd. at 20:33-37; see id. at 5:64-6:4.
`
`c.
`
`Representative Claim
`
`Claim 1 of the ’506 patent recites:
`
`1. A methodfor treating papules and pustules of rosacea in a
`humanin needthereof, the method comprising
`administering orally to said human doxycycline, or a
`pharmaceutically acceptable salt
`thereof,
`in an
`amountthat
`
`is effective to treat the papules and pustules of
`(i)
`rosacea;
`
`is 10-80% of a 50 mg dose of doxycycline per day;
`
`(ii)
`and
`
`4 Petitioner asserts that Example 38 is directed to treating common acne
`(acne vulgaris), presumably based oninclusion criteria requiring the
`presence of comedones, non-inflammatory lesions which are not a symptom
`of rosacea. See Pet. 9, 23, 25; Ex. 1001, 1:20, 19:54; Ex. 1004 § 13. Patent
`Ownerdoesnot dispute this characterization. See Prelim. Resp. 21.
`
`5
`
`
`
`Case IPR2015-01777
`Patent 8,603,506 B2
`
`(iii) results in no reduction of skin microflora during a
`six-month treatment, without administering a
`bisphosphonate compound.
`
`The remaining asserted claims recite “an amount [of doxycycline]
`
`which provides a serum concentration in the range of about 0.1 to about 0.8
`
`ug/ml” (claims 7, 14, and 20), “40-80% of a 50 mg dose of doxycycline per
`
`day” (claim 8), and “doxycycline, or a pharmaceutically acceptable salt
`
`thereof, in an amount of 40 mgper day”(claim 15).
`
`d.
`
`Asserted Grounds of Unpatentability
`
`Petitioner asserts the following grounds of unpatentability.
`Claims challenged|Basis,|___Reference
`
`PERIOSTAT
`
`1, 7, 8, 14, 15, and 20
`
`1, 8,15
`
`7, 14, and 20
`
`Sneddon?
`Golub®
`Torresani’
`PERIOSTAT®
`Golub
`Torresani
`Jansen?
`Golub
`
`Torresant
`
`Jansen
`
`§ 103
`
`§ 103
`
`> Sneddon, A Clinical Trial of Tetracycline in Rosacea, 78 BRIT.J.
`DERMATOL. 649 (1966). Ex. 1006.
`6 Golub et al., Low-dose doxycycline therapy: Effect on gingival and
`crevicularfluid collagenase activity in humans, 25 J. PERIODONT. RES. 321
`(1990). Ex. 1048.
`7 Torresaniet al., Clarithromycin versus doxycycline in the treatment of
`rosacea, 36 INT’L. J. DERMATOL. 938 (1997). Ex. 1010.
`8 PERIOSTAT™,PHYSICIANS’ DESK REFERENCE (54" ed. 2000). Ex. 1042.
`* Jansen and Plewig, Rosacea:classification and treatment, 90 J. R. Soc.
`MED.144 (1997). Ex. 1034.
`
`
`
`Case IPR2015-01777
`Patent 8,603,506 B2
`
`ANALYSIS
`
`Asaninitial matter, we note that Patent Ownerasserts that the Board
`
`should exercise its discretion and denyinstitution of this Petition as
`
`duplicative of groundsraised in IPR2015-01782. Prelim. Resp. 52-58.
`While we have considered Patent Owner’s position, we decline to do so.
`
`a.
`
`Claim Construction
`
`In an inter partes review, the Board interprets a claim term in an
`
`unexpired patent accordingto its broadest reasonable construction in light of
`
`the specification of the patent in which it appears. 37 C.F.R. § 42.100(b); In
`
`re Cuozzo Speed Techs., LLC, 793 F.3d 1268, 1275-79 (Fed. Cir. 2015),
`cert. granted sub nom., Cuozzo Speed Techs., LLC v. Lee, No. 15-446, 2016
`
`WL 205946 (U.S. Jan. 15, 2016).
`
`Underthat standard, and absent any special definitions, we assign
`
`claim termstheir ordinary and customary meaning, as would be understood
`by one of ordinary skill in the art at the time of the invention,'° in the context
`
`of the entire patent disclosure. Jn re Translogic Tech., Inc., 504 F.3d 1249,
`
`1257 (Fed. Cir. 2007). And “[a]lthough an inventor is indeed free to define
`
`the specific terms used to describe his or her invention, this must be done
`| with reasonable clarity, deliberateness, and precision.
`‘Where an inventor
`choosesto be his own lexicographerand to give terms uncommon meanings,
`
`he must set out his uncommondefinition in some manner within the patent
`
`disclosure’ so as to give one of ordinary skill in the art notice of the change.”
`
`'0 Patent Ownerprovisionally adopts, as do we, Petitioner’s definition of a
`person ofordinary skill in the art as ‘“‘a licensed and practicing dermatologist
`with aslittle as one year oftreating patients in a hospital, clinical, and/or
`private setting.” Prelim. Resp. 25; Pet. 36 (both quoting Ex. 1004 { 11).
`
`7
`
`
`
`Case IPR2015-01777
`Patent 8,603,506 B2
`
`In re Paulsen, 30 F.3d 1475, 1480 (Fed. Cir. 1994)(citation omitted). “In
`such cases, the inventor’s lexicography governs.” Phillips v. AWH Corp.,
`
`415 F.3d 1303, 1316 (Fed. Cir. 2005) (en banc). Only terms whichare in
`controversy need to be construed, however, and then only to the extent
`necessary to resolve the controversy. Vivid Techs., Inc. v. Am. Sci. & Eng’g,
`Inc., 200 F.3d 795, 803 (Fed. Cir. 1999). For this reason, we provide
`
`express constructionsfor only the following terms.
`
`i. Rosacea
`
`Theparties agree that the °506 patent identifies rosacea (“acne
`
`rosacea”) as a form of acne. Pet. 30-31; Prelim. Resp. 7. Although
`
`Petitioner contends that one of ordinary skill in the art would notclassify
`
`rosacea as a form ofacne (Pet. 22; Ex. 1004 Jf 12, 13), we apply the
`
`inventor’s clearly expressed definition that “acne include[s] .
`
`.
`
`. acne
`
`rosacea” (Ex. 1001 4:31-41). With respect to the symptomsof rosacea,
`
`however, neither party contends that uncommon meaningsapply. Pet.
`
`30-31; Prelim. Resp. 6-8. We therefore construe rosacea as a form of acne
`
`having symptomsincluding papules, pustules, erythema, and telangiectasia,
`
`where the predominantlesions are papules and pustules. See Ex. 1001,
`
`4:23-43; Ex. 1004, J 7, 19 (“The predominantlesions [in rosacea] are
`
`papules and pustules.’ ([Ex. 1056] at 680; see also Exh. 1046, at 852, 958;
`
`Exh. 1047, at 1023, 1175.).”
`
`.
`
`ii. Papules and Pustules
`
`The 7506 patent does not define the terms “papules” and “pustules”as
`
`other than as “[iJnflammatory lesions” or blemishes of the skin. See Ex.
`
`1001, 3:17-19, 4:24-27, 19:54—55. Petitioner does not expressly suggest a
`
`meaning for these terms butpoints to its expert’s statementthat “‘[a] papule
`
`
`
`Case IPR2015-01777
`Patent 8,603,506 B2
`
`is asmall, solid, elevated lesion .. . smaller than 1 cm in diameter, and the
`
`major portion of a papule projects abovethe plane of the surrounding skin,””
`oe
`whereas,“‘[a] pustule is a circumscribed, raised lesion that contains a
`
`purulent exudate. . .. Pus, composedofleukocytes, with or without cellular
`debris, may contain bacteria or may be sterile....°” Pet. 23; Ex 1004 § 19
`(both quoting Ex. 1056, 27, 31). Petitioner contendsthat “[t]hese definitions
`
`align well with those provided by applicant during prosecution.” Pet. 23
`
`(citing Ex. 1070, 6).!! We, nevertheless, note that, unlike the disclosure of
`the ‘506 patent, the definition of “pustule” quoted by Petitioner’s expert is
`not clearly defined as a lesion ofthe skin.
`
`Patent Ownercontends that the terms should be accordedtheir plain
`
`and ordinary meanings; objects to the definitions provided by Petitioner’s
`
`expert as unnecessarily limiting; and points, instead, to the definitions set
`forth in the prosecution leading to the issuanceofthe ’506 patent. Pet. at
`
`10-11 (citing Ex. 1070, 6).
`
`In view of the above, and applying the broadest reasonable definition
`
`consistent with the specification, we interpret “papules and pustules” as
`
`inflammatory lesions or blemishesof the skin, where “‘papules”are solid,
`
`rounded bumpsrising from the skin that are each usually less than 1
`
`centimeter in diameter, and “pustules” are small, inflamed, pus-filled,
`
`blister-like lesions of the dermis or epidermis.
`
`11 U.S. Serial No. 13/277,789, Response to Office Action, dated May 14,
`2012.
`
`
`
`Case IPR2015-01777
`Patent 8,603,506 B2
`
`b.
`
`Principles ofLaw
`
`_ Aclaim is unpatentable under 35 U.S.C. § 103 if the differences
`
`between the claimed subject matter and the prior art are such that the subject
`
`matter, as a whole, would have been obviousat the time the invention was
`
`madeto a person havingordinary skill in the art to which said subject matter
`
`pertains. KSR Int’l Co. v. Teleflex Inc., 550 U.S. 398, 406 (2007).
`
`The question of obviousness is resolved on the basis of underlying factual
`
`determinations including: (1) the scope and content of the priorart; (2) any
`
`differences between the claimed subject matter and the priorart; (3) the level
`
`of ordinary skill in the art; and (4) objective evidence of nonobviousness.
`Graham v John Deere Co., 383 U.S. 1, 17-18 (1966).
`A prima facie case of obviousnessis established whentheprior art
`itself would appear to have suggested the claimed subject matter to a person
`
`of ordinary skill in the art. Jn re Rinehart, 531 F.2d 1048, 1051 (CCPA
`
`1976). The level of ordinary skill in the art is reflected by the prior art of
`
`record. See Okajima v. Bourdeau, 261 F.3d 1350, 1355 (Fed. Cir. 2001);
`Inre GPAC Inc., 57 F.3d 1573, 1579 (Fed. Cir. 1995); In re Oelrich,
`579 F.2d 86, 91 (CCPA 1978).
`
`Weanalyze the asserted grounds of unpatentability in accordance with
`
`the above-stated principles.
`
`c.
`
`The Asserted References
`
`Webegin our discussion with a brief summary ofthe references
`
`asserted.
`
`i. Sneddon
`
`Sneddon, published in 1966, demonstrates the efficacy of tetracycline
`
`(250mg,twice daily) in the treatment of rosacea. Ex. 1006. Sneddonstates
`
`10
`
`
`
`Case IPR2015-01777
`Patent 8,603,506 B2
`
`that there are “diametrically opposed views”on the underlying cause of
`
`rosacea including emotionaldistress, gastric or intestinal disturbances, and
`
`demodexskin mites. /d. at 649. Consistent with this lack of understanding
`
`regarding the etiology of rosacea, Sneddonstates that “[t]he mechanism of
`[tetracycline’s] beneficial action is as yet unknown, but the observation that
`it controls not only postulation but erythema suggeststhat it is not entirely
`
`an antibacterial or antidemodectic effect. Has it some action on intestinal
`
`absorption?” Jd. at 652.
`
`i. Torresani
`
`Torresani reports on a comparison between oral doxycycline (100
`
`mg/twice daily for 4 weeks followed by 100 mg/once daily for 4 weeks) and
`
`clarithromycin (250 mg/twice daily for 4 weeks followed by 250 mg/once
`
`daily for 4 weeks). Ex. 1010, 942, Ex. 1004 9 31. Although finding the
`
`clarithromycin regimenpotentially more promising, Torresani showedthat
`
`the doxycycline treatment improved the symptomsof rosacea including the
`numberofpapules and pustules. Ex. 1010, 944, 945, Figs. 3 and 4; Ex. 1004
`q 31.
`
`Torresani, published in 1997,states that “[t]he etiology and
`
`pathogenesis of rosaceaare still unknown,”butthat “[t]he therapeutic
`
`efficacy of tetracyclines seemsto be related to their anti-inflammatory
`
`efficacy.” Ex. 1010, 945 (citing reference 6: Martin et al., Effect of
`
`tetracycline on leukotaxis, 129 J. Infect. Dis. 110 (1974). Torresani also
`
`notes that an etiologic relationship between rosacea and Helicobacter pylori
`
`infections has been suggested based on correlations between that bacterial
`
`infection and rosacea. /d. at 946.
`
`1]
`
`
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`Case IPR2015-01777
`Patent 8,603,506 B2
`
`iii. Golub
`
`Golub, published in 1990, teachesthat “[t]etracyclines are often
`
`advocated as useful adjuncts in periodontal therapy based ontheir
`
`effectiveness against periodontopathogens; an additional advantageis their
`
`unique ability, amongantibiotics, to be highly concentrated within the fluid
`
`of the periodontal pocket.” Ex. 1048, 325. Golub further teachesthat
`
`“[c]ollagen breakdownis an essential pathway in the pathogenesis of
`
`periodontal and other diseases,” and posits that “tetracycline .
`
`.
`
`. can inhibit
`
`mammalian collagenases and collagen breakdown by a mechanism
`independentof the antimicrobial efficacy of these drugs.” Jd. at 321-22.
`Golubstates that,
`
`prescribed,
`routinely
`humans,
`on
`studies
`several
`[i]Jn
`. were found
`antimicrobially-effective doses of tetracyclines .
`.
`to reduce the collagenase activity in the fluid of the periodontal
`pocket which originates from the adjacent host tissues. The
`current study was carried out to determine whether a newer,
`“semi-synthetic tetracycline, could be administered to humansin
`a
`low-dose
`regimen[,] which would effectively
`inhibit
`collagenase activity in the gingival tissue as well as in the
`crevicular fluid.
`
`Id. at 322.
`
`Golubpresents the results of two studies of patients with periodontal
`
`disease. In the first study, patients administered 30 mg doxycycline, twice
`
`daily, for two weeks as an adjunct to periodontal pre-treatment and surgery,
`
`showeda statistically significant reduction in gingival collagenase activity,
`
`but not gingival pocket depth, or the severity of gingival inflammation. Jd.
`
`at Table 1, 322, 324, 328 (“[I]n study no. 1, in which a more complex
`clinical protocol was followed to obtain excised gingival specimens,the
`severity of inflammation in the gingival tissues did not appear to be reduced
`
`12
`
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`Case IPR2015-01777
`Patent 8,603,506 B2
`
`by the low-dose doxycycline therapy, even though collagenaseactivity in
`these tissues was suppressed.”); see alsoid. at Fig. 4 (equating gingival
`
`index (G.I.) to inflammation). In the second study, patients administered 20
`
`mg doxycycline, twice daily, for two weeks with no additional treatment or
`
`surgery, showedsignificant reductions in the collagenase activity of their
`
`gingival crevicularfluids, and in the severity of gingival inflammation. Jd.
`
`at 323, 324-325, Table I, Abstract.
`
`Golubalso states that novel properties of tetracycline drugs:
`
`help explain their clinical effectiveness and may also expand
`their
`future
`applications
`beyond their
`current
`use
`as
`antimicrobials. As one example, tetracyclines now appear to
`possess anti-inflammatory properties when administered to
`patients with certain skin diseases[ ] such as rosacea[,] ... which
`are not believed to have a microbialetiology.
`Id. at 325 (citations omitted). Golub posits that the mechanismsunderlying
`
`the non-antimicrobial properties of tetracyclines may includethe inhibition
`
`of prostaglandin production, superoxide radical scavenging, and the
`
`inhibition of mammalian collagenase and other metalloproteinase activities.
`Id.
`|
`
`iv. PERIOSTAT
`
`Published in 2000, PERIOSTATis a Physician’s Desk Reference
`entry describing Periostat® as “a 20 mg capsule formulation of doxycycline
`
`hyclate for oral administration.” Ex. 1042, 944. Under “Dosage and
`
`Administration,” the reference states that, “Periostat 20 mg twice daily as an
`
`adjunct following scaling and root planning may be administered for up to 9
`
`months.” Jd. at 946. The reference further states that ‘“[t]he dosage of
`
`doxycycline achieved with this product during administration is well below
`
`the concentration required to inhibit microorganisms commonly associated
`
`13
`
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`Case IPR2015-01777
`Patent 8,603,506 B2
`
`with adult periodontitis.” Jd. at 945.
`
`v. Jansen
`
`Jansen reviewsthe classification and treatment of rosacea as of 1997,
`
`describing rosacea generally as:
`a chronic skin disorder affecting the facial convexities,
`characterized by frequent flushing, persistent erythema, and
`telangiectases. During episodes of inflammation additional
`features are swelling, papules and pustules. The disease was
`originally called acne
`rosacea,
`a misleading term that
`unfortunately persists.”
`
`Ex. 1034, 144. Jansenstates that “[t]he exact etiology of rosaceais
`
`unknownand theories abound.” Jd. Jansen notes that various theories
`
`include, gastrointestinal disturbances, Helicobacter pylori infection,
`
`hypersenstitivity to D. folliculorum mites, which may “induce[] papule or
`
`pustule formation in pre-existing rosacea,” and abnormalities in the dermis
`
`surrounding blood vessels. /d.
`
`Jansen teachesthat although bacteriological studies of inflammatory
`
`pustules from Stage II rosacea “reveal nothing of interest” (id. at 145),
`
`“Trjosacea generally responds well to oral antibiotics” (id. at 148). Noting
`
`that “[t]etracyclines and erythromycin reduce leucocyte migration and
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`phagocytosis,” Jansen suggests that “[t]he mechanism of antibiotics may be
`anti-inflammatory rather than antibacterial.” Jd. With respect to specific
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`treatments, Jansen states that doxycycline “[is] usually effective in
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`controlling papulopustula rosacea.” Jd. “One should start with large doses,”
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`for example, 50 milligrams of doxycycline twice daily. “As soon as
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`papulopustules are fully controlled (usually after two to three weeks) doses
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`of ...50mg... doxycycline, per day are generally sufficient.” Jd.
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`d.
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`Obviousness over Sneddon, Golub, Torresani, and PERIOSTAT
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`Petitioner asserts that claims 1, 7, 8, 14, 15, and 20 would have been
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`obvious over the combination of Sneddon, Golub, Torresani, and
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`PERIOSTAT. Pet. 24-45. To briefly summarize Petitioner’s argument, it
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`would have been obviousfor one of ordinary skill in the art to reduce the
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`dose of tetracyclines taught by Sneddon——and,in particular, the dose of
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`doxycycline taught by Torresani—forthe treatmentof the papules and
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`pustule of rosacea, to the 40 milligram per day dose taught by Golub and
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`PERIOSTATfor the treatment of periodontal disease, because (1) “the
`papules and pustulesofrosacea were knownto be inflammatory, and not
`bacterial;” (2) Golub taught that periodontal disease is an inflammatory
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`condition treatable with low dose doxycycline; (3) doxycycline was known
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`to have “at least some anti-inflammatory properties at almost any dose;”(4)
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`reduced dosages would provide benefits including lowercost, increased
`patient compliance, and reducedside effects; and (5) to minimizetherisk of
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`side effects, one of ordinary skill in the art would havereasonto start
`treatment with a low dose, “[i]f a low dose did not work, the dose could be
`increased until an effective dose was reached.” See Pet. 6-8, 32—38; Ex.
`1004 4 43, 53.
`|
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`Petitioner’s argument begins with the premise that “the papules and
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`pustules of rosacea were knownto be inflammatory, and not bacterial” such
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`that a person of ordinary skill in the art would have been motivatedto treat
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`the papules and pustules of rosacea with doses of doxycycline having anti-
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`‘inflammatory, but not antibiotic activity. See Pet. 6, 33, 50; Ex. 1004 { 43;
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`Prelim Resp. 13-14. In support, Petitioner points to Golub’s statement that
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`“tetracyclines now appearto possess anti-inflammatory properties when
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`administered to patients with certain skin diseases, diseases such as rosacea .
`.
`. which are not believed to have a microbial etiology” (Pet. 30; Ex. 1004
`137 (both citing Ex. 1048, 325)), and Torresani’s statement that“[t]he
`therapeutic activity of tetracyclines seemsto berelated to their anti-
`inflammatory efficacy” (Pet. 30-31; Ex. 1004 37 (both citing Ex. 1010,
`945)); see also Ex. 1034, 148 (suggesting that the mechanism of antibiotics
`in treating rosacea “may beanti-inflammatory ratherthan antibacterial”).
`Asset forth on pages 13-17 of Patent Owner’s Preliminary Response,
`however,the art of record indicates that the underlying causes of rosacea
`
`were unknownat as ofthe filing date of the *506 patent. See e.g., Ex. 1010,
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`945, 946 (stating that the “[T]he etiology and pathogenesis of rosacea are
`
`still unknown,”and suggesting a relationship between rosacea and
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`Helicobacter pylori infection); Ex. 1034, 144 (stating that “[t]he exact
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`etiology of rosacea is unknownandtheories abound,” including potential
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`roles for gastrointestinal disturbances, Helicobacter pylori infection, and
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`hypersenstitivity to D. folliculorum mites); Ex. 2008, 777 (stating that
`“[R]osacea is a common condition of unknownetiology,” and reporting that
`the eradication of Helicobacter pylori infection with antibiotics “leads to a
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`dramatic improvementin the symptoms of rosacea.”). Moreover, art cited
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`by Patent Ownershowsthat the etiology of rosacea was not “known”to be
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`“not bacterial’ even after the filing date of the ’506 patent. See Pet. 16-17
`
`(citing Ex. 2010, 479, 480; Ex. 2011, 24; Ex. 2012, 87). Accordingly, based
`
`on the evidence of record, Petitioner has not demonstrated that one of
`ordinary skill in the art understoodthat the underlying cause ofthe papules
`and pustules of rosacea was “not bacterial.”
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`Implicit in Petitioner’s argumentis that one of ordinary skill in the art
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`would have understoodthat the inflammation associated with the papules
`and pustules of rosacea shared a commonpathway with that seen in
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`periodontal disease. See e.g., Pet. 10 (citing Ex. 1004 Ff 39, 57; Ex, 1048);
`
`id. at 33, 49. Petitioner’s express conclusionthat “[t]he inflammatory
`
`pathways of periodontal disease were knownto exist in papules and pustules
`
`of rosacea,” however, is unpersuasive in light of the evidence provided in
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`the Petition.
`
`Asnoted by Patent Owner, Golub’s limited disclosure regarding
`rosacea provides nodetails regarding the mechanisms of inflammation
`associated with this disease. See Prelim. Resp. 18-19. Petitioner’s expert,
`however, points to passages in WO 00/18230 (Ex. 1013) for support. See
`Ex. 1004 57 (citing Ex. 1013:1:10-16, 5:15-20). WO 00/18230 suggests
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`that (1) proteolytic damage to connective tissues and basement membranes
`
`is an inflammatory responsethat contributes to pathological changesin
`diverse organsandtissues; (2) extracellular protein degradation/destruction
`
`plays a prominentrole a wide range of conditions and diseases, including
`
`“skin diseases such as acne. .
`
`. [and] dental diseases such as periodontal
`
`diseases,” and (3) “non-antimicrobial tetracyclines [have been used ]to treat
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`tissue destructive conditions, chronic inflammation, bone destruction, cancer
`
`and other conditions associated with excess activity of metalloproteinases.”
`
`Ex. 1013:1:10-16, 4:11-19; 5:15—20. The referenced passages do not
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`persuadeusthat one ofordinary skill in the artwould have recognized that
`the inflammatory response associated with the papules and pustules of
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`rosacea involved an excessactivity of metalloproteinases responsive to non-
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`antimicrobial tetracyclines or, more broadly, that the inflammatory response
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`associated with the papules and pustules of rosacea shared a common
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`pathway with that associated with periodontal disease.
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`Patent Ownerarguesthat Petitioner has failed to establish a
`motivation to combinethecited prior art with a reasonable expectation of
`
`success because Sneddonand Torresaniare directed to the treatment of
`rosacea ofthe skin, whereas Golub and PERIOSTAT are directed to the
`treatment periodontitis, a disease of the gums. Prelim. Resp. 25-26, 35-36.
`
`Weagree. Sneddon and Torresanirelate to a different medical specialty,
`describe treating a different ailment, and focus on different organ ofthe
`body as compared to Golub and PERIOSTAT. Seeid. Petitioner fails to
`adequately address these differences, and thus, fails to persuade usthat one -
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`of ordinary skill in the art would have, with a reasonable expectation of
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`success, expected that the 40 milligram daily doses of doxycycline used to
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`treat periodontitis would have been efficacious in the treatment of rosacea.
`As Patent Owner points out, a similar argument was considered
`during the prosecution of the application that ultimately issued as the °506
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`patent. Prelim. Resp. 29-30; see Pet. 16-21. In particular, Applicant argued
`that there was no reason to combinethe Perricone!” reference, teaching the
`treatment of facial acne with, inter alia, an antibiotic dose of tetracycline,
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`with the Plugfelder reference,!> disclosing the use of sub-antimicrobial doses
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`for the treatment of an eye disease (Meibomian gland disease or “MGD)
`associated with rosacea. Ex. 1070, 7-12; Ex. 1072.'4 In an Examiner’s
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`2 Perriconeet al., U.S. 6,365,623 B1, issued April 2, 2002.
`13 Pflugfelderet al., U.S. 6,455,583 B1, issued Sept. 24, 2002.
`14 U.S. Serial No. 13/277,789, Declaration under 37 C.F.R. § 1.132, dated
`Feb. 22, 2013.
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`interview, Applicant argued that there is no reason to combine the two
`references because “treating Meibomian gland disease and rosacea are not
`related.” Ex. 1071, 16. Invited to respond in writing, Applicant elaborated
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`that, “success in treating eye disease with a sub-antibiotic treatment is not
`relevant to treating a skin disease with an antibiotic treatment. Medical
`science is much too unpredictable to make such a connection.” Jd. at 8; see
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`id. at 16; see also Ex. 1070, 8 (““There would be no reasonfor a skilled
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`artisan to believe that a treatment that is effective to treat an ocular disorder
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`would treat a skin condition. Medicine is too unpredictable for such a
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`conjecture.”’).
`Similar reasoning applies in the present case. Even were we
`persuadedthat one ofordinary skill in the art would have recognized that the
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`inflammation associated with the papules and pustules of rosacea shared a
`
`common pathway with that associated with periodontal disease, Petitioner
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`does not persuadeus that a skilled artisan would have reasonably expected
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`that the sub-microbial dose of doxycycline taught by Golub and
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`PERIOSTATfor the treatment of a gum disease would be effective in
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`treating a disease of the skin.
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`Underscoring the unpredictability and lack of reasonable expectation
`
`of success of applying Golub and PERIOSTATto a different disease and
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`tissue type, we note that Golub’s study numberone,a “more complex
`clinical protocol” involving 60 milligrams of doxycycline per day, showed
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`suppressed collagen activity but did not significantly reducing inflammation.
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`See Ex. 1048, 328. This suggests that the benefits of doxycycline in Golub’s
`work may depend on the condition ofthe gum tissuetreated,i.e., the disease
`state, and thus underscores the unpredictability of applying Golub’s
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`teachingsto a different disease in a different tissue type.
`The disparate results of Golub’s two studies treating the same tissue
`type also undercut Petitioner’s reliance on the assertion that doxycycline was
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`knownto have “at least some anti-inflammatory properties at almost any
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`dose.” Pet. 35 (citing Ex. 1004
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`42). This statement is supported by
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`referenceto in vitrostudies using isolated immunecells and,as Petitioner’s
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`expert makesclear, “does not mean that one would expectvirtually any dose
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`to be clinically effective.” Ex. 1004 § 42 (citing Ex. 1031,'5 312; Ex. 1032,
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