Dr. Reddy's Laboratories, Ltd.v.Galderma Laboratories, Inc.

Patent Trial and Appeal Board

Feb 16, 2016

13277789 (P.T.A.B. Feb. 16, 2016)

Trials@uspto.gov Paper 12
Tel: 571-272-7822 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.
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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
1, 7, 8, 14, 15, and 20 § 103
Sneddon5
Golub6
Torresani7
PERIOSTAT8
1, 8, 15 § 103
Golub
Torresani
Jansen9
7, 14, and 20 § 103
Golub
Torresani
Jansen
PERIOSTAT

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.
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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.
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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,
[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, 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 unpredictability and lack of reasonable expectation
of success of applying Golub and PERIOSTAT to a different disease and
tissue type, we note that Golub’s study number one, a “more complex
clinical protocol” involving 60 milligrams of doxycycline per day, showed
suppressed collagen activity but did not significantly reducing inflammation.
See Ex. 1048, 328. This suggests that the benefits of doxycycline in Golub’s
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 assertion that doxycycline was
known to have “at least some anti-inflammatory properties at almost any
dose.” Pet. 35 (citing Ex. 1004 ¶ 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.” Ex. 1004 ¶ 42 (citing Ex. 1031,15 312; Ex. 1032,16
178–79).
Finally, we note that fully seven years after the publication of Golub,
Torresani continued to teach the administration of high-dose tetracyclines
(doxycycline) for the treatment of rosacea. Cf. Ex. 1048 (published 1990)
and Ex. 1010 (published 1997); see also Ex. 1034, 148 (teaching that, as of
1997, “[o]ne should start with large doses,” e.g., 50 milligrams doxycycline
twice daily.); Prelim. Resp. 28 (arguing that, as of the priority date of the
’506 patent, “the prevalent teaching for using tetracyclines in treating
rosacea was to us a high, antibacterial dose, and to reduce the dose, if at all,
only after the papules and pustules were treated and under control”)
(citations omitted). That Golub was published at least a decade prior to the
filing date of the ‘506 patent17 underscores the impermissible hindsight

15 Naess et al., In vivo and in vitro effects of doxyclycline on leucocyte
membrane receptors, 62 CLIN. EXP. IMMUNOL. 310 (1985).
16 Akamatsu et al., Effect of Doxycycline on the Generation of Reactive
Oxygen Species, 72 ACTA DERM VENEREOL 178 (1992).
17 On its face, the ’506 patent issued from a chain of continuation and
divisional applications first filed on April 5, 2002. We take no position here
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reconstruction inherent in Petitioner’s argument. See Prelim. Resp. 40–41.
For the reasons discussed above, we conclude that Petitioner has not
established a reasonable likelihood that it would prevail in showing any of
the challenged claims would have been obvious over the combination of
Sneddon, Golub, Torresani, and PERIOSTAT.
e. Obviousness over Golub, Torresani, Jansen and PERIOSTAT
Petitioner also argues that the asserted claims would have been
obvious over Golub, Torresani, and Jansen (claims 1, 8, and 15), and further
with respect to PERIOSTAT (claims 7, 14, and 20). Pet. 45–56. Petitioner
relies on Jansen’s teaching that bacteriological studies of inflammatory
pustules from Stage II rosacea “reveal nothing of interest,” to support its
contention that the papules and pustules of rosacea “are inflammatory in
nature, not bacterial.” See Pet. 49, 50. As noted above, however, Jansen
teaches that as of 1997, “[t]he exact etiology of rosacea is unknown and
theories abound” (Ex. 1034, 144) and, while the mechanism of antibiotics
may be anti-inflammatory rather than antibacterial, “one should start with
large doses,” e.g., 50 milligrams of doxycycline twice daily (id. at 148). For
the reasons previously discussed in Section I, Petitioner does not persuade us
that one of ordinary skill in the art understood that the underlying etiology of
the papules and pustules of rosacea was “not bacterial.”
In addition to the reliance on Jansen, the instant grounds focus first on
Golub’s use of low dose doxycycline for the treatment of periodontal
disease, rather than the conventional high-dose treatment for rosacea taught

regarding whether the ’506 patent is entitled to benefit of the earlier filing
date(s) of provisional applications Nos. 60/325,489 and 60/281,916.
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22
by, for example, Torresani. See, e.g., Pet. 5–6. This reshuffling of
references fails to persuade us Petitioner has established a reasonable
likelihood it would prevail in showing any of the challenged claims would
have been obvious for the reasons set forth in Section I.
CONCLUSION
For the foregoing reasons, the information presented in the Petition
and accompanying evidence does not establish a reasonable likelihood that

Petitioner would prevail in showing the unpatentability of claims 1, 7, 8, 14,
15, and 20 of the ’506 patent.
ORDER
Accordingly, it is
ORDERED that Petitioner’s request for an inter partes review of
claims 1, 7, 8, 14, 15, and 20 of the ’506 patent is denied.

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PETITIONER:
William L. Mentlik
Michael H. Teschner
Brian R. Tomkins
Maegan A. Fuller
LITTENBERG, KRUMHOLZ & MENTLIK, LLP
WMentlik.ipr@ldlkm.com
MTeschner.ipr@ldlkm.com
BTomkins.ipr@ldlkm.com
MFuller.ipr@ldlkm.com

PATENT OWNER:

Stephen Maebius
Sujnit Talapatra
Michael Houston
FOLEY & LARDNER LLP
smaebius@foley.com
stalapatra@foley.com
mhouston@foley.com

Gerald Flattmann
PAUL HASTINGS LLP
geraldflattmann@paulhastings.com