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
`ROBERT A. POLLOCK, Administrative Patent Judges.
`
`POLLOCK, Administrative Patent Judge.
`
`
`
`DECISION
`Denying Institution 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
`ROBERT A. POLLOCK, Administrative Patent Judges.
`
`POLLOCK, Administrative Patent Judge.
`
`
`
`DECISION
`Denying Institution 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
`inter partes review of claims 1, 7, 8, 14, 15, and 20 of US 8,603,506 B2 (Ex.
`1001; “the ’506 patent”). Galderma Laboratories Inc. (“Patent Owner”)1
`filed a Patent Owner Preliminary Response. Paper 9 (“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.
`
`a.
`Related Proceedings
`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; Paper 6, 2.
`In addition to the case before us, Petitioner has requested inter partes
`review of claims 1, 7, 8, 14, 15, and 20 of US 8,603,506 B2 on other
`grounds in Case Nos. IPR2015-01778 and IPR2015-01782.
`
`
`1 Petitioner further indicates that the Complaint in Civil Action No. 15-670
`states that Nestlé Skin Health S.A. is now the owner of the ‘506 patent. Pet.
`2 n.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.
`
`
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`
`b.
`The ’506 Patent
`The ’506 patent is directed to the treatment of “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”),2 a skin disorder “characterized by inflammatory
`lesions (erythema) and permanent dilation of blood vessels (telangectasia).”
`Id. at 4:31–43. The specification further states the “[t]he present invention is
`particularly effective in treating comedones.” Id. at 4:23–43.3
`By way of background, the ’506 patent discloses that the efficacy of
`systemically-administered tetracycline compounds in 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 “release microbial mediators of inflammation into the dermis or trigger
`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.” Id. at 2:21–32, 3:14–25.
`
`
`
`2 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 Owner does not contest, that comedones are
`not a feature of rosacea. Pet. 9, 25; see Prelim. Resp. 23–24; Ex. 1004 ¶ 13.
`
`3
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`The ’506 patent teaches that although tetracyclines are administered in
`conventional antibiotic therapy, antibiotic doses of these compounds can
`result in undesirable side effects such as the reduction or elimination of
`healthy microbial flora and the production of antibiotic resistant
`microorganisms. Id. at 3:7–17, 3:31–36. To address the need for effective
`treatments that minimize these side effects, the ’506 patent discloses that “all
`known types of acne” may be treated by administering a tetracycline
`compound in an amount having “substantially no antibiotic activity (i.e.
`substantially no antimicrobial activity)” and, thus, “does not significantly
`prevent the growth of . . . bacteria.” Id. 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 compounds having known antibiotic 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 amount that 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 compounds include 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-
`
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`antibiotic (i.e., sub-antibiotic) of doxycycline based on steady-state
`pharmacokinetics. Id. at 5:49–52. In terms of serum concentration,
`doxycycline may also be administered in an amount that results in a serum
`concentration between about 0.1 and 0.8 μg/ml. Id. at 6:29–32.
`Example 38 of the ’506 patent discloses that in a six-month, placebo-
`controlled trial for the treatment of acne4 using 20 mg doxycycline hyclate,
`twice daily, doxycycline-treated patients showed a statistically significant
`reduction in both comedones and inflammatory lesions (defined as “papules
`and pustules, less than or equal to 5 nodules”) as compared to placebo. Id. 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.” Id. at 20:33–37; see id. at 5:64–6:4.
`
`c.
`Representative Claim
`Claim 1 of the ’506 patent recites:
`1. A method for treating papules and pustules of rosacea in a
`human in need thereof, the method comprising
`administering orally to said human doxycycline, or a
`pharmaceutically acceptable salt thereof, in an
`amount that
`(i) is effective to treat the papules and pustules of
`rosacea;
`(ii) is 10–80% of a 50 mg dose of doxycycline per day;
`and
`
`
`4 Petitioner asserts that Example 38 is directed to treating common acne
`(acne vulgaris), presumably based on inclusion 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
`Owner does not dispute this characterization. See Prelim. Resp. 21.
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`(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
`μg/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 mg per day” (claim 15).
`
`d.
`Asserted Grounds of Unpatentability
`Petitioner asserts the following grounds of unpatentability.
`Claims challenged
`
`Basis
`
`Reference
`Sneddon5
`Golub6
`Torresani7
`PERIOSTAT8
`Golub
`Torresani
`Jansen9
`Golub
`Torresani
`Jansen
`PERIOSTAT
`
`1, 7, 8, 14, 15, and 20
`
`1, 8, 15
`
`7, 14, and 20
`
`§ 103
`
`§ 103
`
`§ 103
`
`
`5 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
`crevicular fluid collagenase activity in humans, 25 J. PERIODONT. RES. 321
`(1990). Ex. 1048.
`7 Torresani et al., Clarithromycin versus doxycycline in the treatment of
`rosacea, 36 INT’L. J. DERMATOL. 938 (1997). Ex. 1010.
`8 PERIOSTATTM, PHYSICIANS’ DESK REFERENCE (54th ed. 2000). Ex. 1042.
`9 Jansen and Plewig, Rosacea: classification and treatment, 90 J. R. SOC.
`MED. 144 (1997). Ex. 1034.
`
`6
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`
`ANALYSIS
`As an initial matter, we note that Patent Owner asserts that the Board
`should exercise its discretion and deny institution of this Petition as
`duplicative of grounds raised 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 according to 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).
`Under that standard, and absent any special definitions, we assign
`claim terms their ordinary and customary meaning, as would be understood
`by one of ordinary skill in the art at the time of the invention,10 in the context
`of the entire patent disclosure. In 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
`chooses to be his own lexicographer and to give terms uncommon meanings,
`he must set out his uncommon definition in some manner within the patent
`disclosure’ so as to give one of ordinary skill in the art notice of the change.”
`
`
`10 Patent Owner provisionally adopts, as do we, Petitioner’s definition of a
`person of ordinary skill in the art as “a licensed and practicing dermatologist
`with as little as one year of treating patients in a hospital, clinical, and/or
`private setting.” Prelim. Resp. 25; Pet. 36 (both quoting Ex. 1004 ¶ 11).
`
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`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 which are 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 constructions for only the following terms.
`i. Rosacea
`The parties 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 not classify
`rosacea as a form of acne (Pet. 22; Ex. 1004 ¶¶ 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 symptoms of rosacea,
`however, neither party contends that uncommon meanings apply. Pet.
`30–31; Prelim. Resp. 6–8. We therefore construe rosacea as a form of acne
`having symptoms including papules, pustules, erythema, and telangiectasia,
`where the predominant lesions are papules and pustules. See Ex. 1001,
`4:23–43; Ex. 1004, ¶¶ 7, 19 (“‘The predominant lesions [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 ’506 patent does not define the terms “papules” and “pustules” as
`other than as “[i]nflammatory 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 but points to its expert’s statement that “‘[a] papule
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`is a small, solid, elevated lesion . . . smaller than 1 cm in diameter, and the
`major portion of a papule projects above the plane of the surrounding skin,’”
`whereas, “‘[a] pustule is a circumscribed, raised lesion that contains a
`purulent exudate. . . . Pus, composed of leukocytes, with or without cellular
`debris, may contain bacteria or may be sterile . . . .’” Pet. 23; Ex 1004 ¶ 19
`(both quoting Ex. 1056, 27, 31). Petitioner contends that “[t]hese definitions
`align well with those provided by applicant during prosecution.” Pet. 23
`(citing Ex. 1070, 6).11 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 of the skin.
`Patent Owner contends that the terms should be accorded their 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 issuance of the ’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 blemishes of the skin, where “papules” are solid,
`rounded bumps rising 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.
`
`9
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`b.
`Principles of Law
`A claim 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 obvious at the time the invention was
`made to a person having ordinary 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 prior art; (2) any
`differences between the claimed subject matter and the prior art; (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 obviousness is established when the prior art
`itself would appear to have suggested the claimed subject matter to a person
`of ordinary skill in the art. In 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);
`In re GPAC Inc., 57 F.3d 1573, 1579 (Fed. Cir. 1995); In re Oelrich,
`579 F.2d 86, 91 (CCPA 1978).
`We analyze the asserted grounds of unpatentability in accordance with
`the above-stated principles.
`
`c.
`The Asserted References
`We begin our discussion with a brief summary of the references
`asserted.
`
`i. Sneddon
`Sneddon, published in 1966, demonstrates the efficacy of tetracycline
`(250mg, twice daily) in the treatment of rosacea. Ex. 1006. Sneddon states
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`that there are “diametrically opposed views” on the underlying cause of
`rosacea including emotional distress, gastric or intestinal disturbances, and
`demodex skin mites. Id. at 649. Consistent with this lack of understanding
`regarding the etiology of rosacea, Sneddon states that “[t]he mechanism of
`[tetracycline’s] beneficial action is as yet unknown, but the observation that
`it controls not only postulation but erythema suggests that it is not entirely
`an antibacterial or antidemodectic effect. Has it some action on intestinal
`absorption?” Id. at 652.
`ii. 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 ¶ 31. Although finding the
`clarithromycin regimen potentially more promising, Torresani showed that
`the doxycycline treatment improved the symptoms of rosacea including the
`number of papules and pustules. Ex. 1010, 944, 945, Figs. 3 and 4; Ex. 1004
`¶ 31.
`Torresani, published in 1997, states that “[t]he etiology and
`pathogenesis of rosacea are still unknown,” but that “[t]he therapeutic
`efficacy of tetracyclines seems to 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. Id. at 946.
`
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`iii. Golub
`Golub, published in 1990, teaches that “[t]etracyclines are often
`advocated as useful adjuncts in periodontal therapy based on their
`effectiveness against periodontopathogens; an additional advantage is their
`unique ability, among antibiotics, to be highly concentrated within the fluid
`of the periodontal pocket.” Ex. 1048, 325. Golub further teaches that
`“[c]ollagen breakdown is 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
`independent of the antimicrobial efficacy of these drugs.” Id. at 321–22.
`Golub states that,
`routinely prescribed,
`[i]n
`several
`studies on humans,
`antimicrobially-effective doses of tetracyclines . . . were found
`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 humans in
`a
`low-dose
`regimen[,] which would effectively
`inhibit
`collagenase activity in the gingival tissue as well as in the
`crevicular fluid.
`Id. at 322.
`Golub presents 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,
`showed a statistically significant reduction in gingival collagenase activity,
`but not gingival pocket depth, or the severity of gingival inflammation. Id.
`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
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`by the low-dose doxycycline therapy, even though collagenase activity in
`these tissues was suppressed.”); see also id. 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, showed significant reductions in the collagenase activity of their
`gingival crevicular fluids, and in the severity of gingival inflammation. Id.
`at 323, 324-325, Table I, Abstract.
`Golub also 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 microbial etiology.
`Id. at 325 (citations omitted). Golub posits that the mechanisms underlying
`the non-antimicrobial properties of tetracyclines may include the inhibition
`of prostaglandin production, superoxide radical scavenging, and the
`inhibition of mammalian collagenase and other metalloproteinase activities.
`Id.
`
`iv. PERIOSTAT
`Published in 2000, PERIOSTAT is 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.” Id. 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
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`with adult periodontitis.” Id. at 945.
`v. Jansen
`Jansen reviews the 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. Jansen states that “[t]he exact etiology of rosacea is
`unknown and theories abound.” Id. 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. Id.
`Jansen teaches that although bacteriological studies of inflammatory
`pustules from Stage II rosacea “reveal nothing of interest” (id. at 145),
`“[r]osacea generally responds well to oral antibiotics” (id. at 148). Noting
`that “[t]etracyclines and erythromycin reduce leucocyte migration and
`phagocytosis,” Jansen suggests that “[t]he mechanism of antibiotics may be
`anti-inflammatory rather than antibacterial.” Id. With respect to specific
`treatments, Jansen states that doxycycline “[is] usually effective in
`controlling papulopustula rosacea.” Id. “One should start with large doses,”
`for example, 50 milligrams of doxycycline twice daily. “As soon as
`papulopustules are fully controlled (usually after two to three weeks) doses
`of . . . 50 mg . . . doxycycline, per day are generally sufficient.” Id.
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`d.
`Obviousness over Sneddon, Golub, Torresani, and PERIOSTAT
`Petitioner asserts that claims 1, 7, 8, 14, 15, and 20 would have been
`obvious over the combination of Sneddon, Golub, Torresani, and
`PERIOSTAT. Pet. 24–45. To briefly summarize Petitioner’s argument, it
`would have been obvious for one of ordinary skill in the art to reduce the
`dose of tetracyclines taught by Sneddon–—and, in particular, the dose of
`doxycycline taught by Torresani–—for the treatment of the papules and
`pustule of rosacea, to the 40 milligram per day dose taught by Golub and
`PERIOSTAT for the treatment of periodontal disease, because (1) “the
`papules and pustules of rosacea were known to be inflammatory, and not
`bacterial;” (2) Golub taught that periodontal disease is an inflammatory
`condition treatable with low dose doxycycline; (3) doxycycline was known
`to have “at least some anti-inflammatory properties at almost any dose;” (4)
`reduced dosages would provide benefits including lower cost, increased
`patient compliance, and reduced side effects; and (5) to minimize the risk of
`side effects, one of ordinary skill in the art would have reason to 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 ¶ 43, 53.
`Petitioner’s argument begins with the premise that “the papules and
`pustules of rosacea were known to be inflammatory, and not bacterial” such
`that a person of ordinary skill in the art would have been motivated to treat
`the papules and pustules of rosacea with doses of doxycycline having anti-
`inflammatory, but not antibiotic activity. See Pet. 6, 33, 50; Ex. 1004 ¶ 43;
`Prelim Resp. 13–14. In support, Petitioner points to Golub’s statement that
`“tetracyclines now appear to 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
`¶37 (both citing Ex. 1048, 325)), and Torresani’s statement that “[t]he
`therapeutic activity of tetracyclines seems to be related 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 be anti-inflammatory rather than antibacterial”).
`As set forth on pages 13–17 of Patent Owner’s Preliminary Response,
`however, the art of record indicates that the underlying causes of rosacea
`were unknown at as of the filing date of the ’506 patent. See e.g., Ex. 1010,
`945, 946 (stating that the “[T]he etiology and pathogenesis of rosacea are
`still unknown,” and suggesting a relationship between rosacea and
`Helicobacter pylori infection); Ex. 1034, 144 (stating that “[t]he exact
`etiology of rosacea is unknown and theories abound,” including potential
`roles for gastrointestinal disturbances, Helicobacter pylori infection, and
`hypersenstitivity to D. folliculorum mites); Ex. 2008, 777 (stating that
`“[R]osacea is a common condition of unknown etiology,” and reporting that
`the eradication of Helicobacter pylori infection with antibiotics “leads to a
`dramatic improvement in the symptoms of rosacea.”). Moreover, art cited
`by Patent Owner shows that the etiology of rosacea was not “known” to be
`“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 understood that the underlying cause of the papules
`and pustules of rosacea was “not bacterial.”
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`Implicit in Petitioner’s argument is that one of ordinary skill in the art
`would have understood that the inflammation associated with the papules
`and pustules of rosacea shared a common pathway with that seen in
`periodontal disease. See e.g., Pet. 10 (citing Ex. 1004 ¶¶ 39, 57; Ex, 1048);
`id. at 33, 49. Petitioner’s express conclusion that “[t]he inflammatory
`pathways of periodontal disease were known to exist in papules and pustules
`of rosacea,” however, is unpersuasive in light of the evidence provided in
`the Petition.
`As noted by Patent Owner, Golub’s limited disclosure regarding
`rosacea provides no details 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
`that (1) proteolytic damage to connective tissues and basement membranes
`is an inflammatory response that contributes to pathological changes in
`diverse organs and tissues; (2) extracellular protein degradation/destruction
`plays a prominent role 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
`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
`persuade us that one of ordinary skill in the art would have recognized that
`the inflammatory response associated with the papules and pustules of
`rosacea involved an excess activity of metalloproteinases responsive to non-
`antimicrobial tetracyclines or, more broadly, that the inflammatory response
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`associated with the papules and pustules of rosacea shared a common
`pathway with that associated with periodontal disease.
`Patent Owner argues that Petitioner has failed to establish a
`motivation to combine the cited prior art with a reasonable expectation of
`success because Sneddon and Torresani are directed to the treatment of
`rosacea of the skin, whereas Golub and PERIOSTAT are directed to the
`treatment periodontitis, a disease of the gums. Prelim. Resp. 25–26, 35–36.
`We agree. Sneddon and Torresani relate to a different medical specialty,
`describe treating a different ailment, and focus on different organ of the
`body as compared to Golub and PERIOSTAT. See id. Petitioner fails to
`adequately address these differences, and thus, fails to persuade us that one
`of ordinary skill in the art would have, with a reasonable expectation of
`success, expected that the 40 milligram daily doses of doxycycline used to
`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
`patent. Prelim. Resp. 29–30; see Pet. 16–21. In particular, Applicant argued
`that there was no reason to combine the Perricone12 reference, teaching the
`treatment of facial acne with, inter alia, an antibiotic dose of tetracycline,
`with the Plugfelder reference,13 disclosing the use of sub-antimicrobial doses
`for the treatment of an eye disease (Meibomian gland disease or “MGD)
`associated with rosacea. Ex. 1070, 7–12; Ex. 1072.14 In an Examiner’s
`
`
`12 Perricone et al., U.S. 6,365,623 B1, issued April 2, 2002.
`13 Pflugfelder et 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
`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.” Id. at 8; see
`id. at 16; see also Ex. 1070, 8 (“There would be no reason for a skilled
`artisan to believe that a treatment that is effective to treat an ocular disorder
`would treat a skin condition. Medicine is too unpredictable for such a
`conjecture.”).
`Similar reasoning applies in the present case. Even were we
`persuaded that one of ordinary skill in the art would have recognized that the
`inflammation associated with the papules and pustules of rosacea shared a
`common pathway with that associated with periodontal disease, Petitioner
`does not persuade us that a skilled artisan would have reasonably expected
`that the sub-microbial dose of doxycycline taught by Golub and
`PERIOSTAT for the treatment of a gum disease would be effective in
`treating a disease of the skin.
`Underscoring the unpredictabili
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