United States Court of Appeals for the Federal Circuit
06-1019
ALZA CORPORATION,
Plaintiff-Appellant,
v.
MYLAN LABORATORIES, INC.
and MYLAN PHARMACEUTICALS, INC.,
Defendants-Appellees.
Gregory L. Diskant, Patterson, Belknap, Webb & Tyler LLP, of New York, New
York, argued for plantiff-appellant. With him on the brief were Jeffrey I.D. Lewis, and
Richard J. McCormick.
John B. Wyss, Wiley, Rein, & Fielding LLP, of Washington, DC, argued for
defendants-appellees. With him on the brief were James H. Wallace, Jr., Kevin P.
Anderson, and Robert J. Scheffel.
Appealed from: United States District Court for the Northern District of West Virginia
Chief Judge Irene M. Keeley
United States Court of Appeals for the Federal Circuit
06-1019
ALZA CORPORATION
Plaintiff-Appellant,
v.
MYLAN LABORATORIES, INC.
and MYLAN PHARMCEUTICALS, INC.
Defendants-Appellees.
________________________
DECIDED: September 6, 2006
________________________
Before GAJARSA, Circuit Judge, CLEVENGER, Senior Circuit Judge, and PROST,
Circuit Judge.
GAJARSA, Circuit Judge.
Alza Corp. (“Alza”) appeals from the district court’s judgment, after a bench trial,
of noninfringement and invalidity of claims 1-3, 11, 13 and 14 of U.S. Patent No.
6,124,3551 (“the ’355 patent”) in favor of Mylan Laboratories, Inc. and Mylan
Pharmaceuticals, Inc. (collectively, “Mylan”). Alza Corp. v. Mylan Labs., Inc., 388 F.
Supp. 2d 717 (N.D.W. Va. 2005) (“Alza II”). The infringement arose from Mylan’s filing
of two Abbreviated New Drug Applications (“ANDAs”) for a generic version of the once-
a-day extended release formulation of the anti-incontinence drug oxybutynin, id. at 720,
which Alza has been marketing as Ditropan XL®. Id. at 738. This court has jurisdiction
1
The ’355 patent issued to Guittard et al. and was assigned to Alza.
pursuant to 28 U.S.C. § 1295(a)(1). For the reasons stated below, we affirm the district
court’s judgment of noninfringement and invalidity.
I. BACKGROUND
This litigation arose from Mylan’s and Impax’s filings of ANDAs for once-daily,
controlled-release oxybutynin formulations. Oxybutynin is a drug used to treat urinary
incontinence. Once-a-day dosing provides the usual benefits of convenience, steady-
dosing, and in addition, possibly reduced absorption of a metabolite that leads to side-
effects. Claim 2 of the ’355 patent is representative.
2. A sustained-release oxybutynin formulation for oral
administration to a patient in need of treatment for urge incontinence
comprising a therapeutic dose of an oxybutynin selected from the group
consisting of oxybutynin and its pharmaceutically acceptable salt that
delivers from 0 to 1 mg in 0 to 4 hours, from 1 mg to 2.5 mg in 0 to 8
hours, from 2.75 to 4.25 mg in 0 to 14 hours, and 3.75 mg to 5 mg in 0 to
24 hours for treating urge incontinence in the patient.
col. 17, ll. 31-38 (emphasis added).
The district court construed the ’355 patent claims in its Markman Order, reported
at Alza Corp. v. Mylan Labs., Inc., 349 F. Supp. 2d 1002 (N.D.W. Va. 2004) (“Alza I”).
The court construed the word “deliver” to refer to the rate of in vivo release in the
gastrointestinal (“GI”) tract. See id. at 1019.
Alza did not present direct evidence that Mylan’s ANDA formulation released
drug in the GI tract at the rates claimed by the ’355 patent. However, it did offer two
other types of evidence: 1) the rate at which the generic product released oxybutynin in
an in vitro dissolution apparatus, and 2) the rate at which the ANDA product resulted in
the accumulation of oxybutynin in the bloodstream.
06-1019 2
The district court found that Alza had failed to meet its burden of proof on
infringement. The district court also found the asserted claims of the ’355 patent to be
invalid as both anticipated and obvious in light of the prior art. For the reasons stated
below, we affirm the invalidity holding on obviousness grounds, and consequently, we
do not need to reach Alza’s arguments regarding anticipation. We also affirm the
holding of noninfringement.
II. DISCUSSION
A. Standard of review
Infringement is a question of fact that, after a bench trial, we review for clear
error. See, e.g., Ferguson Beauregard/Logic Controls, Div. of Dover Res., Inc. v. Mega
Sys., LLC, 350 F.3d 1327, 1338 (Fed. Cir. 2003). Under the clear error standard, a
reversal is permitted only when this court is left with a definite and firm conviction that
the district court was in error. Medichem, S.A. v. Rolabo, S.L., 437 F.3d 1157, 1164
(Fed. Cir. 2006).
As for obviousness, a claimed invention is unpatentable if the differences
between it 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.” 35 U.S.C. § 103(a) (2000); In re Kahn, 441 F.3d 977, 985 (Fed. Cir. 2006) (citing
Graham v. John Deere Co., 383 U.S. 1, 13-14, (1966)). Obviousness is a question of
law, reviewed de novo, based upon underlying factual questions which are reviewed for
clear error following a bench trial. Ruiz v. A.B. Chance Co., 357 F.3d 1270, 1275 (Fed.
Cir. 2004). These “underlying factual inquiries includ[e]: (1) the scope and content of
the prior art; (2) the level of ordinary skill in the prior art; (3) the differences between the
06-1019 3
claimed invention and the prior art; and (4) objective evidence of nonobviousness.” In
re Dembiczak, 175 F.3d 994, 998 (Fed. Cir. 1999). Similarly, “[t]he presence or
absence of a motivation to combine references in an obviousness determination is a
pure question of fact,” In re Gartside, 203 F.3d 1305, 1316 (Fed. Cir. 2000); accord
Winner Int’l Royalty Corp. v. Wang, 202 F.3d 1340, 1348 (Fed. Cir. 2000), as is the
presence or absence of a “reasonable expectation of success” from making such a
combination, Medichem, S.A. v. Rolabo, S.L., 437 F.3d 1157, 1165 (Fed. Cir. 2006).
Because “a patent retains its statutory presumption of validity, see 35 U.S.C. § 282, . . .
the movant retains the burden to show the invalidity of the claims by clear and
convincing evidence as to underlying facts.” McGinley v. Franklin Sports, Inc., 262 F.3d
1339, 1349 (Fed. Cir. 2001) (internal quotations omitted).
In Graham, the Court held that that the obviousness analysis begins with several
basic factual inquiries: “[(1)] the scope and content of the prior art are to be determined;
[(2)] differences between the prior art and the claims at issue are to be ascertained; and
[(3)] the level of ordinary skill in the pertinent art resolved.” 383 U.S. at 17. After
ascertaining these facts, the Court held that the obviousness vel non of the invention is
then determined “against th[e] background” of the Graham factors. Id. at 17-18
(emphasis added). Clearly, the Court recognized the importance of guarding against
hindsight, as is evident in its discussion of the role of secondary considerations as
“serv[ing] to guard against slipping into use of hindsight and to resist the temptation to
read into the prior art the teachings of the invention in issue.” Id. at 36.
The Court of Appeals for the Federal Circuit’s and its predecessor’s “motivation
to combine” requirement likewise prevents statutorily proscribed hindsight reasoning
06-1019 4
when determining the obviousness of an invention. Kahn, 441 F.3d at 986 (“[T]he
‘motivation-suggesting-teaching’ requirement protects against the entry of hindsight into
the obviousness analysis.”); In re Fridolph, 30 CCPA 939, 942 (1943) (“[I]n considering
more than one reference, the question always is: does such art suggest doing the thing
the [inventor] did.”). According to the “motivation-suggesting-teaching” test, a court
must ask “whether a person of ordinary skill in the art, possessed with the
understandings and knowledge reflected in the prior art, and motivated by the general
problem facing the inventor, would have been led to make the combination recited in the
claims.” Kahn, 441 F.3d at 988 (citing Cross Med. Prods., Inc., v. Medtronic Sofamor
Danek, Inc., 424 F.3d 1293, 1321-24 (Fed. Cir. 2005)).
This requirement has been developed consistent with the Supreme Court’s
obviousness jurisprudence as expressed in Graham and the text of the obviousness
statute that directs us to conduct the obviousness inquiry “at the time the invention was
made” 35 U.S.C. § 103. As we explained in Kahn,
The motivation-suggestion-teaching test picks up where the analogous art
test leaves off and informs the Graham analysis. To reach a non-
hindsight driven conclusion as to whether a person having ordinary skill in
the art at the time of the invention would have viewed the subject matter
as a whole to have been obvious in view of multiple references, the Board
must provide some rationale, articulation, or reasoned basis to explain
why the conclusion of obviousness is correct. The requirement of such an
explanation is consistent with governing obviousness law . . . .
441 F.3d at 987. We further explained that the “motivation to combine” requirement
“[e]ntails consideration of both the ‘scope and content of the prior art’ and ‘level of
ordinary skill in the pertinent art’ aspects of the Graham test.” Id. at 986.
At its core, our anti-hindsight jurisprudence is a test that rests on the
unremarkable premise that legal determinations of obviousness, as with such
06-1019 5
determinations generally, should be based on evidence rather than on mere speculation
or conjecture. Our court’s analysis in Kahn bears repeating:
A suggestion, teaching, or motivation to combine the relevant prior
art teachings does not have to be found explicitly in the prior art, as “the
teaching, motivation, or suggestion may be implicit from the prior art as a
whole, rather than expressly stated in the references. . . . The test for an
implicit showing is what the combined teachings, knowledge of one of
ordinary skill in the art, and the nature of the problem to be solved as a
whole would have suggested to those of ordinary skill in the art.”
However, rejections on obviousness grounds cannot be sustained by
mere conclusory statements; instead, there must be some articulated
reasoning with some rational underpinning to support the legal conclusion
of obviousness. This requirement is as much rooted in the Administrative
Procedure Act [for our review of Board determinations], which ensures
due process and non-arbitrary decisionmaking, as it is in § 103.
441 F.3d at 987-88 (quoting In re Kotzab, 217 F.3d 1365, 1370 (Fed. Cir. 2000))
(citations omitted) (emphases added)). There is flexibility in our obviousness
jurisprudence because a motivation may be found implicitly in the prior art. We do not
have a rigid test that requires an actual teaching to combine before concluding that one
of ordinary skill in the art would know to combine references. This approach, moreover,
does not exist merely in theory but in practice, as well. Our recent decisions in Kahn
and in Cross Medical Products amply illustrate the current state of this court’s views.
See Kahn, 441 F.3d at 988 (affirming the PTO’s obviousness finding, explaining that a
motivation to combine may be found in implicit factors, such as the “knowledge of one of
ordinary skill in the art, and [what] the nature of the problem to be solved as a whole
would have suggested to those of ordinary skill in the art”); Cross Med. Prods., 424 F.3d
at 1322 (reversing a district court ruling of nonobviousness and explaining that “the
motivation to combine need not be found in prior art references, but equally can be
06-1019 6
found in the knowledge generally available to one of ordinary skill in the art” such as
knowledge of a problem to be solved).
In conclusion, our approach has permitted us to continue to address an issue of
law not readily amenable to bright-line rules, as we recall and are guided by the wisdom
of the Supreme Court in striving for a “practical test of patentability.” Graham, 383 U.S.
at 17.
B. Description of the technology
The patent at issue is directed generally to an extended release form of
oxybutynin. Because the subject matter of the patent falls roughly under the rubric of
pharmacology, we give a brief orientation to the field, based upon the record. In
general, when a drug is swallowed, it is (1) dissolved in the gastrointestinal (“GI”) tract;
(2) absorbed from the GI tract into the bloodstream; (3) distributed from the blood into
body tissues; and (4) metabolized and eliminated from the bloodstream. The GI tract
includes the stomach, small intestine and the colon, and orally administered drugs pass
through these portions of the GI tract in turn. Drugs may be administered in different
dosage forms,2 which may include not only the drug itself but also ingredients intended
to modulate the rate of release of the drug from the dosage form.
Dosage forms may be described as immediate-release, e.g., such as where the
drug is quickly released in the stomach, or as sustained/extended-release, where the
drug is slowly released as the formulation traverses the GI tract. The rate of absorption
of a drug from the GI tract into the bloodstream may change as it passes through the GI
2
Here we are discussing oral dosage forms, specifically.
06-1019 7
tract. The rate of absorption for a dissolved drug in a given portion of the GI tract also
varies from drug to drug.
After roughly 8-12 hours a typical dosage form will reach the colon. If,
hypothetically, a particular drug is simply not absorbed from the colon into the
bloodstream, then it may make little sense to develop an extended-release dosage form
that is capable of “withholding” the release of some fraction of that drug until it reaches
the colon. In other words, under these hypothetical conditions, there may be little
motivation to design an oral dosage form capable of releasing drug more slowly than
over an approximately 8-12 hour time course, because such drug would be released in
the colon, where it is (hypothetically) not absorbed.
The ’355 patent claims an extended release oxybutynin formulation. Alza argues
that one of ordinary skill in the art would not have believed that oxybutynin could be
absorbed in the colon. Absent such absorption, Alza contends that one of ordinary skill
in the art lacked the motivation to make the claimed extended release formulation, and
that the district court therefore erred in holding that the asserted claims are invalid as
obvious over the prior art. For the reasons set forth below, Alza’s arguments fail.
C. Invalidity
The district court based its invalidity holding both on anticipation and
obviousness grounds. Because we affirm its holding based on obviousness, we do not
need to address the parties’ anticipation arguments.
In finding the asserted claims of the ’355 patent to be obvious, the district court
considered, inter alia, the following prior art: U.S Patent Nos. 5,399,359 (“the Baichwal
patent”); 5,082,688 (“the Wong patent”); and 5,330,766 (“the Morella patent”).
06-1019 8
The Morella patent discloses a “sustained-release pharmaceutical composition
including an active ingredient of high solubility in water . . . .” According to the
specification, highly soluble drugs had posed special challenges for the development of
sustained release forms, which the inventors had set out to solve. “Sustained-release”
is defined as release of the active ingredient at a rate that maintains therapeutic, non-
toxic blood levels “over an extended period of time e.g. 10 to 24 hours or greater.”
Highly water soluble drugs were considered to be those having an aqueous solubility of
at least roughly 1 part in 30. The commercially available hydrochloride salt of
oxybutynin is freely soluble at neutral pH. The patent uses morphine as an example of
an active ingredient that can be used in its compositions. Figure 5 demonstrates that
one such composition is capable of dispensing morphine at what appears to be an
approximately steady rate over the course of 24 hours. Claim 2 of the patent claims
“genitourinary smooth muscle relaxants” as one of several types of active ingredients to
use in the dosage form identified in claim 1. The specification also identifies oxybutynin
as a highly water soluble genitourinary smooth muscle relaxant. Morella also teaches
that “the dissolution rate of the soluble drug at various pH’s can be modified at will.”
The Baichwal patent teaches a 24 hour extended release oxybutynin formulation.
These formulations use an enteric-coated polymer matrix similar to Mylan’s accused
product. It also teaches methods of modifying the dosage forms to slow the release
rates. During prosecution of the ’355 patent, the inventor overcame an anticipation
rejection by arguing that his invention had a release rate slower than those of the
06-1019 9
dissolution data presented in Baichwal.3 The examiner agreed and withdrew his
rejection.
The Wong patent teaches a bilayer osmotic pump dosage form (“the OROS
system”) used in the preferred embodiment of the ’355 patent. Wong teaches that this
system can be used to deliver any drug over a 24 hour period, and Figure 11 of the
patent discloses release rates falling within the claimed release rates of the ’355 patent.
The Wong patent does not specifically teach using oxybutynin with the claimed release
technology, but it does teach using several categories of drugs of which oxybutynin is a
member, such as anti-cholinergics, analgesis, muscle relaxants and urinary tract drugs.
In analyzing the obviousness issue, the district court first identified the level of
ordinary skill in the art, finding the person of ordinary skill to have either an advanced
degree in pharmacy, biology, chemistry or chemical engineering and at least two years
of experience with controlled-release technology; or a bachelor’s degree in one (or
more) of those fields plus five years of experience with such technology. Second, the
court examined whether there was a motivation “in the prior art or elsewhere that would
have led one of the ordinary skill in the art to combine references,” Alza II, 388 F. Supp.
2d at 737 (citing Ruiz, 234 F.3d at 664 (internal quotations omitted)), and with a
“reasonable expectation of success,” id. (citing In re O’Farrell, 853 F.2d 894, 904 (Fed.
Cir. 1988)). Third, the district court examined secondary considerations of
nonobviousness. After making these factual determinations, it concluded that Mylan
had established a strong prima facie case of obviousness, which Alza had failed to
rebut through secondary considerations. The court concluded that Mylan had
3
Tables 15 and 18 of Baichwal, for example, disclose in vitro dissolution
rates in which roughly half of the drug is dissolved by four hours.
06-1019 10
demonstrated Alza’s patent to be invalid for obviousness by clear and convincing
evidence.4 We agree.
While we have carefully considered all of the parties’ arguments, we discuss
principally the dispute over satisfaction of one predicate to a finding of obviousness: that
a person of ordinary skill in the art would have had a “motivation to combine” the prior
art to achieve the claimed invention and that she would have had a “reasonable
expectation of success” in doing so. As an initial matter, we agree with the district court
that “on a purely mechanical level, a person of ordinary skill in the art would have a
reasonable expectation of success of manufacturing a 24 hour controlled-release
oxybutynin formulation . . . . once motivated to use oxybutynin.” Id. at 739. For
example, Wong teaches a rate adjustable extended release dosing technology and
release rates falling within the claimed parameters. Baichwal and Wong likewise teach
ways of achieving slow rates of release, with Baichwal actually teaching extended-
release oxybutynin, although arguably not as slowly as is claimed in the ’355 patent.5
Indeed, Alza’s principal argument is that no one of ordinary skill in the art would
have been motivated to adapt the Morella, Baichwal and Wong technology to
oxybutynin in the first place, because a person of ordinary skill in the art would have had
no reason to expect that such an extended release oxybutynin formulation would have
therapeutic value. The issues, as explained above, reduce essentially to whether one
of ordinary skill in the art in 1995 would have had a reasonable expectation that
4
Having reviewed Alza’s sundry contentions that the district court made
findings inconsistent with the appropriate burdens of proof for infringement and
invalidity, we find them to be without merit.
5
The patent examiner initially rejected the ‘355 patent as anticipated by
Baichwal, but subsequently allowed its issuance.
06-1019 11
oxybutynin would be colonically absorbed and therefore would have been motivated to
produce the claimed extended release formulation.
The district court concluded that “the weight of the evidence clearly and
convincingly establishes that a person of ordinary skill in the art in 1995 would
reasonably expect oxybutynin to absorb in the colon . . . [and] have a reasonable
expectation of success of producing a 24 hour oxybuytnin formulation meeting the
claims of the ’355 patent.”6 Alza II, 388 F. Supp. 2d at 740. Alza argues, however, that
the district court erred because “[t]here was no prior art evidence supporting this
finding.” According to Alza, “[t]here was no contemporaneous documentation
supporting the view that any one factor—lipophilicity or anything else—existed to
identify successful candidates for once-a-day delivery.” It also argues that two prior art
references “decisively undercut” the opinion of Mylan's expert, Dr. Amidon, which the
district court cited in support of its conclusion. See Alza II, 388 F. Supp. 2d at 739-740.
As an initial matter, it is essential to recognize that, as we have explained above,
under our non-rigid “motivation-suggesting-teaching” test, a suggestion to combine
need not be found in the prior art. See Cross Med. Prods., 424 F.3d at 1322 (“[T]he
motivation to combine need not be found in prior art references, but equally can be
found in the knowledge generally available to one of ordinary skill in the art . . . .”).
6
The ’355 patent issued on September 26, 2000 and claimed priority as far
back as 1995. See ’355 patent, col. 1, ll. 5-12. The district court treated 1995 as the
relevant date for the obviousness inquiry, see Alza II, 388 F. Supp. 2d at 740, as do
both parties in their obviousness arguments before this court. See, e.g., Alza Reply Br.
at 13 (stating that “[t]he dispositive obviousness issue was whether colonic absorption
of oxybutynin was reasonably expected in 1995”) (emphasis added); Mylan Br. at 6 &
n.2 (referring to evidence establishing “the clear expectation of one skilled in the art in
1995” and noting in a footnote that 1995 is “[t]he earliest possible date to which Alza
asserts priority.”) (emphasis added).
06-1019 12
Accordingly, where the testimony of an expert witness is relevant to determining the
knowledge that a person of ordinary skill in the art would have possessed at a given
time, this is one kind of evidence that is pertinent to our evaluation of a prima facie case
of obviousness. We now turn to consider whether the relevant evidence, including the
expert testimony and the prior art, when viewed as a whole supports the findings of the
district court. We conclude that the findings of the district court were not clearly
erroneous.
Mylan’s expert, Dr. Amidon, testified that based on its lipophilicity, he would
“expect oxybutynin to be a highly permeable” compound that is “rapidly absorbed” along
the length of the GI tract, including the colon. Later, when challenged about the
predictive value of lipophilicity, Dr. Amidon explained, “I would say there were some
unknowns, but again lipophilic drugs would be well absorbed. That would be—that was
the general understanding at the time.”
Although Alza argues that two prior art references “decisively undercut Dr.
Amidon’s hindsight opinion,” these references are in fact not inconsistent with the
general principle that the extent of a drug’s colonic absorption correlates with its
lipophilicity. Indeed, the first reference, a 1990 publication in the Journal of
Pharmaceutical Sciences, states that “[i]n general, the more lipophilic drugs were
transported rapidly.” P. Artursson, Epithelial Transport of Drugs in Cell Culture. I: A
Model for Studying the Passive Diffusion of Drugs over Intestinal Absorptive (Caco-2)
Cells. 79 J. Pharm. Sci. 476, 481 (1990). Alza, however, cites this reference narrowly
for its observation that a highly lipophilic analog of a particular drug did not follow the
general rule that lipophilic drugs were transported more quickly. Id. Granted, the
06-1019 13
authors admit that “[t]he reason for this [deviation] is currently unknown,” and they
postulate that it may be related to a physicochemical factor other than lipophilicity,
namely steric hindrance.7 Id. But the mere fact that the colonic absorption rate of a
drug may be predicted most precisely by using “many factors,” rather than “lipophilicity”
alone, does not negate the general predictive utility of lipophilicity in estimating the
extent of colonic absorption.
The second prior art reference cited by Alza, Absorption of Polar Drugs Following
Caecal Instillation in Healthy Volunteers, is similarly unavailing to it. Riley, et al., 6
Aliment. Pharmacol. Ther. 701, 705 (1992). Again, this reference teaches that while the
correlation is not perfect, lipophilicity tended to suggest colonic absorption, stating that
“[t]he relationship between the physical characteristics of a drug and its colonic
absorption is not yet clear but studies in the rat suggest that lipophilic drugs are well
absorbed along the length of the gastrointestinal tract, whereas hydrophobic polar drugs
are absorbed much less from the colon than from the small intestine.” Id. (emphasis
added).
Far from teaching away or detracting from the weight of Dr. Amidon’s testimony,
these prior art references, taken as a whole, are entirely consistent with the finding that
in 1995 a person of ordinary skill in the art would have expected a general, albeit
imperfect, correlation between a drug’s lipophilicity and its colonic absorptivity.
Accordingly, we cannot perceive clear error in the district court’s factual findings that
while colonic absorption was not guaranteed, the evidence, viewed as a whole, is clear
7
Dr. Chancellor, Alza’s expert, likewise characterized colonic absorption as
having been understood as being dependent on several physicochemical and
physiological variables, of which lipophilicity was one.
06-1019 14
and convincing that a person of ordinary skill in the art would nonetheless have
perceived a reasonable likelihood of success and that she would have been motivated
to combine prior art references to make the claimed invention.
Likewise, we find no error in the district court’s consideration of secondary indicia
of obviousness. We therefore affirm its legal conclusion of obviousness, finding the
district court to have correctly held that Mylan met its burden of overcoming the
presumption of validity that attaches to an issued patent.
D. Infringement
The ’355 patent specifically describes the rate of oxybutynin release from its
“extended release” formulations, requiring that the time-course of in vivo oxybutynin
release falls within certain boundaries. That is, at certain times, the cumulative amount
of dissolved (released) drug must fall within certain ranges. To prove infringement, Alza
bore the burden of proving, inter alia, that Mylan’s accused generic formulation
exhibited an in vivo release profile falling within the claimed ranges at the relevant
times.
At trial, Alza presented no direct evidence of how quickly the accused product
dissolved in vivo. Alza II, at 722. However, it did offer two kinds of indirect evidence as
measures of the rate of in vivo release. Id. First, it presented evidence of the blood
plasma concentration versus time profiles for both the accused ANDA formulation and
Ditropan, an embodiment of the ’355 patent. Second, it presented evidence of the rate
of release not in the GI tract but in pieces of laboratory apparatus under certain
experimental conditions, so-called in vitro dissolution. The critical deficiency in the
evidence presented by Alza was not that it was “indirect” rather than “direct,” but rather
06-1019 15
that it failed to credibly link these pieces of evidence with the relevant pharmacokinetic
parameter—the rate of in vivo dissolution in the GI tract.
Thus, the district court explained that Alza had failed to demonstrate how
evidence of the rate of dissolution of drug in the GI tract could be extracted from plots of
plasma concentration versus time. The district court accepted Alza’s simplifying
assumption about oxybutynin rapidly being absorbed following dissolution such that the
rates of in vivo dissolution parallel the rate of drug uptake into the blood. However, it
found that only one expert, Dr. Amidon, had “endorsed Alza’s subjective comparison of
blood plasma levels with in vivo release rates.” As for that one expert, moreover, he
“rejected the very conclusion that Alza attributed to him.”
Alza criticizes the district court for “fail[ing] to come to grips with the significance
of the testimony” that Dr. Amidon “recanted . . . immediately after he made it.”
Specifically, Alza urges that notwithstanding the expert’s recantation, we should
nonetheless draw our independent conclusions from the “point of his testimony” that
release rates in blood and the appearance in the GI tract are essentially the same. We
have considered Alza’s arguments and find them to lack legal and factual coherency.
Even if we were to presume to be experts and to apply the simplifying assumption that
the drug is rapidly taken up into the bloodstream upon dissolution, it is not clear to us
how to abstract from each plasma concentration versus time curve the rate of uptake
into the bloodstream. This would require factoring out of the curve the effects, inter alia,
of the elimination of drug from the bloodstream over the relevant 24 hour period. But
this is not our province. Such evidence, if it exists, must have been presented at trial, or
in its stead other evidence sufficient to persuade the trial court.
06-1019 16
From what can be discerned, Dr. Amidon’s immediately recanted statement
appears to have been based on his comparison of the relative areas under the curves of
plasma concentration versus time plots of both the accused ANDA formulation and
Ditropan XL. Indeed, Alza reproduces in its appellate brief Dr. Amidon’s testimony that
the accused product has only 92 to 93 percent of the area under the curve of Ditropan
XL. This appears to have resulted in the drawing of a line (referred to by the parties as
“line A”) on a plot of in vitro dissolution of both Ditropan XL and the accused ANDA
formulation, wherein the rate of in vitro dissolution of Mylan’s ANDA formulation has
been adjusted according to that percentage. The basis for, and significance of, line A is
simply not apparent from the record, and Alza fails to provide us with any persuasive
line of argument as to how we should imbue line A with any relevant meaning. In short,
we agree with Mylan that the plasma concentration versus time data fail to establish in
vivo release rates for either Ditropan XL or the accused ANDA product.
The district court similarly found unpersuasive Alza’s evidence that Ditropan XL
and the accused ANDA product sometimes exhibited in vitro dissolution rates falling
within the claims. The court cited testimony by Dr. Amidon explaining that these in vitro
procedures are “not designed to reflect the in vivo dissolution process.” This accords
with the common sense notion that one cannot simply proclaim without proof that he
has constructed an apparatus capable of mimicking pertinent environmental variables of
the GI tract (along the length of the tract, nonetheless). Indeed, the obtained in vitro
dissolution rates vary widely with the choice of experimental parameters. We agree
with the district court that Alza’s evidence of in vitro dissolution rates is irrelevant absent
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evidence demonstrating that the in vitro system is a good model of actual in vivo
behavior. On that point, Alza’s evidence is severely lacking.
We therefore affirm the district court’s finding of noninfringement. In so doing we
explicitly reject Alza’s suggestion that the district court erred in failing to specifically
state that not only did it find Alza’s plasma concentration data and its “in vitro” data to be
inadequate in isolation, but that it had also found the data to be inadequate in
combination. Even if we were to entertain the suggestion that the district court was in
fact unfamiliar with the basic precept that it is the totality of the evidence that it must
consider in making factual determinations, we would merely conclude that where as
here, if each of two pieces of evidence, assessed separately, is severely inadequate to
support a proposition, when their probative values are tallied, they still fall short. While
it is possible to envision cases in which two pieces of evidence may create great
probative value synergistically, this is not one of those cases.
* * *
In conclusion, we affirm the judgment of the district court that the asserted claims
of the ’355 patent were invalid, and that notwithstanding, the patent was not infringed.
AFFIRMED.
Costs to Mylan.
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