anacor/hayman institution decision for '657 patent
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Anacor/Hayman institution decision for '657 patentTRANSCRIPT
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[email protected] Paper No. 24
571.272.7822 Filed: February 23, 2016
UNITED STATES PATENT AND TRADEMARK OFFICE
_____________
BEFORE THE PATENT TRIAL AND APPEAL BOARD
____________
COALITION FOR AFFORDABLE DRUGS X LLC,
Petitioner,
v.
ANACOR PHARMACEUTICALS, INC.,Patent Owner.
Case IPR2015-01780
Patent 7,767,657 B2
Before MICHAEL P. TIERNEY, GRACE KARAFFA OBERMANN, and
TINA E. HULSE, Administrative Patent Judges.
TIERNEY, Administrative Patent Judge.
DECISION
Institution of Inter Partes Review
37 C.F.R. § 42.108
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I. INTRODUCTION
Coalition for Affordable Drugs X, LLC (“Petitioner”), filed a Petition
requesting an inter partes review of claims 1–24 of U.S. Patent 7,767,657
(Ex. 1001, “the ’657 patent”). Paper 3 (“Pet.”). Patent Owner, Anacor
Pharmaceuticals Inc. and Sandoz Inc., (“Patent Owner”) filed a Preliminary
Response. Papers 7 and 17 (“Prelim. Resp.”).
We have jurisdiction under 35 U.S.C. § 314. The standard for
instituting an inter partes review is set forth in 35 U.S.C. § 314(a), which
provides:
THRESHOLD.—The Director may not authorize an inter partes
review to be instituted unless the Director determines that the
information presented in the petition filed under section 311 and
any response filed under section 313 shows that there is a
reasonable likelihood that the petitioner would prevail with
respect to at least 1 of the claims challenged in the petition.
Upon consideration of the Petition and Preliminary Response, we
conclude that the information presented in the Petition demonstrates that
there is a reasonable likelihood that Petitioner would prevail in challenging
claims 1–24 as unpatentable. Pursuant to 35 U.S.C. § 314, we hereby
authorize an inter partes review to be instituted as to claims 1–24 of the ’657
patent.
A. Related Proceeding
The claims of the ’657 patent have been challenged in related inter
partes review proceeding IPR2015-01785. Additionally, the ’657 patent
claims to be a continuation-in-part of U.S. Patent 7,582,62, which is
involved in inter partes review IPR2015-01776. Pet. 4.
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B.
The ’657 Patent
The ’657 patent is titled “Boron-Containing Small Molecules.” Ex.
1001. The ’657 specification describes compounds useful for treating fungal
infections, in particular, topical treatment of onychomycosis and/or
cutaneous fungal infections. Id . at abstract. The compounds are said to have
physiochemical properties that help facilitate the penetration of the nail
plate. Id .
The ’657 patent describes pharmaceutical formulations that include a
pharmaceutically acceptable excipient and a compound of said invention.
Id . at 139:35–37. According to the ’657 patent “Summary of the Invention,”
said invention provides a structure that is described as having the following
formula:
in which R1 and R2 are members independently selected from
H, substituted or unsubstituted alkyl, substituted or
unsubstituted heteroalkyl, substituted or unsubstituted
cycloalkyl, substituted or unsubstituted heterocycloalkyl,
substituted or unsubstituted aryl, and substituted or
unsubstituted heteroaryl. R1 and R2, together with the atoms to
which they are attached, can be optionally joined to form a 4- to7-membered ring. Z1 is a member selected from
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R3a and R4a are members independently selected from H,
cyano, substituted or unsubstituted alkyl, substituted or
unsubstituted heteroalkyl, substituted or unsubstituted
cycloalkyl, substituted or unsubstituted heterocycloalkyl,
substituted or unsubstituted aryl, and substituted or
unsubstituted heteroaryl. R5 is a member selected from halogen
and OR8. R8 is a member selected from H, substituted or
unsubstituted alkyl, substituted or unsubstituted heteroalkyl,
substituted or unsubstituted cycloalkyl, substituted or
unsubstituted heterocycloalkyl, substituted or unsubstituted
aryl, and substituted or unsubstituted heteroaryl. A is a member
selected from CR9a and N. D is a member selected from CR10a
and N. E is a member selected from CR11a and N. G is a
member selected from CR12a and N. R9a, R10a, R11a and
R12a are members independently selected from H, OR*, NR*R**, SR*, —S(O)R*, —S(O)2R*, —S(O)2NR*R**, nitro,
halogen, cyano, substituted or unsubstituted alkyl, substituted
or unsubstituted heteroalkyl, substituted or unsubstituted
cycloalkyl, substituted or unsubstituted heterocycloalkyl,
substituted or unsubstituted aryl, and substituted or
unsubstituted heteroaryl. Each R* and R** are members
independently selected from H, substituted or unsubstituted
alkyl, substituted or unsubstituted heteroalkyl, substituted or
unsubstituted cycloalkyl, substituted or unsubstituted
heterocycloalkyl, substituted or unsubstituted aryl, and
substituted or unsubstituted heteroaryl. R9a and R10a, along
with the atoms to which they are attached, are optionally joined
to form a ring. R10a and R11a, along with the atoms to which
they are attached, are optionally joined to form a ring. R11a and
R12a, along with the atoms to which they are attached, are
optionally joined to form a ring. The combination of nitrogens
(A+D+E+G) is an integer selected from 0 to 3.
Id . at 4:6–5:2. Example 4.2.j of the ’657 patent identifies the
compound 1,3-dihydro-5-fluoro-1-hydroxy-2,1-benzoxaborole as
“C10”, which has the following structure:
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Id . at 180:20–27. The ’657 patent provides several examples
describing the antifungal activity of compound C10 and its ability to
penetrate human nails. Id . at 189:15–196:46.
The ’657 patent states that preferred compounds will have
desirable pharmacological properties, including oral bioavailability,
low toxicity, low serum binding and desirable in vitro and in vivo
half-lives. Id . at 165:66–166:2. According to the ’657 patent,
“[a]ssays may be used to predict these desirable pharmacological
properties.” Id . at 166:6–7. For example, “[t]oxicity to cultured
hepatocyctes may be used to predict compound toxicity.” Id . at
166:9–10.
C.
Illustrative Claim
The ’657 patent contains twenty-four claims, all of which are
challenged by Petitioner. All twenty-four claims are directed to a
pharmaceutical formulation. Claim 1 is the sole independent claim.
Claim 1 is illustrative of the challenged claims and is reproduced
below:
1. A pharmaceutical formulation, comprising:(a) 1,3-dihydro-5-fluoro-1-hydroxy-2,1-benzoxaborole, or a salt
thereof; and
(b) a pharmaceutically acceptable excipient
wherein said pharmaceutical formulation is for topical
administration to an animal suffering from an infection by a
microorganism.
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D.
Prior Art Relied Upon
Petitioner relies upon the following prior art:
U.S. 6,143,794 Chaudhuri Nov. 4, 2000 (Ex. 1004)
U.S. 6,224,887 Samour May 1, 2001 (Ex. 1005)
U.S. 7,074,392 Friedman Jul. 11, 2006 (Ex. 1006)
U.S. 5,498,407 Atlas Mar. 12, 1996 (Ex. 1007)
U.S. 3,816,472 Shapiro June 11, 1974 (Ex. 1008)
US 2002/0165121 A1 Brehove Nov. 7, 2002 (Ex. 1003)
WO 95/33754 Austin Dec. 14, 1995 (Ex. 1002)
Petitioner contends that the challenged claims are unpatentable under
35 U.S.C. § 103 based on the following specific grounds (Pet. 21–60):
References Basis Claims challenged
Austin and Brehove § 103 1–5, 10–16 and 18–
24Austin, Brehove, and Chaudhuri § 103 6
Austin, Brehove, and Samour § 103 7
Austin, Brehove, Friedman, and Atlas § 103 8
Austin, Brehove, Friedman, and Samour § 103 9
Austin, Brehove, and Shapiro § 103 17
E. Level of Ordinary Skill in the Art
Petitioner’s declarants, Dr. Stephen Kahl (Ex. 1009) and Dr. S.
Narasimha Murthy (Ex. 1011), testify that, based on their experience
in pharmacology, a person of ordinary skill in the art at the time of the
invention had an advanced degree, Master’s or Ph.D. or equivalent
experience in chemistry, pharmacology or biochemistry and at least
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two years of experience with the research, development, or production
of pharmaceuticals. Ex. 1009 ¶ 21 and Ex. 1011 ¶ 36. Patent Owner
goes further than Petitioner and states that a person of ordinary skill in
the art would also possess knowledge and experience in medicinal
chemistry and development of potential drugs candidates suitable for
treating onychomycosis and ungual and other infections. We need not
decide at this time whether one skilled in the art would have possessed
the additional knowledge identified by Patent Owner as Patent Owner
acknowledges that Petitioner’s declarants purport to have experience
in the additional fields (Prelim. Resp. 16) and as the prior art itself is
sufficient to demonstrate the level of skill in the art at the time of the
invention. See Okajima v. Bourdeau, 261 F.3d 1350, 1355 (Fed. Cir.
2001) (the prior art itself can reflect the appropriate level of ordinary
skill in the art).
II. ANALYSIS
A. Claim Interpretation
In an inter partes review, the Board interprets claim terms in an
unexpired patent according to the broadest reasonable construction in light
of the specification of the patent in which they appear. 37 C.F.R. § 100(b);
In re Cuozzo Speed Techs., LLC , 793 F.3d 1268, 1278–79 (Fed. Cir. 2015),
cert. granted sub nom. Cuozzo Speed Techs., LLC v. Lee, 84 U.S.L.W. 3218
(U.S. Jan. 15, 2016) (No. 15-446). Under that standard, and absent any
special definitions, we give 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. See In re Translogic Tech., Inc., 504 F.3d 1249, 1257
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(Fed. Cir. 2007). Any special definitions for claim terms must be set forth
with reasonable clarity, deliberateness, and precision. See In re Paulsen,
30 F.3d 1475, 1480 (Fed. Cir. 1994).
Petitioner identifies several claim terms in the challenged claims and
provides definitions for those terms. Pet. 10–15. Patent Owner states that,
where the specification does not already state the meaning of the identified
claim terms, Petitioner has failed to provide sufficient reason why the
ordinary and customary meanings of the claim terms should not be adopted.
Prelim. Resp. 16–20.
At this stage of the proceeding, except for the term 1,3-dihydro-5-
fluoro-1-hydroxy-2,1-benzoxaborole, we determine that it is unnecessary to
construe explicitly the claim terms for purposes of this Decision. See
Wellman, Inc. v. Eastman Chem. Co., 642 F.3d 1355, 1361 (Fed. Cir. 2011)
(“[C]laim terms need only be construed ‘to the extent necessary to resolve
the controversy.’”) (quoting Vivid Techs., Inc. v. Am. Sci. & Eng’g, Inc.,
200 F.3d 795, 803 (Fed. Cir. 1999)).
1.
“1,3-dihydro-5-fluoro-1-hydroxy-2,1-benzoxaborole”
Independent claim 1 recites the compound 1,3-dihydro-5-fluoro-1-
hydroxy-2,1-benzoxaborole. 1,3-dihydro-5-fluoro-1-hydroxy-2,1-
benzoxaborole has the following structure:
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The parties agree that the claimed compound may also be referred to as “5-
fluoro-1,3-dihydro-1-hydroxy-2,1-benzoxaborole.” Pet. 11; Prelim. Resp.
18. Patent Owner further notes that the claimed compound is also known as
“tavaborole.” Id .
We determine that the broadest reasonable interpretation of 1,3-
dihydro-5-fluoro-1-hydroxy-2,1-benzoxaborole includes “5-fluoro-1,3-
dihydro-1-hydroxy-2,1-benzoxaborole” and “tavaborole.” Accordingly, for
ease of reference, we refer to the claimed compound as “tavaborole” in this
Decision.
D. Section 103 Obviousness Challenge
Petitioner raises six (6) challenges based on 35 U.S.C. § 103.
Generally, Petitioner contends that the challenged claims represent a
combination of known prior art elements (tavaborole and topical
formulations), used for their known purpose (antifungal treatment and
topical delivery formulation) to achieve a predictable result (treat or inhibit
the growth of fungus in an animal). Pet. 21–60. Patent Owner opposes
Petitioner’s assertions. Prelim. Resp. 20–59. Based on the current record,
we determine that Petitioner has established a reasonable likelihood that it
would prevail in showing claims 1–24 are unpatentable as obvious over the
cited art.
1.
Background on Obviousness
An invention is not patentable under 35 U.S.C. § 103 if it is obvious.
KSR Int’l Co. v. Teleflex Inc., 550 U.S. 398, 427 (2007). Under § 103:
the scope and content of the prior art are to be determined;
differences between the prior art and the claims at issue are to
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be ascertained; and the level of ordinary skill in the pertinent art
resolved. Against this background, the obviousness or
nonobviousness of the subject matter is determined.
Graham v. John Deere Co., 383 U.S. 1, 17 (1966). In addressing the
findings of fact, “[t]he combination of familiar elements according to known
methods is likely to be obvious when it does no more than yield predictable
results.” KSR, 550 U.S. at 416. As explained in KSR:
If a person of ordinary skill can implement a predictable
variation, § 103 likely bars its patentability. For the same
reason, if a technique has been used to improve one device, and
a person of ordinary skill in the art would recognize that it
would improve similar devices in the same way, using thetechnique is obvious unless its actual application is beyond his
or her skill.
Id. at 417. Accordingly, a central question in analyzing obviousness is
“whether the improvement is more than the predictable use of prior art
elements according to their established functions.” Id .
2.
Austin and Brehove: Claims 1–5, 10–16 and 18–24
Austin relates to the use of oxaboroles as industrial biocides, and
especially as fungicides for the protection of plastic materials. Ex. 1002,
Abstract. The Abstract further states that “[p]referred compounds are 5- and
6-fluoro or bromo-1,3-dihydro-1-hydroxy-2,1-benzoxaborole including O-
esters thereof.” Id. Austin notes that it has been found that compounds
containing an oxaborole ring are “particularly effective against micro-
organisms such as bacteria, algae, yeasts and particularly fungi, especially
fungi which cause degradation of plastics materials.” Id. at 1:35–38.
Austin tested three compounds falling within the scope of its preferred
5- and 6-fluoro or bromo-1,3-dihydro-1-hydroxy-2,1-benzoxaboroles,
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including tavaborole. Specifically, Austin discloses tavaborole as Example
64, along with the results of a study showing tavaborole has effective
antifungal activity against five different fungi: Aspergillus niger ,
Aureobasidium pullulans, Candida albicans, Gliocladium roseum, and
Penicillium pinophylum. Id. at 37 (Table 9). Of the three preferred
compounds tested, tavaborole demonstrated the lowest Minimum Inhibitory
Concentration (“MIC”) values against several pathogens, including Candida
albicans. Id . In other words, tavaborole inhibited the visible growth of
Candida albicans at the lowest level of concentration of the three preferred
compounds tested. Ex. 1009 ¶ 35.
Austin teaches that its compounds may be used with water-miscible
organic solvents such as ethanol or glycols, including propylene glycol. Ex.
1002 at 6:34–37. According to Austin, the concentration of the oxaborale in
its biocide composition may range from 10 to 20% by weight relative to the
total weight of the biocide composition, which for tavaborole an ethanol
solution would be 7.9%–15.8% w/v. Ex. 1011 ¶¶ 167–169.
Brehove relates to the topical treatment of nail infections such as
onychomycosis caused by bacteria, fungi, and other pathogens. Ex. 1003
¶ 3. Brehove explains that onychomycosis is a nail disease typically caused
by Candida albicans, Trichophyton mentagrophytes, Trichophyton rubrum,
or Epidermpophyton floccusum. Id. ¶ 5. Brehove states that Candida
albicans is the most common pathogen causing onychomycosis. Id . ¶ 18.
Brehove teaches that to be effective for onychomycosis, the topical
treatment should exhibit a powerful potency for pathogens, be permeable
through the nail barrier, and be safe for patient use. Id. ¶ 6. According to
Brehove, “[t]here exists a need in the art for a topical application that
combines these traits in high degree.” Id.
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Brehove states that the “safety and non-toxicity of organo-boron
compounds has been questioned.” Id. ¶ 13. On the one hand, Brehove
describes one reference that states that boron compounds are “very toxic,”
and may be considered an industrial poison. Id . ¶ 14. On the other hand,
Brehove describes references that found the toxicity of a certain boron-
containing compound to be “very low” and a boron containing antifungal
fuel additive called Biobor® JF, when combined with naptha, is said to
cause “mild irritation.” Id. ¶¶ 14–15 and 23 and Ex. 1033 at 1.
Biobor® JF contains a combination of 2,2’-(1-methyltrimethylene
dioxy) bis-(4-methyl-1, 3, 2-dioxaborinane) (referred to by Brehove as “S1”)
and 2,2’-oxybis (4, 4, 6-trimethyl-1, 3, 2-dioxaborinane) (referred to by
Brehove as “S2”). Ex. 1003 ¶¶ 15, 30. Brehove describes the results of both
in vitro and in vivo testing of the antifungal activity of S1 and S2 against
Candida albicans. Id. ¶¶ 30–38.
Brehove describes several topical treatment formulations including
one that is applied nightly in a petroleum jelly or mineral oil base and
another formulation that is applied one per week in a cellulose acetate
lacquer base. Id . ¶ 18. Brehove teaches that its active ingredient may be
used in combination with penetration enhancers to increase the permeability
of the skin to a drug. Id . ¶ 27. According to Brehove, its formulations
achieve efficacy in treating onychomycosis without skin irritation or
noticeable side effects. Id . ¶ 18. For example, Brehove states that a male
volunteer with onychomycosis on both feet applies the solution to their
entire toenail and 250 days later, the nail is fully-grown and completely free
of infection with no skin irritation observed. Id . ¶ 35.
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a. Analysis
Petitioner argues that claims 1–5, 10–16 and 18–24 are unpatentable
as obvious over the combination of Austin and Brehove. Through claim
charts and its declarants’ testimony, Petitioner asserts that the combination
teaches each limitation of the claims. Pet. 22–32; Exs. 1009, 1011. For
example, Petitioner relies upon Austin’s teaching that tavaborole is a
compound that is effective in inhibiting Candida albicans and Brehove’s
teaching that topical formulations, such as lacquers, are effective in treating
Candida albicans. Ex. 1002, 37 (Table 9) and Ex. 1003 ¶¶ 18 and 30–38.
Having reviewed the arguments and evidence, we are persuaded that
Petitioner has shown sufficiently that each limitation of the challenged
claims is taught by the combination of Austin and Brehove.
Petitioner then provides a detailed explanation supported by the
testimony of its two declarants as to why a person of ordinary skill in the art
would have employed Austin’s tavaborole with Brehove’s topical
formulations for treating Candida albicans and onychomycosis with a
reasonable expectation of success. Pet. 32–36. Dr. Murthy testifies in
support of Petitioner and testifies that a person of ordinary skill in the art
would have had reason to combine Austin’s tavaborole with Brehove topical
formulations as both Austin and Brehove describe boron-based compounds
for inhibiting Candida albicans, and as Brehove teaches formulations that
deliver a boron-based compound for treating onychomycosis, which is
predominantly caused by Candida albicans, without skin irritation or side
effects. Ex. 1011 ¶ 148.
Patent Owner disagrees with Petitioner’s analysis of the prior art. In
its Preliminary Response, Patent Owner does not appear to challenge that the
combination of references teaches each limitation of the claims. Instead,
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Patent Owner argues that Petitioner has failed to meet its burden to show
that a person of ordinary skill in the art would have combined Austin and
Brehove in the manner recited in the claims with a reasonable expectation of
success.
Patent Owner argues that Petitioner has failed to explain why a person
of ordinary skill in the art would have chosen any compound from Austin as
a starting point for further investigation. Prelim. Resp. 22. According to
Patent Owner, a person of ordinary skill in the art would have understood
that biocides, such as taught by Austin, are designed to kill living organisms.
Id . at 23. Patent Owner states that nothing in Austin discloses or suggests
that its industrial biocides may be used for therapeutic purposes in or on
humans or animals. Id . at 24.
Austin teaches that tavaborole, as well as other biocides, inhibit
Candida albicans, which is the most common pathogen causing
onychomycosis. Brehove teaches that an antifungal boron-based fuel
additive, Biobor® JF, likewise was effective in inhibiting Candida albicans
and formulated the boron-based fuel additive into a topical composition for
treatment of nail infections.
Dr. Murthy testifies one skilled in the art would have understood that
Austin’s industrial biocides are effective in treating Candida albicans, and
that boron-based compounds were well known in the art as biocides. Ex.
1011, e.g., ¶¶ 141–143, 153. Dr. Murthy further testifies that Brehove
demonstrated to one of ordinary skill in the art topical applications of an
industrial boron-based biocide to a human was effective in treating Candida
albicans and onychomycosis without any noticeable skin irritation or side
effects. Id . at ¶ 153. We credit Dr. Murthy’s testimony at this stage of the
proceeding as it is consistent with the cited prior art. Based on the current
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record, we hold that one of ordinary skill in the art would have had sufficient
reason to select a compound from Austin for therapeutic purposes.
Patent Owner contends that one skilled in the art would have expected
the following of boron-containing compounds:
Given Austin’s focus on effective industrial biocides, it is not
surprising that the reference provides no information at all
about the toxicity or therapeutic efficacy of its boron-containing
compounds in humans or animals. To a POSA in 2005
considering compounds for use in humans and animals, this
would have been a glaring omission, especially when the art,
including Dr. Kahl’s article, taught a POSA to expect boron-
containing compounds to be toxic. See, e.g., Exs. 2002, 2005-
2014, 2018 & 2026.
Prelim. Resp. 24. Patent Owner, at this stage of the proceeding, does not
provide a sufficient explanation for why one skilled in the art would have
been led to expect that “boron-containing compounds” are toxic, and would
not have been led to use such compounds. Additionally, Patent Owner’s
allegations of a “glaring omission” of toxicity appear to be inconsistent with
Patent Owner’s ’657 specification and prosecution history, which described
and claimed millions of boron-containing compounds for pharmaceutical
formulations but as to toxicity merely stated that “[t]oxicity to cultured
hepatocyctes may be used to predict compound toxicity.” Ex. 1001, at
166:9–10, Ex. 1013 at 102–104Further, Petitioner’s declarant, Dr. Kahl,
testifies that “[b]oron-containing compounds are generally considered safe.”
Ex. 1006 ¶ 30. Also, Brehove identifies at least one article that states that
the toxicity of the dioxiborinane tested was “very low.” Ex. 1003 ¶ 15.
Thus, at this stage of the proceeding, we are persuaded that Petitioner has
made a sufficient showing that a person of ordinary skill in the art would not
have been dissuaded from Austin’s boron-containing compounds.
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Patent Owner also argues that a person of ordinary skill in the art
would not have selected tavaborole from the millions of compounds
disclosed in Austin. Prelim. Resp. 25–30. It is well settled that a reference
may be relied upon for all that it would have reasonably suggested to one
having ordinary skill in the art. Merck & Co., Inc. v. Biocraft Labs., Inc.,
874 F.2d 804, 807 (Fed. Cir. 1989). Here, Austin discloses 5-fluoro
benzoxaboroles as preferred fungicides in the Abstract and tavaborole is one
of three preferred compounds tested that effectively inhibits Candida
albicans, which is a cause of onychomycosis. Pet. 23; Ex. 1011 ¶¶ 189–190.
Accordingly, evaluating Austin for all that it teaches, we conclude on the
present record that one skilled in the art would have recognized that
tavaborole is a preferred fungicide for inhibiting Candida albicans, which is
a cause of onychomycosis.
Patent Owner argues that Brehove would not supply a reasonable
expectation of success because a skilled artisan would not have been
convinced that dioxaborinanes are not toxic, given an alleged lack of data in
Brehove. Prelim. Resp. at 32–34, 38–39. Patent Owner also argues that a
skilled artisan would not have combined the references given the structural
differences between tavaborole and dioxaborinanes. Id . at 34–38.
Petitioner, however, offers the testimony of its declarant, Dr. Murthy, who
states that both Austin and Brehove disclose boron heterocycles and that a
person of ordinary skill in the art would have expected that compounds that
share sufficient similar structural features would likely share similar
functional features, such as the inhibition of additional fungi responsible for
onychomycosis. Ex. 1011 ¶ 155. As to the alleged lack of in vivo data in
Brehove, Petitioner directs us to Brehove’s disclosure of examples in which
boron-containing compositions are applied to volunteers suffering from
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onychomosis. Pet. 32 (citing Ex. 1003 ¶¶ 34–38; Ex. 1011 ¶ 145) (other
citations omitted). As Dr. Murphy points out, in those examples, “Brehove’s
topical compositions effectively eradicated the onychomycosis with ‘[n]o
skin irritation . . . and no [evidence of] side effects.’” Ex. 1011 ¶ 145
(quoting Ex. 1003 ¶ 34) (citing Ex. 1003 ¶¶ 18, 22, 30, 34–38). On this
record, Petitioner advances information—specifically, Brehove’s examples,
and the reported results of those examples—that offsets Patent Owner’s bare
argument that Brehove lacks in vivo data. . 1003 ¶¶ 34–38. Further, Patent
Owner’s ’657 prosecution history described and claimed millions of boron-
containing compounds for pharmaceutical formulations but likewise did not
provide in vivo testing for each of the compounds falling within the scope of
its claimed pharmaceutical formulations. Ex. 1001 at 166:9–10, Ex. 1013 at
102–104.Thus, although we acknowledge Patent Owner’s arguments, on this
record and at this stage of the proceeding, we determine that Petitioner has
set forth sufficient evidence to show that a person of ordinary skill in the art
would have had a reason to employ Austin’s tavaborole in Brehove’s topical
formulations with a reasonable expectation of success in treating
onychomycosis caused by Candida albicans. See Pet. 29–36.
Claims 18 and 19 are dependent claims directed to pharmaceutical
formulations where the formulation is for a topical administration to an
animal suffering from a dermatophyte (claim 18) or Tinea unguium,
Trichophyton rubrum and Trichophyton mentagrophytes (claim 19). Patent
Owner contends that Petitioner has failed to demonstrate that one of ordinary
skill in the art following the teachings of Austin and Brehove would have
treated onychomycosis and other infections requiring nail infection such as
recited in claims 18 and 19. Prelim. Resp. 40–46. Patent Owner alleges that
one of ordinary skill in the art would have understood that 90–95% of
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onychomycosis infections are caused by dermatophytes. Id . at 40. Patent
Owner contends that Austin does not suggest, or provide data to support,
that the boron-containing compounds it discloses would be effective against
dermatophytes as Austin presents data on Candida albicans and other non-
dermatophytes and Brehove fails to remedy this deficiency. Id . at 40–42.
Claims 18 and 19 are composition claims, as opposed to method
claims. On this record, Patent Owner does not provide a sufficient
explanation as to how its composition claims for treating dermatophytes,
Tinea unguium, Trichophyton rubrum and Trichophyton mentagrophytes,
which can cause onychomycosis, differ from a composition arrived at from
the teachings of Austin and Brehove for treating onychomycosis caused by
Candida albicans. See Pet. 29–36. Additionally, Brehove is not limited to
treating onychomycosis caused by Candida albicans. Specifically, Brehove
describes its invention as curing or preventing the spread of nail infections,
such as onychomycosis, caused by bacteria, fungi or other pathogens by
treating with a boron-containing compound. Ex. 1003 ¶¶ 1, 17–18. Dr.
Murthy testifies that a person of ordinary skill in the art would have
expected that compounds that share sufficient similar structural features,
such as the boron heterocycles of Austin and Brehove would likely share
similar functional features. Ex. 1011 ¶ 155.
Patent Owner also contends that a person of ordinary skill in the art
would have expected compounds to exhibit poor nail penetration absent data
evidencing low keratin binding. Prelim. Resp. 45. Dr. Murthy testifies that
one skilled in the art would have recognized that tavaborole has a lower
molecular weight than the boron-containing compound of Brehove and
would have been expected to have better penetration of the nail plate. Ex.
1011 ¶ 153. Further, Brehove teaches that its boron-containing active
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ingredient in treating onychomycosis can be combined with a penetration
enhancer to increase the permeability of the skin to the drug. Ex. 1003 ¶ 27.
Brehove also teaches that one skilled in the art could employ mineral oil,
petroleum jelly and paraffin wax to permit extended continuous diffusion
and penetration into the nail. Id . at 25. Based upon the evidence of record,
we conclude at this stage that one skilled in the art would have understood
that a composition containing tavaborole in combination with the nail
penetrating ingredients of Brehove would have had a reasonable expectation
of success of treating onychomycosis.
Accordingly, we determine that Petitioner has established a
reasonable likelihood that it would prevail in showing claims 1–5, 10–16
and 18–24 are unpatentable as obvious over Austin and Brehove.
3. Austin, Brehove, and Chaudhuri: Claim 6
Claim 6 depends from claim 1 and requires that the pharmaceutical
composition of claim 1 comprise propylene glycol and ethanol in a ratio of
about 1:4 and about 1:10 weight per volume of tavaborole.
Chaudhuri is directed to topical formulations for treating nail fungal
diseases. Ex. 1004. Chaudhuri states that treating onychomycosis can be
difficult and that it would be advantageous to have a topical formulation
capable of penetrating the nail barrier and treating nail fungal diseases. Id .
at 1:55–65. Chaudhuri states that suitable solvents for its composition
include lower alkanols, such as ethanol, and dihyxdroxyalcohols, such as
propylene glycol. Id . at 6:2–7. In particular, Chaudhuri provides an
example containing 5–20% weight propylene glycol and 20–80% weight
ethanol and 0.5 to 15% weight antifungal. Id . at 8:57–9:10, Table B. One
skilled in the art would have understood Chaudhuri’s Table B proportions as
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equating to a ratio of 1:4 propylene glycol to ethanol and 1:10 wt/volume of
antifungal. Ex. 1011, ¶¶ 100, 193.
Petitioner cites Austin for its description of organic solvents, such as
ethanol and propylene glycol in combination with a biocide, with preferably
10 to 20% by weight concentration of biocide. Pet. 38. Petitioner relies
upon Chaudhuri for its teaching that an effective nail treatment formulation
for onychomycosis would employ a 1:4 ratio of propylene glycol to ethanol
and 1:10 wt/volume antifungal. Pet. 40.
Patent Owner contends that one skilled in the art would recognize that
Chaudhuri does not describe compounds that are structurally similar to the
boron-containing compounds of Austin and Brehove. Prelim. Resp. 49–50.
Patent Owner also contends that one of ordinary skill in the art would not
have combined the teachings of Austin, Brehove and Chaudhuri as
Chaudhuri does not report on antifungal activity for its compounds in the
same manner as Austin. Id . at 50.
Based on the record presented, we credit the testimony of Dr. Murthy
as it is consistent with the teachings of the prior art of record and find that
Petitioner has demonstrated that nail treatment formulations containing
ethanol, propylene glycol and antifungal compounds in the claimed
proportions were known in the art and effective in treating onychomycosis.
We conclude, on this record, that Petitioner has provided sufficient and
credible evidence to demonstrate that one skilled in the art would have
combined the known antifungal tavaborole with the known nail treatment
formulations for their known use (treating nail onychomycosis) to achieve a
predictable result (penetrating a nail with an antifungal compound to treat
onychomycosis).
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4. Austin, Brehove, and Samour: Claim 7
Claim 7 depends from claim 1 and requires that the pharmaceutical
composition of claim 1 comprises 70% ethanol, about 20% poly(vinyl
methyl ether-alt-maleic acid monobutyl ester) and about 10% tavaborole.
Samour describes a nail lacquer formulation that is effective for the
treatment or prevention of fungal infections, such as onychomycosis.
Samour’s nail lacquer formulation incorporates an antifungal agent and,
when applied to nails, yields a hard, durable, substantially clear, long-lasting
film that is effective in treating fungal infestations associated with nails. Ex.
1005, 3:5–13. Samour teaches that an effective amount of active antifungal
agent preferably ranges from 1 to 10% by weight of the composition. Id . at
12:9–14. Suitable film-forming polymers for the composition include
acrylic polymers such as Gantrez ES-425 (poly(vinyl methyl ether-alt-
maleic acid monobutyl ester)). Id . at 7:54–62, Ex. 1011 ¶¶ 103, 208 and Ex.
1035 at 5. Samour teaches that an effective amount of film-forming polymer
is preferably 15 to about 50%, and especially from 20 to 40% by weight of
composition. Id . at 8:38–44, Ex. 1011 ¶¶ 103, 208. Samour exemplifies a
number of lacquer formulations including a formulation having 71%
ethanol, 24% film-forming polymer and 5% antifungal. Ex. 1005, 9:31–49,
22:20–36.
According to Dr. Murthy, formulating a pharmaceutical composition,
such as that recited in claim 7, requires nothing more than routine
experimentation. Ex. 1011, ¶ 212. Petitioner cites Austin for its description
of organic solvents, such as ethanol and propylene glycol in combination
with a biocide, with preferably 10 to 20% by weight concentration of
biocide. Pet. 40–41. Petitioner relies upon Brehove for its teaching that
onychomycosis treatments can be formulated with evaporating solvents,
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such as alcohols. Pet. 41. Petitioner cites Samour for teaching one skilled in
the art that an effective nail treatment formulation for onychomycosis can be
formulated using 20 to 40% film-forming polymer such as Gantrez ES-425,
a solvent such as ethanol in an amount of about 71% and an antifungal agent
in an amount of from 1 to 10% of the composition. Id . at 41–44. Based on
the teachings of Austin, Brehove and Samour, Dr. Murthy concludes that
one skilled in the art would have had a reasonable expectation of success of
formulating an effective onychomycosis treatment using tavaborole with the
improved nail lacquer formulation described in Samour. Ex. 1011 ¶¶ 211–
216.
Patent Owner contends that Samour fails to describe a boron-
containing compound and does not provide the effectiveness or toxicity of
any antifungal compound. Prelim. Resp. 52. Patent Owner further contends
that Samour describes the use of skin penetration enhancers but does not
provide data on penetration data containing tavaborole. Id . at 53.
Based on the record presented, we credit the testimony of Dr. Murthy
as it is consistent with the teachings of the prior art of record. We conclude,
at this stage of the proceeding, that Petitioner has provided sufficient and
credible evidence to demonstrate that one skilled in the art would have
combined the known antifungal tavaborole with the known nail treatment
formulations for their known use (treating nail onychomycosis) to achieve a
predictable result (penetrating a nail with an antifungal compound to treat
onychomycosis).
5.
Austin, Brehove, Friedman, and Atlas: Claim 8
Claim 8 depends from claim 1 and requires that the pharmaceutical
composition comprises about 56% ethanol; about 14% water; about 15%
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poly(2-hydroxyethyl methacrylate); about 5% dibutyl sebacate and about
10% of tavaborole.
Friedman describes a topical sustained release composition for
delivery of antifungal agents to nails. Friedman describes a number of
methacrylic polymers for use as a film-forming polymer and describes
plasticizers, such as dibutyl sebacate, with a preferable weight ratio of
plasticizer to polymer of about 0.4:1 to about 0.3:1. Ex. 1006, 5:51–64.
Friedman teaches that a suitable solvent includes ethanol, preferably about
60 to 90% w/w of the composition. Id . at 6:1–9. Dr. Murthy testifies that
60% to about 90% w/w ethanol corresponds to 47.4% to about 71.1% w/v
ethanol. Ex. 1011 ¶ 225 n.8.
Atlas describes the use of hydrogel polymers as excellent carriers for
the release of drugs. Ex. 1007 at 1:5–14. Atlas states that poly(2-
hydroxyethyl methacrylate) (“P-HEMA”) was the most widely used
hydrogel. Id . at Abstract. Atlas teaches that P-HEMA hollow fibers act as a
reservoir and matrix for diffusion-controlled delivery to skin and nails. Id .
at 2:58–64. Atlas Example 4 describes a cosmetic nail polish composition
having P-HEMA. Id . at 3:57–4:7.
Dr. Murthy testifies that one of ordinary skill in the art would have
understood that the composition of claim 8 represents nothing more than
routine experimentation using well-known pharmaceutical components. Ex.
1011 ¶¶ 230–234. Dr. Murthy further testifies that one of ordinary skill in
the art would have had a reasonable expectation of success of combining the
known components given that it was known that high-swelling polymers
were preferred for pharmaceutical lacquer formulations and that the use of
P-HEMA was a well-known high-swelling hydrogel. Id . at 235–236.
Patent Owner contends that one would not have combined the
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teachings of the cited references due to the structural differences between
Austin and Brehove and that Friedman fails to teach a boron-containing
compound. Prelim. Resp. 54.
Based on the record presented, we credit the testimony of Dr. Murthy
as it is consistent with the teachings of the prior art of record. We conclude,
on this record, that Petitioner has provided sufficient and credible evidence
to demonstrate that one skilled in the art would have combined the known
antifungal tavaborole with the known nail treatment formulations for their
known use (nail drug delivery systems and treating nail onychomycosis) to
achieve a predictable result (forming an effective nail lacquer delivery
composition with an antifungal compound to treat onychomycosis).
6.
Austin, Brehove, Friedman, and Samour: Claim 9
Claim 9 depends from claim 1 and requires that the pharmaceutical
composition comprises about 56% ethanol; about 14% water; about 15%
poly(2-hydroxyethyl methacrylate); about 5% dibutyl sebacate and about
10% of tavaborole.
Regarding claim 9, Petitioner and Patent Owner present essentially the
same reasons as provided above with respect to claims 7 and 8. For the
reasons stated above regarding the challenges with respect to claims 7 and 8,
we likewise determine that Petitioner has made a sufficient showing as to
why a person of ordinary skill in the art would have combined the teachings
of Austin, Brehove, Friedman and Samour and arrived at the composition of
claim 9.
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7. Austin, Brehove, and Shapiro: Claim 17
Claim 17 depends from claim 14, which depends from claim 1. Claim
17 requires the fungus or yeast be selected from Trichophyton concentricum,
Trichophyton violaceum, Trichophyton schoenleinii, Trichophyton
verrucosum, Trichophyton soudanense, Microsporum gypseum,
Microsporum equinum, Candida guilliermondii, Malassezia globosa,
Malassezia obtuse, Malassezia restricta, Malassezia slooffiae and
Aspergillus flavus.
Shapiro describes antifungal compounds for treating fungal infections.
Ex. 1008, 1:15–16. Shapiro teaches that its antifungal compounds are
effective against fungi including Trichophyton rubrum, Trichophyton
mentagrophytes, Trichophyton verrucosum, and Microsporum gypseum. Id .
at 2:3–14.
Petitioner states that one skilled in the art would have combined the
teachings of Austin, Brehove and Shapiro because Brehove and Shapiro
teach treating or inhibiting onychomycosis in humans with pharmaceutical
drug formulations and Shapiro describes antifungal compounds that have
cross-activity against a number of different fungi linked to onychomycosis.
Pet. 60.
Patent Owner contends that Shapiro’s compounds are structurally
different than those of Brehove. Prelim. Resp. 58. Patent Owner states that
one skilled in the art would not have expected a formulation of tavaborole
for topical application would succeed. Id . at 59.
Claims 17 is a composition claim, as opposed to a method claim. On
this record, Patent Owner does not provide a sufficient explanation as to how
its composition claims for treating the recited fungi differs from a
composition arrived at from the teachings of Austin and Brehove for treating
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onychomycosis caused by Candida albicans. See Pet. 29–36. Further,
Shapiro teaches one skilled in the art that antifungal drugs may exhibit
cross-activity between fungi linked to onychomycosis and fungi linked to
other fungal infections. Ex. 1011 ¶ 272.
III. CONCLUSION
For the foregoing reasons, we determine that the information presented
in the Petition, notwithstanding the Preliminary Response, establishes that
there is a reasonable likelihood that Petitioner would prevail in
demonstrating unpatentability of claims 1–24. The Board has not yet made a
final determination of the patentability of any of claims 1–24 of the ’657
patent.
IV. ORDER
Accordingly, it is
ORDERED that pursuant to 35 U.S.C. § 314, an inter partes review is
hereby instituted as to claims 1–24 of the ’657 patent on the following
grounds:
References Basis Claims challenged
Austin and Brehove § 103 1–5, 10–16 and 18–
24
Austin, Brehove, and Chaudhuri § 103 6
Austin, Brehove, and Samour § 103 7
Austin, Brehove, Friedman, and Atlas § 103 8Austin, Brehove, Friedman, and Samour § 103 9
Austin, Brehove, and Shapiro § 103 17
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FURTHER ORDERED that pursuant to 35 U.S.C. § 314(c) and 37
C.F.R. § 42.4, notice is hereby given of the institution of a trial commencing
on the entry date of this decision.
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Patent 7,767,657 B2
PETITIONER:
Jeffrey Blake
Kathleen Ott
PATENT OWNER:
Andrea Reister
Enrique Longton