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United States Court of Appeals for the Federal Circuit
04-1344
ALZA CORPORATION
and JANSSEN PHARMACEUTICA, INC.,
Plaintiffs-Appellees,
v.
MYLAN LABORATORIES INC.,
MYLAN TECHNOLOGIES INC., and MYLAN PHARMACEUTICALS INC.,
Defendants-Appellants.
Gregory L. Diskant, Patterson, Belknap, Webb & Tyler LLP, of New York, New
York, argued for plaintiffs-appellees. With him on the brief was Jeffrey I.D. Lewis.
E. Anthony Figg, Rothwell, Figg, Ernst & Manbeck, of Washington, DC, argued
for defendants-appellants. With him on the brief were Joseph A. Hynds and Sharon L.
Davis.
Appealed from: United States District Court for the District of Vermont
Chief Judge William K. Sessions III
United States Court of Appeals for the Federal Circuit
04-1344
ALZA CORPORATION
and JANSSEN PHARMACEUTICA, INC.,
Plaintiffs-Appellees,
v.
MYLAN LABORATORIES INC.,
MYLAN TECHNOLOGIES INC., and MYLAN PHARMACEUTICALS INC.,
Defendants-Appellants.
__________________________
DECIDED: December 10, 2004
__________________________
Before NEWMAN, Circuit Judge, ARCHER, Senior Circuit Judge, and DYK, Circuit
Judge.
Opinion for the court filed by Senior Circuit Judge ARCHER. Opinion concurring-in-part
and dissenting-in-part filed by Circuit Judge DYK.
ARCHER, Senior Circuit Judge.
Mylan Laboratories Inc., Mylan Technologies Inc. and Mylan Pharmaceuticals
Inc. (collectively “Mylan”) appeal the judgment of the United States District Court for the
District of Vermont holding that U.S. Patent No. 4,588,580 (“the ‘580 patent”) is not
anticipated or obvious in view of U.S. Patent No. 4,470,962 (“the Keith patent”) and that
the ‘580 patent is not unenforceable as having been procured by inequitable conduct.
Alza Corp. v. Mylan Labs. Inc., 310 F. Supp. 2d 610 (D. Vt. 2004). Because the district
court correctly construed the claim term “skin permeable form” to exclude fentanyl
citrate, we affirm its validity determinations. Further, because we discern no error in the
district court’s finding of a lack of intent to deceive, we affirm the district court’s holding
that the ‘580 patent is not unenforceable due to inequitable conduct.
I
Alza Corp. and Janssen Pharmaceutica, Inc. (collectively “Alza”) brought an
infringement suit against Mylan for infringing the ‘580 patent. The ‘580 patent is drawn
to a system for the transdermal administration of fentanyl, a powerful narcotic, for an
extended period of time at analgetically effective rates.1 Prior to the ‘580 patent,
transdermal system designs in the form of a patch were based upon two principles: 1)
a drug with high solubility should be used, since more drug in solution meant a greater
ability to push drug through the skin; and 2) huge drug excesses should be used to
super-saturate the system so delivery could be continued for a prolonged period of
time.2 This design, however, was inappropriate for a narcotic, due to the large
excesses of a controlled substance that remained in discarded patches which could
then be abused. Thus, the inventors of the ‘580 patent set out to develop a fentanyl
patch that minimized the amount of narcotic drug that would be used in the system.
The inventors discovered that the skin permeability of fentanyl – the balance of
flux and concentration necessary for adequate delivery to humans – was highly
dependent on the chemical form of the drug:
We have discovered that fentanyl citrate, the form in which fentanyl is
presently administered, has such a low skin permeability that it is not at all
1
At the time the inventors were developing a transdermal system for
administering fentanyl, fentanyl was “normally administered as the citrate, either as a
bolus injection or infusion or a continuous infusion for the purpose of producing
anesthesia or analgesia.” ‘580 patent, col. 1, ll. 22-25.
2
This is because as drug left solution to go into the skin, excess drug in the
patch (above the system’s saturation level) would dissolve, replacing the drug that was
leaving.
04-1344 2
suitable for transdermal delivery, even with the use of permeation
enhancers. Instead, we have found that, in order to obtain the delivery
rates noted above, the drug should be incorporated in the transdermal
therapeutic system in the form of the base.
‘580 patent, col. 3, ll. 10-14. The ‘580 patent directed to the transdermal administration
of fentanyl in the base form issued on May 13, 1986.
Two reexamination proceedings followed. The subject of the first proceeding
was an article written by an Alza scientist, Michaels. Michaels taught that high solubility
in water is a desirable feature for a transdermally delivered drug. The applicants
submitted a declaration explaining that Michaels therefore suggested that fentanyl
would not be a suitable transdermal candidate because of its low water solubility. The
examiner allowed the claims, reasoning that Michaels did not suggest the use of
fentanyl base because of Michaels’s desire for high solubility. The subject of the
second reexamination proceeding was the Keith patent. The Keith patent is directed
principally to a nitroglycerin transdermal patch, but it also includes fentanyl in a list of
potential transdermal candidates. Keith teaches using a ten-fold excess of drug to force
drug through the skin and keeping the drug in a neutral-to-slightly-acidic solution (pH
6.5 to 7.0) for stability. Gale, one of the ‘580 patent’s inventors, submitted a declaration
that due to the pH requirements for stability, the Keith patent taught the use of fentanyl
citrate, a form of fentanyl expressly rejected in the ‘580 patent. Gale concluded that any
system disclosed by the Keith patent “would be unsuitable for administering fentanyl at
analgetically effective rates.” Based on the differences between Keith and the ‘580
patent, the examiner reaffirmed the ‘580 patent:
the form of fentanyl produced under the procedures of the [Keith] patent
would be in the citrate salt form. . . . As such, the Keith et al reference
fails to teach one having an ordinary skill in the art to make and use a
04-1344 3
device which would transdermally administer a skin-permeable form of
fentanyl (or its derivatives) to a human subject at an analgetically effective
rate and for a sufficient period of time to induce and maintain analgesia as
taught by the patent in Re-examination.
One embodiment of the ’580 patent is sold by Janssen as the Duragesic® patch.
Mylan developed a generic transdermal fentanyl patch that is a bioequivalent to
Duragesic®. Mylan filed an Abbreviated New Drug Application (“ANDA”) seeking
approval to market its patch before the ‘580 patent expires. The ‘580 patent issued on
May 13, 1986. It was due to expire in July of 2004; however, following the Food and
Drug Administration’s approval of the pediatric use of Duragesic®, the patent will now
expire on January 23, 2005.3
The asserted claims are claim 59 as it depends from claim 11, claim 59 as it
depends from claim 15, claim 61 as it depends from claim 31, and claim 27 as it
depends from claim 25. Claim 59 as it depends from claim 11 recites
A process for inducing and maintaining analgesia in a human being by the
transdermal administration of [fentanyl base] which comprises:
transdermally administering to said human being through an area of intact
skin,
a skin permeable form of said [fentanyl base] at an analgetically effective
rate and continuing the administration of said [fentanyl base] to said
human being at said rate for an extended period of time at least sufficient
to induce analgesia;
wherein said extended period of time is in the range of [at least about 3
days] to seven days.
(emphasis added). Claim 59 as it depends from claim 15 is identical to the above claim,
but adds the further limitation “wherein the steady state administration rate of said
[fentanyl base] is maintained within the range of about 25 to 150 µg/hr for a substantial
portion of said [at least about 3 days].” Claim 61 as it depends from claim 31 recites
3
At oral argument, both parties conceded that this case will be moot after
this date.
04-1344 4
A medical device for inducing and maintaining analgesia in a human being
by the continuous transdermal administration to a human being of
[fentanyl base] at an analgetically effective administration rate and [for at
least about 3 days] comprising, in combination:
(a) a reservoir for said [fentanyl base] having a skin proximal, material
releasing surface area in the range of about 5-100 cm2, said reservoir
containing between 0.1 and 50% by weight of a skin permeable form of
said [fentanyl base] in amounts and at a concentration adequate to permit
delivery of said [fentanyl base] through the intact [skin] of said human
being at a flux within the range of from 0.5 to 10 µg/cm2/hr for at least
about 24 hours; and
(b) means for maintaining said reservoir in material transmitting
relationship to said skin.
(emphasis added). Claim 27 as it depends from claim 25 recites
A medical device for the transdermal administration to a human being of
[fentanyl base] at an analgetically effective rate for an extended period of
time of at least about 24 hours and sufficient to induce and maintain
analgesia which comprises:
(a) reservoir means containing a skin permeable form of [fentanyl base] in
an amount sufficient to deliver said [fentanyl base] at said analgetically
effective rate for said extended period of time; and
(b) means for maintaining said reservoir means in material transmitting
relationship to an area of intact skin on said human being,
wherein said area is in the range of about 5-100 cm2 and the device
delivers said [fentanyl base] through the skin of said human being at a flux
within the range of about 0.5 to 10 µg/cm2/hr.
(emphasis added).
The claim term at issue here is “skin permeable form.” The parties initially
agreed on the definition of “skin permeable form”: “fentanyl that is in a form that can
pass through the skin.” However, at trial the district court determined that this definition
was not sufficiently precise to answer the questions relevant to the litigation.
Accordingly, the court modified the parties’ definition of the claim limitation and
construed it to mean “fentanyl that is in a form that can pass through the skin, excluding
solutions of fentanyl citrate.” In view of this construction, the court found that Mylan’s
04-1344 5
ANDA for a transdermal fentanyl patch was an act of infringement.4 The court next
determined that the Keith reference did not anticipate the ‘580 patent, because the form
of fentanyl that was taught in that reference (fentanyl citrate) was expressly disclaimed
by the inventors of the ‘580 patent in the specification and during the patent’s
prosecution. Further, the court concluded that the ‘580 patent would not have been
obvious because Mylan had not shown a reason, suggestion, or motivation to combine
the teachings of Keith with any reference that teaches one to use the base form of the
drug in solution. Finally, in addressing Mylan’s contentions of inequitable conduct, the
district court found that there was one statement in the declaration submitted by Gale
during the second reexamination proceeding that, “although literally true, had the
potential to mislead the patent examiner.” Id. at 59. However, the court held that it
“[could] not find that Gale acted with the requisite deceitful intent.” Id. at 60.
Mylan appeals these findings, and we have jurisdiction pursuant to
28 U.S.C. § 1295(a)(1).
II
Claim construction is an issue of law that we review de novo. Liquid Dynamics
Corp. v. Vaughan Co., 355 F.3d 1361, 1367 (Fed. Cir. 2004). Anticipation, on the other
hand, is a question of fact and after a bench trial is reviewed under the clearly
erroneous standard. Merck & Co. v. Teva Pharms. USA, Inc., 347 F.3d 1367, 1369
(Fed. Cir. 2003). Additionally, a district court’s finding of obviousness is reviewed de
novo, with any underlying factual findings reviewed for clear error. Winner Int’l Royalty
Corp. v. Wang, 202 F.3d 1340, 1348 (Fed. Cir. 2000). Finally, we review a district
4
Mylan did not appeal this finding of infringement.
04-1344 6
court’s conclusions on inequitable conduct for an abuse of discretion and its threshold
findings on materiality and intent for clear error. Brasseler U.S.A. v. Stryker Sales
Corp., 267 F.3d 1370, 1379 (Fed. Cir. 2001).
III
A
In determining the meaning of disputed claim language, a court looks first to the
intrinsic evidence of record, examining, in order, the claim language itself, the
specification, and the prosecution history. Interactive Gift Express, Inc. v. Compuserve,
Inc., 256 F.3d 1323, 1331 (Fed. Cir. 2001) (citing Vitronics Corp. v. Conceptronic, Inc.,
90 F.3d 1576, 1582 (Fed. Cir. 1996)).
The parties had agreed upon the construction of the term “skin permeable form”:
“fentanyl that is in a form that can pass through the skin.” However, in its claim
construction following trial, the district court modified this construction by adding the
phrase “excluding solutions of fentanyl citrate.”
Here, the term “skin permeable form” when referring to fentanyl base is not plain
on its face to one of ordinary skill in the art. As the district court explained, “the base
form of fentanyl has been generally described as the skin permeable form of the drug.”
As such, if “skin permeable form of fentanyl” simply means “the base form of fentanyl,”
the inclusion of the word “base” in the claims would be redundant. Additionally, “skin
permeable” is sometimes used by scientists to refer to flux, the rate at which a drug
passes through the skin, and sometimes used to refer to the permeability coefficient, the
relationship between flux and the concentration of the drug. Accordingly, the claim term
“skin permeable form” is not plain on its face. We, therefore, must look to the
04-1344 7
specification and prosecution history to see if they shed any light on what is meant by
the term “skin permeable form” in the ‘580 patent.
The specification states
We have discovered that fentanyl citrate, the form in which fentanyl is
presently administered, has such a low skin permeability that it is not at all
suitable for transdermal delivery even with the use of permeation
enhancers. Instead we have found that, in order to obtain the delivery
rates noted above, the drug should be incorporated in the transdermal
therapeutic system in the form of the base.
‘580 patent, col. 33, ll. 10-17. This clearly demonstrates to one of ordinary skill in the art
that fentanyl citrate (the acidic form of the drug) is not a skin permeable form of fentanyl
in the context of the invention of the ‘580 patent.
The prosecution history confirms that fentanyl citrate is not a skin permeable
form of fentanyl as used in the claims. When the Keith reference was before the
examiner during the second reexamination proceeding, Gale submitted a declaration
detailing the differences between the reference and the claimed invention. Gale
explained that Keith taught the production of a diffusion matrix containing fentanyl
citrate, which the inventors of the ‘580 patent had expressly disclaimed:
[In describing possible diffusion matrices, the Keith patent] teaches that an
“appropriate” amount of fentanyl, which is a basic substance, could be
either (1) an amount of fentanyl that would not cause the pH of the matrix
to increase above 7 or (2) any amount of fentanyl as long as the pH of the
matrix is adjusted to 6.5 to 7 with citric acid. Thus, without trying to
ascertain a specific quantity of fentanyl that would constitute an
“appropriate” amount, I believe it is clear that the disclosure of the Keith
patent requires that the fentanyl be present in the matrix at a pH no
greater than 7. . . . Because fentanyl has a pK of 8.3, the fentanyl present
in the Keith et al. matrix would exist virtually completely in the form of
fentanyl citrate. As a result, to the extent that the Keith patent could be
considered to disclose making a transdermal fentanyl delivery system by
including fentanyl in the diffusion matrices of the Keith patent, such a
system would be unsuitable for administering fentanyl at analgetically
effective rates. . . . The ‘580 patent at col. 3, lines 6-14 and col. 1, lines
04-1344 8
22-25 discloses that the only form of fentanyl that was then being used for
medical purposes, fentanyl citrate, is unsuitable for transdermal
administration because of its low transdermal flux. . . . Thus, in contrast to
our disclosure and claims in the ‘580 patent, the Keith patent suggests the
production of a diffusion matrix containing fentanyl citrate, which we
specifically stated in the ‘580 patent was unsuitable for transdermal
delivery, even with permeation enhancers.
Gale Declaration, ¶¶ 8-11 (emphasis added).
Both the prosecution history and the specification disclaimed fentanyl citrate
because it was unsuitable for transdermal administration and therefore not a “skin
permeable form” of fentanyl. For this reason, we agree with the district court’s claim
construction of “skin permeable form” as “fentanyl that is in a form that can pass through
the skin, excluding solutions of fentanyl citrate.”
Mylan and Alza argue this case as if the district court had construed the term
“skin permeable form” to mean a fentanyl solution with a pH higher than 7.5. However,
it did not. The court simply stated that the skin permeable form excluded fentanyl citrate
without restricting that term to any particular range of pH values.
All of Mylan’s arguments on claim construction are directed to a purported pH
level determined by the district court. However, as we just explained, the district court
placed no pH limitation on its construction of “skin permeable form.” Mylan contends
that the district court’s claim construction is contrary to the plain meaning of the term
“skin permeable form” and asserts that the proper construction of the term is “fentanyl
that is in a form that can pass through the skin,” which could include fentanyl citrate
04-1344 9
solutions.5 However, as demonstrated above, such a construction is contrary to the
‘580 patent’s specification and prosecution history’s clear disavowal of fentanyl citrate.
Finally, we are not persuaded by Mylan’s argument that the district court’s
construction is inconsistent with the specification. Mylan asserts that because Alza’s
own data shows adequate flux is obtainable from fentanyl citrate solutions, this
somehow disproves the discussion in the specification about the low skin permeability
of fentanyl citrate. Alza points out, however, that this argument assumes that “skin
permeability” in the specification refers to the flux, which is the rate at which a product
flows through the skin, and not to the relationship between that flux and concentration
(the “permeability coefficient”).6 The record supports Alza’s contention that the
discussion of skin permeability in the specification is not about the flux at which the
product flows through the skin, but rather the permeability coefficient. Mylan also
asserts that this claim construction excludes preferred embodiments disclosed in the
patent. Mylan cites no evidence to support its assertion and only speculates based on
the Keith matrix which was buffered. 7 Thus, we are unpersuaded by this argument.
B
5
This is based on the premise that regardless of whether a fentanyl solution
contains primarily fentanyl in the base form or primarily fentanyl in the acidic form, it is
the base form of the drug that will actually permeate the skin.
6
Flux describes the rate at which a drug will pass the skin, whereas
permeability coefficient describes that rate in proportion to concentration. (“[F]lux, which
is the amount that would go through the skin, . . . equals the permeability coefficient
times the concentration.” Trial Transcript, August 29, 2003, at 85.)
7
A buffered solution is one that resists a change in pH upon addition of a
small amount of acid or base. As such, when adding small amounts of fentanyl base to
a solution buffered to remain around pH 7.0, as in the Keith patent, the pH would not be
expected to change much, if at all. Such an addition would, however, likely have an
effect on an unbuffered solution, such as that taught in the ‘580 patent.
04-1344 10
The district court found that the Keith patent did not teach the claim limitation
“skin permeable form,” and therefore could not anticipate the claims of the ‘580 patent.
We agree.
As we have stated above, the term “skin permeable form” in the context of the
‘580 patent is fentanyl that is in a form that can pass through the skin, excluding
solutions of fentanyl citrate.
However, the specification of the ‘580 patent illustrates various solutions
considered to be fentanyl citrate. Specifically, in the specification the patentees
characterize the form in which fentanyl is “presently administered” as fentanyl citrate.
The specific solution referred to is Sublimaze®, a fentanyl citrate solution with a pH of 4
to 7.5. ‘580 patent, col. 1, ll. 19-23 (citing Physician’s Desk Reference 1027-29 (1984)).
As such, the specification identifies at least one pH range to explain fentanyl solutions
considered to be fentanyl citrate and therefore excluded from the invention.
Additionally, in the Gale declaration, the inventors expressly disclaimed the solutions
taught by the Keith reference, explaining that the fentanyl present in the Keith matrix
would exist virtually completely in the form of fentanyl citrate, because it would have a
pH of approximately 7, which was expressly stated as unsuitable for transdermal
delivery of fentanyl.
Because the Keith reference teaches adjusting solutions to a pH of 6.5-7.0, it
clearly teaches a fentanyl citrate solution that was expressly disclaimed by the ‘580
patent’s inventors. Accordingly, because the Keith reference did not disclose a “skin
permeable form” of fentanyl within the meaning of the ‘580 patent and that limitation
04-1344 11
was in each of the asserted claims, the Keith reference does not anticipate the ‘580
patent.8
C
The district court found that “Mylan had not shown a reason, suggestion or
motivation to combine the teachings of Keith, to use solutions of fentanyl citrate . . . with
any reference that teaches one to use the base form of the drug in solution.” Alza, slip
op. at 48. We agree. The Keith reference specifically teaches a solution that is
approximately 95% fentanyl citrate and only 5% fentanyl base. Indeed, the reference
teaches adjusting the solution’s pH value to levels that necessarily achieve such a
solution. Michaels taught that high solubility in water and oil is a desirable feature for a
transdermally delivered drug, therefore suggesting that fentanyl would not be a good
transdermal candidate due to its low solubility. As such, Michaels even teaches away
from using fentanyl transdermally. We agree with the district court’s analysis of the prior
art references of record and find that Mylan did not produce evidence of the
combinability of those references with the Keith patent to result in the claimed invention
of the ‘580 patent. Mylan’s arguments on appeal again rest on the premise that the
district court’s claim construction is incorrect. Those arguments are moot in view of our
affirmance of the district court’s claim construction.9
8
Whether other claim limitations are anticipated by the Keith patent was
also in dispute in this case. However, because we find that the skin permeable form
limitation was not met, we need not consider the other limitations. Additionally, Mylan’s
enablement arguments are moot in view of our determination that the Keith patent is not
an anticipatory reference.
9
Because Mylan has not made a prima facie case of obviousness, we need
not address the parties’ assertions regarding the district court’s discussion of secondary
considerations.
04-1344 12
D
Mylan’s final challenge on appeal is to the district court’s finding of no inequitable
conduct. In order to prove inequitable conduct, Mylan must provide clear and
convincing evidence of “affirmative misrepresentations of a material fact, failure to
disclose material information, or submission of false material information, coupled with
an intent to deceive.” Purdue Pharma L.P. v. Boehringer Ingelheim GmbH, 237 F.3d
1359, 1366 (Fed. Cir. 2001) (quoting Baxter Int’l, Inc. v. McGaw, Inc., 149 F.3d 1321,
1327 (Fed. Cir. 1998)).
Mylan asserted that Gale engaged in inequitable conduct before the United
States Patent and Trademark Office. Specifically, Mylan pointed to seven statements in
Gale’s declaration during the second reexamination proceeding which it asserted were
false and misleading. The district court found that only one of these statements had the
potential to be misleading but then examined the totality of the circumstances and found
that Gale lacked the requisite intent to deceive in order to find inequitable conduct.
Mylan appeals only as to this statement which recites:
Skin permeability studies conducted by Alza researchers provided the
basis for the comments in the ‘580 patent (col. 3, lines 10-14) regarding
the low skin permeability of fentanyl citrate and its unsuitability for
transdermal administration. Data generated in these studies supported
the conclusion that the skin permeability of fentanyl citrate was too low to
permit analgetically effective transdermal fentanyl administration rates to
be obtained from reasonably sized transdermal systems.
Dale Decl. at ¶ 12 (emphasis added).
The district court found that the statement was literally true, because the studies
did support the researcher’s conclusions that they should proceed with a base form of
fentanyl because a citrate form would not meet their goals of maximum flux with minimal
04-1344 13
total drug. The court went on to say, however, that it had the potential to mislead the
examiner, because it was technically possible to use the Keith patent to create a
fentanyl transdermal system (albeit one that “might not have been pretty,” Alza, slip op.
at 58). On the question of intent, the court held “in light of all the circumstances, the
Court cannot find that Gale acted with the requisite deceitful intent when he failed to
point out that the data he submitted to the patent examiner included values that would
suggest that one could also achieve an adequate flux in a transdermal system that used
a sufficiently large amount of fentanyl citrate.” Id. at 60. We discern no clear error or
abuse of discretion in the district court’s findings and conclusions. Nothing Mylan
argues persuades us otherwise. Indeed, as the court stated, “[i]n context, the
statements in Gale’s declaration were true. No information was omitted. No information
was affirmatively misstated.” Id. Gale’s declaration simply focused on the key
distinctions between his patent and the Keith patent -- that Keith taught the use of a
neutral or slightly acidic solution of fentanyl, which made it an unsuitable system for the
administration of fentanyl in Gale’s opinion, as stated in the ‘580 patent. Additionally,
the district court had the benefit of observing Gale’s testimony on direct, as well as
cross-examination, and was able to question Gale himself prior to making a
determination as to Gale’s credibility. On the record before us we will not overturn the
trial court’s decision.
IV
We affirm the district court’s construction of the claim limitation “skin permeable
form” and its determinations that the ‘580 patent was neither anticipated nor obvious by
04-1344 14
the Keith patent. Additionally, we affirm the district court’s holding that the ‘580 patent
was not unenforceable due to inequitable conduct.
AFFIRMED
04-1344 15
United States Court of Appeals for the Federal Circuit
04-1344
ALZA CORPORATION
and JANSSEN PHARMACEUTICA, INC.,
Plaintiffs-Appellees,
v.
MYLAN LABORATORIES INC.,
MYLAN TECHNOLOGIES INC., and MYLAN PHARMACEUTICALS INC.,
Defendants-Appellants.
DYK, Circuit Judge, concurring-in-part and dissenting-in-part.
I agree with the majority that the patentee effectively disclaimed coverage of the
Keith patent in the specification of the ’580 patent, and that the Keith patent does not
anticipate. However, I write separately because I cannot agree with the majority’s
affirmance of the district court’s finding of no inequitable conduct.
I
Claim 59 as it depends from claim 11 includes the claim language at issue and
states:
A process for inducing and maintaining analgesia in a human being by the
transdermal administration of [fentanyl base] which comprises
transdermally administering to said human being through an area of intact
skin,
a skin permeable form of said [fentanyl base] at an analgetically effective
rate and continuing the administration of said [fentanyl base] to said
human being at said rate for an extended period of time at least sufficient
to induce analgesia
wherein said extended period of time is in the range of [at least about 3
days] to seven days.
’580 patent (emphasis added). At issue is whether the prior art Keith patent discloses
the “skin permeable form” limitation. The Keith patent discloses a transdermal patch
using a solution of fentanyl citrate. While the fentanyl citrate itself is not skin permeable,
such a fentanyl citrate solution also includes some amount of fentanyl base, which is
skin permeable. The patentee’s contention is that the pH of the Keith solution, which is
directly related to the proportion of base and citrate in the solution, is not covered by the
patent.
Conspicuously absent from the claims of the patent is any sort of pH limitation.
The majority nonetheless finds that there is such a limitation in the patent. First, the
majority, like the district court, construes the disputed limitation “skin permeable form”
as meaning “fentanyl that is in a form that can pass through the skin, excluding
solutions of fentanyl citrate.” Ante at 9. The claim language itself does not exclude
“solutions of fentanyl citrate.” The majority gets to the exclusion of “solutions of fentanyl
citrate” by finding a disclaimer in the specification, which states:
We have discovered that fentanyl citrate, the form in which fentanyl is
presently administered, has such a low skin permeability that it is not at all
suitable for transdermal delivery even with the use of permeation
enhancers. Instead we have found that, in order to obtain the delivery
rates noted above, the drug should be incorporated in the transdermal
therapeutic system in the form of the base.
’580 patent, col. 3, ll. 10-17 (emphasis added). The majority concludes that fentanyl
citrate was at the time administered by intravenous solution or infusion solution. The
question then becomes: what at the time was considered to be a solution of “fentanyl
citrate?” The majority determines that such solutions are appropriately defined by their
04-1344 2
pH. The patent contains a reference to Sublimaze®, the FDA-approved form of fentanyl
citrate, stating that fentanyl’s “use as approved by the FDA in the United States is
described in the 1984 Physician’s Desk Reference, pages 1027 through 1029 with
reference to the drug SUBLIMAZE® manufactured by McNeil Lab for Janssen
Pharmaceutica, Inc.” Id. at col. 1, ll. 18-22. The referenced Physician’s Desk
Reference described Sublimaze® as “(fentanyl) as the citrate” and described the use of
“[s]odium hydroxide for adjustment of pH to 4.0-7.5.” (J.A. at 7381.) The majority
concludes that the then-presently-administered form of fentanyl citrate thus had a pH of
4.0 to 7.5. A pH within or below that range is thus disclaimed. Since the solution
disclosed in Keith had a pH of 6.5 to 7.0, Keith does not anticipate.
This analysis seems to me to be correct and to lead to a finding of no
anticipation. I am troubled, however, by the majority’s reliance on the admittedly
misleading Gale declaration to support this result. Indeed, I think that the Gale
declaration raises substantial questions of inequitable conduct.
II
The declaration of Gale, one of the inventors, was submitted by the patentee
during reexamination to support patentability over the newly disclosed Keith reference.
It stated, in pertinent part:
9. Because fentanyl has a pK of 8.3 [sic], the fentanyl present in
the Keith et al. matrix would exist virtually completely in the form of
fentanyl citrate. As a result, to the extent that the Keith patent could be
considered to disclose making a transdermal fentanyl delivery system by
including fentanyl in the diffusion matrices of the Keith patent, such a
system would be unsuitable for administering fentanyl at analgetically
effective rates.
10. . . . The ’580 patent at col. 3, lines 6-14 and col. 1, lines 22-25,
discloses that the only form of fentanyl that was then being used for
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medical purposes, fentanyl citrate, is unsuitable for transdermal
administration because of its low transdermal flux. . . .
11. Thus, in contrast to our disclosure and claims in the ’580
patent, the Keith patent suggests the production of a diffusion matrix
containing fentanyl citrate, which we specifically stated in the ’580 patent
was unsuitable for transdermal delivery, even with permeation enhancers.
Gale Declaration ¶¶ 9-11 (emphases added). The declaration went on to explain the
basis for Gale’s belief that a fentanyl citrate system is unsuitable:
12. Skin permeability studies conducted by ALZA researchers
provided the basis for comments in the ’580 patent (col. 3, lines 10-14)
regarding the low skin permeability of fentanyl citrate and its unsuitability
for transdermal administration. Data generated in these studies supported
the conclusion that the skin permeability of fentanyl citrate was too low to
permit analgetically effective transdermal fentanyl administration rates to
be obtained from reasonably sized transdermal systems. Copies of
laboratory notebook entries documenting these studies are attached as
Exhibit 2.
Gale Declaration ¶ 12 (emphasis added). Focusing on the underscored portion of
paragraph 12, the district court found that “[t]he statement, although literally true, had
the potential to mislead the patent examiner.” Alza Corp. v. Mylan Labs., No. 2:02-cv-
20, 2:02-cv-213, slip op. at 59 (D. Vt. Mar. 25, 2004) There would seem to be no basis
for finding the statement “literally true.” The data in the studies showed that solutions
with a pH of 6.5 to 7.0 would work. The district court specifically credited Gale’s trial
testimony that the skin permeability of fentanyl at the pHs taught by Keith would in fact
“‘permit analgetically effective transdermal fentanyl administration to be obtained from
reasonably-sized transdermal systems.’” Id. at 58. The district court concluded that “[a]
Keith fentanyl transdermal system might not have been pretty, it might not have been
marketable, it might have contained massive amounts of residual drug, but it could have
gotten an analgesic dose of fentanyl across an area of skin.” Id. at 58-59.
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The majority, agreeing with the district court, suggests that the district court found
the statement to be “literally true, because the studies did support the researcher’s
conclusions that they should proceed with a base form of fentanyl because a citrate
form would not meet their goals of maximum flux with minimal total drug.” Ante at 13-
14. But the statement in the Gale declaration has nothing to do with the patentee’s
concerns with the amount of drug (“minimal total drug”) being used. It relates only to
the unworkability of the Keith disclosure.
III
The district court also found that Gale’s misleading statement “was material; the
patent examiner based his decision to issue the reexamination certificate on the fact
that ‘the citrate form of fentanyl has a very low level of transdermal permeability.’” Alza,
slip op. at 59. However, the district court, having found that the patentee made a
materially misleading statement during reexamination, concluded that there had been
no showing of intent, a finding which the majority sustains. That conclusion in my view
rests on an entirely erroneous factual predicate—that the patentee’s statement was
“true.” Id. Indeed, the district court explicitly found “that as of 1998 when his
declaration was submitted, [Gale] knew that the data also showed that fentanyl, at the
pHs taught by the Keith patent, would in fact have high enough skin permeability” to
make an analgetically effective, reasonably-sized transdermal system. Id. at 58. I
conclude that a remand is necessary to reconsider the issue of intent, particularly since
the district court appears to have found that Gale himself knew that the statement was
false, and some of the district court’s other grounds for finding a lack of intent are
problematic at best.
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The district court found lack of intent because the patentee requested
reexamination based on the Keith patent; the question is not whether the patentee has
bad intent before the reexamination, but whether it had bad intent during the
reexamination—in concealing the true nature of the Keith disclosure. The district court’s
reliance on the disclosure of the data underlying the Gale declaration (the Lee data) is
also questionable. We have held that a patentee knowing of a misrepresentation made
during prosecution cannot cure that misrepresentation by merely supplying “the
examiner with accurate facts without calling his attention to the untrue or misleading
assertions sought to be overcome.” Rohm & Haas Co. v. Crystal Chem. Co., 722 F.2d
1556, 1572 (Fed. Cir. 1983). Here, the patentee made an untrue assertion and
simultaneously submitted accurate facts not in accord with that assertion. Such a
submission of accurate facts does not cure a false statement.
Therefore, contrary to the majority, I would set aside the district court’s decision
and remand for further factual findings on the intent component of inequitable conduct.
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