us to. ov
`Trials
`Tel: 571-272-7822
`
`Paper 10
`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 IPR2015-01782
`
`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
`
`I‘I
`
`
`
`
`Trials
`Tel: 571-272-7822
`
`Paper 10
`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 IPR2015-01782
`
`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
`
`I‘I
`
`
`
`
`
`IPR2015-01782
`
`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”)l
`
`filed a Patent Owner Preliminary Response. Paper 8 (“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 ofclaims 1, 7, 8, 14, 15, and 20 ofUS 8,603,506 B2 on other
`
`grounds in Case Nos. IPR2015-01777 and IPR2015-01778.
`
`‘ Petitioner further indicates that the Complaint in Civil Action No. 15-670
`states that Nestle’ Skin Health SA. 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.
`
`
`
`Case IPR2015-01782
`
`Patent 8,603,506 B2
`
`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 4223—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—3 1; 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 fl 13.
`
`3
`
`
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`Case IPR2015-01782
`
`Patent 8,603,506 B2
`
`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, 5:3 5—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 serum
`
`concentration.” Id. at 5:36—42; 627—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. Id.
`
`at 5:43—45; 5:59—63. The specification teaches that this 40 milligram per
`
`day dose provides the maximum non-antibiotic'(i.e., sub-antibiotic) dose of
`
`
`
`Case IPR2015-01782
`
`Patent 8,603,506 B2
`
`doxycycline based on steady-state pharmacokinetics. Id. at 5:49—52. In
`
`terms of serum concentration, doxycycline may also be administered in an
`
`amount which results in a serum concentration between about 0.1 and 0.8
`
`[lg/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-monthdoxycycline treatment “resulted in no
`
`reduction of skin microflora .
`
`.
`
`. nor an increase in resistance counts when -
`
`compared with placebo.” Id. at 20:33—37; see id. at 5:64—6:4.
`
`0. 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
`
`(iii) results in no reduction of skin microflora during a six-month
`treatment, without administering a bisphosphonate compound.
`
`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
`ofrosacea. See Pet. 9, 23, 25; Ex. 1001, 1:20, 19:54; Ex. 1004 1] 13. Patent
`Owner does not dispute this characterization. See Prelim. Resp. 21.
`
`5
`
`
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`Case IPR2015-01782
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`Patent 8,603,506 B2
`
`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 mg per day” (claim 15).
`
`d. Asserted Grounds of Unpatentability
`
`Petitioner asserts the following grounds of unpatentability.
`
`Bikowski5
`
`PERIOSTAT6
`1, 7, 8, 14, 15, and 20
`Golub7
`
`
`
`1, 7, 8, 14, 15, and 20
`
`-
`
`§ 103
`
`PERIOSTAT
`
`Bikowski
`
`
`
`a. Claim Construction
`
`ANALYSIS
`
`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 CPR. § 42.100(b); In
`
`re Cuozzo Speed Techs, LLC, 778 F.3d 1271, 1278—81 (Fed. Cir. 2015),
`
`cert. granted sub nom., Cuozzo Speed Techs, LLC v. Lee, No. 15—446, 2016
`
`WL 205946 (US. Jan. 15, 2016). Under that standard, and absent any
`
`5 Bikowski, Treatment ofRosacea with Doxycycline Monohydrate, 66(2)
`CUTIS 149 (2000). Ex. 1011.
`6 PERIOSTATTM, PHYSICIANS’ DESK REFERENCE (54th ed. 2000). Ex. 1042.
`7 Golub et al., Low—dose doxycycline therapy: Effect on gingival and
`crevicularfluid collagenase activity in humans, 25 J. PERIODONT. RES. 321
`(1990). Ex. 1048.
`
`
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`Case IPR2015-01782
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`Patent 8,603,506 B2
`
`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,8 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.”
`'
`
`In re Paulsen, 30 F.3d 1475, 1480 (Fed. Cir. 1994) (citation omitted). “In
`
`such cases, the inventor’s lexicography governs.” Phillips v. A WH 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. 12, 22; Prelim. Resp. 9. Although
`
`Petitioner’s expert contends that “a dermatologist of ordinary skill in the art
`
`would not lump things like acne vulgaris and rosacea together” (Ex. 1004 1111
`
`8 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. 7; Pet. 25 (both quoting Ex. 1004 1] 11).
`
`7
`
`
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`Case IPR2015-01782
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`Patent 8,603,506 B2
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`13) we, nevertheless 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. 8—10. 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, 1111 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
`“C
`
`meaning for these terms but points to its expert’s statement tha
`
`[a] papule I
`
`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,’”
`“6
`
`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 11 19
`
`(both quoting Ex. 1056, 27, 31) (italics removed). Petitioner contends that
`
`“[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 of the skin.
`1 Patent Owner contends that the terms should be accorded their plain
`
`and ordinary meanings; objects to the definitions provided by Petitioner’s
`
`
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`Case IPR2015-01782
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`Patent 8,603,506 B2
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`expert as unnecessarily limiting; and points, instead, to the definitions set
`
`forth in the prosecution leading to the issuance of the ’506 patent. Prelim.
`Resp. 10—11 (citing Ex. 1070, 6).9
`I
`
`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 one
`
`centimeter in diameter, and “pustules” are small, inflamed, pus-filled,
`
`blister-like lesions of the dermis or epidermis.
`
`iii.
`
`“Administering. .
`
`. [a] dose ofdoxycycline per day”
`
`The parties do not expressly address the meaning “[a]dministering .
`[a] dose of doxycycline per day.” The plain language of the independent
`
`.
`
`.
`
`claims, however, requires that the administered dose “results in no reduction
`
`of skin microflora during a six-month treatment.” Consistent with the claim
`
`language, Example 38 of the Specification discloses the administration of a
`
`daily dose of doxycycline (20 mg, twice daily) for six months. 'Ex. 1001,
`
`19:37—20:37. Taken in context, we construe “[a]dministering .
`
`.
`
`. [a] dose of
`
`doxycycline per day” as requiring administering a dose of doxycycline each
`
`day.
`
`b. Principles ofLaw
`
`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
`
`9 US Serial No. 13/277,789, Response to Office Action, dated May 14,
`2012.
`
`
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`Case IPR2015-01782
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`Patent 8,603,506 B2
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`made to a person having ordinary skill in the art to which said subject matter
`
`pertains. KSR Int ’1 Co. v. Teleflex Inc., 550 US. 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 C0., 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 Okajz'ma‘v. Bourdeau, 261 F.3d 1350, 1355 (Fed. Cir. 2001);
`
`In re GPAC Inc., 57 F.3d 1573, 1579 (Fed. Cir. 1995); In re OeIrich,
`
`579 F.2d 86, 91 (CCPA 1978).
`
`We analyze the asserted grounds of unpatentability in accordance with
`
`the above-stated principles.
`
`0. The Asserted References
`
`We begin our discussion with a brief summary of the references
`
`asserted under grounds 1 and 2.
`
`i. Bikowski
`
`Bikowski, published in 2000,10 states that “[a]lthough the exact
`
`etiology is unknown, rosacea is thought by most experts to be an
`
`1° The ’506 patent issued from a chain of continuation and divisional
`applications first filed on April 5, 2002,-and further claims the benefit of
`provisional applications including No. 60/325,489, filed April 5, 2001. Ex.
`1001, 1:5—16. Although Patent Owner reserves the right to demonstrate
`
`10
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`Case IPR2015-01782
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`Patent 8,603,506 B2
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`inflammatory process incited by vascular instability with subsequent leakage
`
`of fluid and inflammatory mediators.” Ex. 1011, 149 (emphasis omitted).
`
`Bikowski teaches that oral antibiotics are a well-established treatment of
`
`rosacea, referencing Sneddon [Ex. 1006] for the use of 250 milligram doses
`
`of tetracycline, twice daily (id. at 1011, 149, 151), and noting that second
`
`generation tetracyclines such as doxycycline “have increased bioavailability,
`
`improved absorption when taken with food, and broader antibacterial
`
`activity” (id. at 1.51).
`
`Bikowski teaches that “[t]he clinician’s goal is to achieve rapid
`
`remission with the oral agent and to maintain remission with [a] topical
`
`medication if at all possible. .
`
`.
`
`. intermittent low-dose systemic antibiotics in
`
`addition to daily topical treatment may be necessary to maintain complete
`
`remission in the majority of patients.” Id.
`
`Bikowski presents case studies of two rosacea patients treated with
`
`oral doxycycline monohydrate, but not topical medications. See id. at 150.
`
`Patient 1 was treated with 100 milligrams of doxycycline per day for six
`
`months. Id. Patient 2 also elected “systemic antibiotic therapy” and was
`
`treated for two months with 50 milligrams per day, at which time “she was
`
`essentially clear” and the oral doxycycline “was decreased to 50 mg every
`
`other day for long-term maintenance therapy.” Id.
`
`ii. Golub
`
`Golub, published in 1990, teaches that “[t]etracyclines are often
`
`advocated as useful adjuncts in periodontal therapy based on their
`
`entitlement to benefit of this earlier priority date and an invention date prior
`to the publication of Bikowski (Prelim. Resp. 38), we need not address that
`issue at this time.
`
`11
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`Patent 8,603,506 B2
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`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 (internal citations omitted).
`
`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,
`
`[i]n several studies on humans, routinely prescribed,
`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, doxycycline,
`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.
`’
`
`1d. at 322 (internal citations omitted);
`
`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,
`
`showeda 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
`
`by the low-dose doxycycline therapy, even though collagenase activity in
`
`these tissues was suppressed”); see also id. at Fig. 4 (equating gingival
`
`12
`
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`Patent 8,603,506 B2
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`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 1, 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.
`
`iii. 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. “After oral administration .
`
`.
`
`.
`
`. Doxycycline is
`
`eliminated with a half-life of approximately 18 hours by renal and fecal
`
`excretion of unchanged drug.” Id. at 945. The reference further states that
`
`“[t]he dosage of doxycycline achieved with this product during
`
`administration is well below the concentration required to inhibit
`
`13
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`Patent 8,603,506 B2
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`microorganisms commonly associated with adult periodontitis.” Id.
`
`(1. Obviousness Grounds
`
`Petitioner asserts that claims 1, 7, 8, 14, 15, and 20 would have been
`
`obvious over the combination of Bikowski, Golub, and PERIOSTAT. Pet.
`
`24—41. To summarize, Petitioner argues that it would have been obvious to
`
`reduce the daily dose of doxycycline taught by Bikowski for the treatment of
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`the papules and pustules of rosacea from 50 milligrams, to the 40 milligram
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`daily dose taught by Golub and PERIOSTAT for the treatment of
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`periodontal disease because (1) rosacea and periodontitis were both non-
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`bacterial, inflammatory conditions treatable with doxycycline, and (2)
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`“[a]nti-inflammatory doses of doxycycline were reasonably expected to be
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`lower than those needed for traditional antibiotic treatment.” See e.g., Pet. 5,
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`30, 32. Thus,
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`knowing that 50mg/day was effective, and that an
`antibiotic dose of doxycycline, with all of its attendant side
`effects (Exh.1050 col.3 11.58—62; Exh.1051, at 943 (see
`“Warnings” and “Adverse Reactions”; see also Exh.1004 1H]
`48), Was unnecessary, a dermatologist of ordinary skill in the
`art would have found it obvious to at least try commercially
`available slightly lower doses of doxycycline such as
`PERIOSTAT, and would have had more than a reasonable
`expectation of achieving anti-inflammatory efficiency when
`doing so. (Exhs.1042, at 944—46; 1053; see also Exh.1004 fl
`40, 42, 53, 54, 60)
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`Id. at 32.
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`Petitioner’s arguments that claims 1, 7, 8, 14, 15, and 20 would have
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`been obvious over the combination of Bikowski and PERIOSTAT are
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`similar to those based on the combination of Bikowski, Golub, and
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`PERIOSTAT. See Pet. 41—56. According to Petitioner:
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`14
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`Case IPR2015-01782
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`Patent 8,603,506 B2
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`Ground 2 starts with the premise that by April 5, 2001:
`(1) it was known to treat rosacea with doxycycline (Exh.1004
`11 31, 32; 101 1)); (2) it was known that the papules and pustules
`of rosacea were not bacterial, but more inflammatory
`conditions (Exh.1004 11 33, 1011); and (3) it was known that
`doxycycline was an effective anti-inflammatory agent at the
`claimed doses (Exhs.1004 11 42, 1042, 1048), that is, doses
`below those allegedly considered to have an antibiotic effect.
`
`Pet. 5—6.
`
`In particular, Petitioner argues that Bikowski evidences a trend toward
`lower doses of doxycycline to treat the papUles and pustules of rosacea (id.
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`at 45); expressly relies on Bikowski’s use of 50 milligram dosing every
`
`other day for long-term maintenance therapy (id. at 53); and suggests that
`
`dermatologists were using PERIOSTAT off label for the treatment of skin
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`diseases prior to the filing date of the ’506 patent (id. at 9, 48—49).
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`Both of Petitioner’s grounds are premised on the idea that rosacea is
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`not only an inflammatory condition, but also that it was known to be “not
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`bacterial,” such that one of ordinary skill in the art would have understood
`
`that “there was no medical necessity for using an antibiotic amount of an
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`antibiotic drug if less was needed to take advantage of its anti-inflammatory
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`properties.” See Pet. 7, 42, 46. Considering the evidence of record, we do
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`not find adequate support for that position. Indeed, Bikowski itself
`
`emphasizes that the exact etiology of rosacea is unknown, and thus, does not
`
`foreclose the possibility that the underlying cause of the inflammation is
`
`bacterial. Ex. 1011, 159. To the contrary, Bikowski, expressly describes the
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`50 milligram per day treatment of Patient 2 as “systemic antibiotic therapy”
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`and emphasizes the “broader antibacterial activity” of doxycyclines as
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`compared to tetracycline. Id. at 150, 151.
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`15
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`Case IPR2015-01782
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`Patent 8,603,506 B2
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`As set forth on pages 14—1 8 of Patent Owner’s Preliminary Response,
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`the record before us further illustrates that not only were the underlying
`
`causes of rosacea unknown as of the filing date of the ’506 patent, but that
`
`the suspected underlying causes included bacterial infection. 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”). In addition, art cited
`
`by Patent Owner shows that the etiology of rosacea was still 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).
`
`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.” Accordingly, we are
`
`not persuaded that one of ordinary skill in the art would have, with a
`
`reasonable expectation of success, found it obvious to replace Bikowski’s
`
`antimicrobial 50 milligram daily dose with the sub-microbial, 40 milligram
`
`dose taught by Golub and/or PERIOSTAT.
`
`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
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`16
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`Case IPR2015-01782
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`Patent 8,603,506 B2
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`periodontal disease. See e. g., Pet. 8, 31 (citing Ex. 1004 1111 38, 39; Ex. 1048,
`
`325—26). Petitioner’s support for this position ultimately rests on Golub’s
`
`limited disclosure relating to rosacea, which we do not find persuasive as it
`
`provides no details regarding the mechanisms of inflammation associated
`
`with this disease. See Ex. 1004 111] 38, 39; Ex. 1048, 325—26; Prelim. Resp.
`
`18—19.
`
`Patent Owner argues that Petitioner has failed to establish a
`
`motivation to combine the cited prior art with a reasonable expectation of
`
`success because Bikowski is 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. 24—26. We agree. Bikowski relates to
`
`a different medical specialty, describes 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 by the
`
`Examiner during prosecution of the application that ultimately issued as the
`’506 patent. Prelim. Resp. 28—29; see Pet. 14—19. In particular, Applicant
`
`argued that there was no reason to combine the Perricone11 reference,
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`teaching the treatment of facial acne with, inter alia, an antibiotic dose of
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`“ Perricone et al., US. 6,365,623 B1, issued April 2, 2002.
`
`17
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`Case IPR2015-01782
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`Patent 8,603,506 B2
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`tetracycline, with the Plugfelder reference,12 disclosing the use of sub-
`antimicrobial doses for the treatmentof an eye disease (Meibomian gland
`
`disease or “MGD”) associated with rosacea. Ex. 1070, 7—12; Ex. 1072.13 In
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`an Examiner’s interview, Applicant argued that there is no reason to
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`combine the two references because “treating Meibomian gland disease and
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`rosacea are not related.” Ex. 1071, 16. Invited to respond in writing,
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`Applicant elaborated that, “success in treating eye disease with a sub-
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`antibiotic treatment is not relevant to treating a skin disease with an
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`antibiotic treatment. Medical science is much too unpredictable to make
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`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
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`persuaded. that one of ordinary 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 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 unpredictability and lack of reasonable expectation
`
`of success of applying Golub and PERIOSTAT to a different disease and
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`12 Pflugfelder et al., U.S. 6,455,583 B1, issued Sept. 24, 2002.
`‘3 U.S. Serial No. 13/277,789, Declaration under 37 CPR. § 1.132 [of
`
`Vasant Manna], dated Feb. 22, 2013.
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`18
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`Case IPR2015-01782
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`Patent 8,603,506 B2
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`tissue type, we note that Golub’s study number one, a “more complex
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`clinical protocol” involving 60 milligrams of doxycycline per day, showed
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`suppressed collagen activity but did not significantly reduce inflammation.
`
`See Ex. 1048, 328. This suggests that the benefits of doxycycline in Golub’s
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`work may depend on the condition of the gum tissue treated, i.e., the disease
`
`state, and thus underscores the unpredictability of applying Golub’s
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`teachings to 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 claim that doxycycline was
`
`known to have “at least some anti-inflammatory activity at almost any
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`dose.” Pet. 47 (citing Ex. 1004 1] 42). This statement is supported by
`
`reference to in vitro studies using isolated immune cells and, as Petitioner’s
`
`expert makes clear, “does not mean that one would expect virtually any dose
`
`to be clinically effective.” See Ex. 1004 11 42 (citing Ex. 1031,14 312; Ex.
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`1032,15 178—79). Moreover, with respect to the treatment of rosacea, neither
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`Golub’s studies on periodontal disease, nor Petitioner’s expert’s reliance on
`
`in vitro data, persuades us that “[a]nti-inflammatory doses of doxycycline
`
`were reasonably expected to be lower than those needed for traditional
`
`antibiotic treatment,” as Petitioner contends. See Pet. 32.
`
`With respect to Petitioner’s argument that Bikowski marks a “trend”
`
`to using lower dose doxycycline in the treatment of the papules and pustules
`
`of rosacea, we note that Petitioner omits any citation to its own expert for
`
`14 Naess et al., In vivo and in vit
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