Tris Pharma, Inc. v. Actavis Laboratories Fl, Inc. ( 2018 )

NOTE: This disposition is nonprecedential.
United States Court of Appeals
for the Federal Circuit
______________________
TRIS PHARMA, INC.,
Plaintiff-Appellant
v.
ACTAVIS LABORATORIES FL, INC.,
Defendant-Appellee
______________________
2017-2557, 2017-2559, 2017-2560
______________________
Appeals from the United States District Court for the
District of Delaware in Nos. 1:14-cv-01309-GMS, 1:15-cv-
00393-GMS, 1:15-cv-00969-GMS, Judge Gregory M. Sleet.
______________________
Decided: November 20, 2018
______________________
ERROL TAYLOR, Milbank, Tweed, Hadley & McCloy,
LLP, New York, NY, argued for plaintiff-appellant. Also
represented by ANNA BROOK, JORDAN P. MARKHAM,
FREDERICK ZULLOW.
WILLIAM M. JAY, Goodwin Procter LLP, Washington,
DC, argued for defendant-appellee. Also represented by
BRIAN TIMOTHY BURGESS, WILLIAM G. JAMES, II; DAVID
ZIMMER, Boston, MA; ELIZABETH HOLLAND, LINNEA P.
CIPRIANO, MICHAEL B. COTTLER, CYNTHIA LAMBERT
2 TRIS PHARMA, INC. v. ACTAVIS LABORATORIES FL, INC.
HARDMAN, TIFFANY MAHMOOD, ALEXANDRA D. VALENTI,
New York, NY.
______________________
Before NEWMAN, O’MALLEY, and CHEN, Circuit Judges.
CHEN, Circuit Judge.
Tris Pharma, Inc. (Tris) holds the approved New Drug
Application for Quillivant XR®, an extended release
methylphenidate (MPH) formulation for the treatment of
Attention Deficit Hyperactive Disorder (ADHD). When
Actavis Laboratories, Inc. (Actavis) submitted an Abbre-
viated New Drug Application (ANDA) to the U.S. Food &
Drug Administration (FDA) seeking approval to market
generic versions of Quillivant XR®, Tris sued Actavis for
infringement of U.S. Patent Nos. 8,465,765 (’765 patent),
8,563,033 (’033 patent), 8,778,390 (’390 patent), 8,956,649
(’649 patent), and 9,040,083 (’083 patent). After a five-day
bench trial, the district court found all asserted claims of
the patents-in-suit invalid under 35 U.S.C. § 103. Tris
appealed. Because the district court’s conclusions of law
are based on inadequate fact-findings, we vacate and
remand.
BACKGROUND
MPH is one of the most widely prescribed psychost-
imulants and has been used to treat ADHD since the mid-
1950s. Early formulations of MPH were immediate
release (IR) forms of the drug that exhibited clinical
benefits within 20 to 60 minutes after dosing and whose
effects lasted 2–4 hours. IR forms of MPH, however, had
drawbacks because they had to be administered multiple
times a day, making it challenging for patients to adhere
to the dosing schedule. Sustained release (SR) formula-
tions of MPH were thus developed and available in the
early 1980s for greater dosing convenience and patient
compliance. But those first-generation SR formulations
had their own shortcoming: a slow onset of action. Tris’s
TRIS PHARMA, INC. v. ACTAVIS LABORATORIES FL, INC. 3
Quillivant XR® is an extended release formulation of MPH
comprising an IR component and a SR component. It is a
formulation that achieves a 45-minute therapeutic onset
and 12 hours of therapeutic effect.
Actavis challenged the validity of twenty-one claims
from five patents at the district court, which found all
these claims invalid under 35 U.S.C. § 103. On appeal,
Tris requests that we reverse the district court’s judgment
for seven claims in three patents: ’765, ’033, and ’390
patents. These seven appealed claims are: claims 4 and
10 of the ’033 patent; claims 6 and 20 of the ’765 patent;
and claims 15, 16, and 20 of the ’390 patent. All of the
appealed claims are directed to pharmacokinetic (PK) and
pharmacodynamic (PD) properties of the Quillivant XR®
extended release formulation. 1 These properties include:
(1) an extended duration of action of about 12 hours; (2) a
single mean peak PK profile; (3) a Tmax of about 4 to 5.25
hours (early Tmax); and (4) a 45-minute onset of ac-
tion/therapeutic effects. All of the claims on appeal recite,
among other properties, a single mean peak PK profile
and 12-hour duration of effect limitation. All of the
claims except for claim 20 of the ’765 patent recite the
early Tmax limitation, and claim 10 of the ’033 patent and
claim 20 of the ’765 patent are the only two claims that
require a 45-minute onset of action. Claim 10 of the ’033
1 Pharmacokinetics is the study of what a person’s
body does to a drug after administration. PK values are
measurements of a drug’s behavior in a patient’s blood
plasma. One such value relevant for this appeal, Tmax,
represents the time after administration when the maxi-
mum concentration of the drug in the blood plasma (Cmax)
occurs. The shape of the PK profile, which reflects the
plasma concentration of the drug in the patient’s body
over time, is also an issue in dispute in this case.
4 TRIS PHARMA, INC. v. ACTAVIS LABORATORIES FL, INC.
patent is thus the only asserted claim that recites all four
properties.
A. Prior Art
The district court found that the various combinations
of the PK characteristics (single mean peak and early
Tmax) and PD characteristics (a 45-minute onset of action
and a 12-hour duration of effect) claimed in the patents-
in-suit would have been obvious over the prior art. The
prior art consists of a number of commercially available,
second-generation, extended release formulations of MPH
including Concerta®, Daytrana®, Focalin XR®, Metadate
CD®, and Ritalin LA®; 2 scientific articles; and U.S. Patent
Application Publication No. 2010/0260844 (Scicinski).
Below, we briefly describe the prior art relevant to this
appeal.
Concerta® is an extended release MPH tablet with a
12-hour duration of effect. J.A. 18, 23. The parties dis-
pute whether or not Concerta® exhibits the single mean
peak PK profile limitation because its plasma concentra-
tion profile exhibits a sharp initial increase followed by a
second increase. J.A. 19, 25. The parties also dispute
whether Concerta® exhibits a 45-minute onset of action.
Tris’s expert testified that the clinical efficacy study he
performed showed that Concerta® has a 2-hour onset of
action, J.A. 2213–14, while Actavis’s expert testified that
second-generation products like Concerta® generally have
an onset of action between 30 minutes to 2 hours. J.A.
2 The district court also listed Methylin ER as a
commercially available controlled-release formulation.
J.A. 16. Confusingly, it later presented PK data for
Methylin Oral Solution. J.A. 22. We decline to discuss
the Methylin prior art reference because it is unclear on
which version the district court is relied.
TRIS PHARMA, INC. v. ACTAVIS LABORATORIES FL, INC. 5
2069. Concerta® has a later Tmax of around 6.8 ± 1.8
hours. J.A. 2098.
Daytrana® is an MPH patch that exhibits a single
mean peak PK profile and a 12-hour duration of effect.
J.A. 2215, 2069. However, Daytrana® has a 2-hour onset
of action, and the record as to its Tmax is unclear. J.A.
2069.
Focalin XR® is an extended release MPH capsule.
While it achieves the claimed 12-hour duration of effect,
JA 2069, and 45-minute onset of action, J.A. 3923, its PK
profile does not exhibit a single mean peak, and it exhib-
its a later Tmax around 6.5 hours. J.A. 2080, 2214–15,
2297. Moreover, Tris notes that Focalin XR® only consists
of a single enantiomer d-MPH as the active ingredient
whereas Quillivant XR® and the appealed claims include
both enantiomers.
Metadate CD® is a capsule version of MPH. J.A. 19.
While it has an early Tmax of about 4.5 hours, J.A. 2297,
and a 45-minute onset of action, J.A. 2069, the parties
disagree as to whether its PK profile exhibits a single
mean peak and whether it has a 12-hour duration of
effect. J.A. 22–23. Like Concerta®, Metadate CD®’s PK
profile exhibits a sharp initial increase followed by a
second increase in MPH levels at a later time. J.A. 19.
As for its duration of effect, Tris presented testimony that
Metadate CD®’s effects only last 6 to 8 hours. J.A. 2069,
2204.
Ritalin LA® is a capsule version of MPH. J.A. 21. Ri-
talin LA® exhibits an early Tmax at 5.5 hours and an early
onset of action. J.A. 2069, 2099. Its PK profile exhibits
two peaks (bimodal), J.A. 2615, and it only has 6–8 hours
of effect. J.A. 2069.
Scincinski describes a formulation of MPH that pro-
vides a rapid onset of action within 1 to 1.5 hours, a single
6 TRIS PHARMA, INC. v. ACTAVIS LABORATORIES FL, INC.
Tmax of 5.5 to 7.5 hours, and a therapeutic duration of
about 12 to 14 hours. J.A. 3644.
B. District Court Opinion
Actavis characterized Scincinski as well as the Day-
trana®, Concerta®, and Metadate CD® formulations as all
disclosing a single mean peak PK profile, exhibiting an
early onset of action, and exhibiting an extended duration
of effect. This, Actavis argued, would have suggested to a
skilled artisan that a single mean peak PK profile could
provide the claimed early onset of action and extended
duration of effect. Tris disagreed for two primary reasons.
First, the prior art formulations were developed using
two components: IR and ER formulations of MPH. These
two components together in a formulation typically re-
sulted in two peaks, or a bimodal profile, with the first
peak resulting from the IR component of the formulation
and the second from the ER component. Further, Tris
asserted that this bimodal profile was important to coun-
teract “acute tolerance” or “tachyphylaxis.” Acute toler-
ance is the theory that as the day progresses, higher
levels of the drug in the blood are required to produce the
same therapeutic effects. Thus, in order to achieve sus-
tained effects, the formulations in the prior art, according
to Tris, were designed to mimic the peaks and valleys of
multiple immediate release dosing regimens—one peak
for the IR formulation and a second peak for the ER
formulation.
Second, Tris argued that prior art formulations of
MPH have a late Tmax to achieve the sustained duration of
action. To support this position, Tris pointed to Metadate
CD® and Ritalin LA®, both of which have an early Tmax
but a shorter duration of action of around 6 to 8 hours.
Concerta®, on the other hand, achieves the 12-hour dura-
tion of effect but has a later Tmax that is outside the
claimed range of about 4 to 5.25.
TRIS PHARMA, INC. v. ACTAVIS LABORATORIES FL, INC. 7
The district court stated that, “[w]hile [it] believe[d]
Tris’[s] evidence regarding the second generation products
[wa]s persuasive, it [wa]s not dispositive on the obvious-
ness inquiry.” J.A. 39. Rather, the district court found
that Daytrana® clearly exhibits a single mean peak PK
profile, and thus Actavis had demonstrated that a prior
art reference taught this particular claim limitation.
Importantly, the district court found that Scicinski
describes an oral form of MPH with a long duration of
action, rapid onset, and a single mean peak PK profile.
The district court reasoned that a skilled artisan would
have undoubtedly looked to Scicinski when formulating
an extended release MPH drug because Scicinski’s pur-
pose of a fast onset, long-lasting MPH formulation aligned
with what the parties agreed a skilled artisan would have
been motivated to achieve. The district court acknowl-
edged that Scicinski describes a hypothetical product but
declined to discount Scicinski simply because it contains a
prophetic example. The district court also credited Ac-
tavis’s expert’s testimony that skilled artisans would have
used the known technique of deconvolution to achieve a
product that meets the target PK profile like that de-
scribed in Scicinski:
Q: Now, once a person of ordinary skill in the art
has decided on a target PK profile, at a very gen-
eral level, what are the next steps towards mak-
ing a product?
A: Okay. The next steps would be to take this
pharmacokinetic profile, this plasma profile and,
utilizing certain mathematical techniques that are
known as deconvolution, separate out the profile
into its elimination characteristics and its absorp-
tion characteristics, and once you define then
simply the absorption characteristics of that
product, then you can design a product that has
dissolution characteristics that could match then
8 TRIS PHARMA, INC. v. ACTAVIS LABORATORIES FL, INC.
the absorption characteristics that you get by do-
ing this deconvolution technique.
J.A. 40 (citing J.A. 2095).
Further, the district court appeared to credit Actavis’s
expert’s testimony regarding the relationship between
Tmax and duration of effect. Actavis’s expert testified that
a skilled artisan would not have targeted a specific Tmax
because that parameter does not control the onset or
duration of the drug. He noted, moreover, that the
claimed Tmax ranges in the prior art of 4.4 to 7 hours
overlapped with the claimed range of 3.6 to 5.78 hours,
taking into account the court’s construction of “about.”
The district court then addressed Tris’s expert’s tes-
timony that a skilled artisan would not have expected a
formulation with a single mean peak PK profile to achieve
both early onset and extended duration of action. Be-
cause Tris’s expert testified that he would defer to a
formulator in terms of what sort of PK curve could be
achieved, the district court found Actavis’s formulator’s
expert testimony that a skilled artisan would have no
trouble achieving early onset of action and extended
duration of effect with a single mean peak PK profile
persuasive. The district court ultimately found that
“Tris’[s] nonobvious[ness] argument hinges primarily on
the [single peak] plasma profile and fails to sufficiently
weigh the pharmacokinetic details that would have been
known to skilled artisans or the prior art teachings that
disclosed how to optimize an MPH product.” J.A. 42.
The district court then examined objective indicia of
nonobviousness, including unexpected results, long-felt
need, commercial success, and copying. As to unexpected
results, the district court held that Tris failed to demon-
strate that the Quillivant XR® formulation exhibited some
superior property or advantage that a skilled artisan
would have found surprising or unexpected. J.A. 45
(citing Procter & Gamble Co. v. Teva Pharm. USA, Inc.,
TRIS PHARMA, INC. v. ACTAVIS LABORATORIES FL, INC. 9
566 F.3d 989, 997 (Fed. Cir. 2009)). Tris argued that its
formulation unexpectedly provided (1) a 45-minute onset
of action and a 12-hour duration of effect with a single
mean peak PK profile and (2) a 12-hour duration of effect
with an early Tmax of about 4 to 5.25 hours. The district
court found these arguments irrelevant because Tris had
not performed the proper comparison to the closest prior
art. Id. (citing Kao Corp. v. Unilever U.S. Inc., 441 F.3d
963, 970 (Fed. Cir. 2006)). And even considering Tris’s
unexpected results argument, the district court observed
that the prior art would have led a skilled artisan to
expect that a single peak PK profile could provide for
rapid onset and extended duration of action. Thus, the
district court concluded that Quillivant XR®’s 12-hour
duration of effect and single mean peak PK profile was
not unexpected.
Regarding long-felt need, the district court found that
the claimed Quillivant XR® formulation did not serve a
long-felt but unmet need. The district court pointed to
Tris’s own expert testimony that Metadate CD®, Ritalin
LA®, and Concerta® had already achieved the goal of once
daily dosing. Additionally, Tris’s expert also testified that
some second-generation MPH formulations could have an
onset of action in as early as 30 minutes. J.A. 2069. And
while Tris’s expert testified that there was a long-felt
need for a drug for children who had trouble swallowing
pills that the Daytrana® patch did not meet due to skin
irritation issues, J.A. 2272, the district court found that
his own writings undermined this contention. J.A. 47
(“This contention is undermined by Dr. McGough’s own
writings where in the book he authored entitled ‘ADHD,’
the doctor writes that Daytrana is a product that is ‘par-
ticularly useful when swallowing is difficult.’”).
As to commercial success, the district court found that
Tris’s evidence only showed a modest level of commercial
success. Finally, the district court found that evidence of
copying was not compelling.
10 TRIS PHARMA, INC. v. ACTAVIS LABORATORIES FL, INC.
Accordingly, the district court found all of Tris’s as-
serted claims invalid for being obvious over the prior art.
Tris appealed. We have jurisdiction pursuant to pursuant
to 28 U.S.C. § 1295(a)(1).
DISCUSSION
“Obviousness is a question of law based on underlying
findings of fact.” Perfect Web Techs., Inc. v. InfoUSA, Inc.,
587 F.3d 1324, 1327 (Fed. Cir. 2009) (citing In re Kubin,
561 F.3d 1351, 1355 (Fed. Cir. 2009)). We review the
district court’s conclusions of law de novo. Eli Lilly & Co.
v. Teva Parenteral Meds., Inc., 845 F.3d 1357, 1372 (Fed.
Cir. 2017). And we review the district court’s factual
findings for clear error. Par Pharm. Inc. v. TWI Pharm.,
Inc., 773 F.3d 1186, 1194–95 (Fed. Cir. 2014).
Under Fed. R. Civ. P. 52(a)(1), “[i]n an action tried on
the facts without a jury or with an advisory jury, the court
must find the facts specially and state its conclusions of
law separately.” Rule 52(a) lays out the separate and
distinct roles of the trial and the appellate court.
“[F]actfinding is the basic responsibility of district courts,
rather than appellate courts. Pullman-Standard v.
Swint, 456 U.S. 273, 291–92 (1982) (citing DeMarco v.
United States, 415 U.S. 449, 450 n.* (1974)). A court of
appeals should not resolve in the first instance a factual
dispute which has not been considered by the district
court. See id. “When the opinion explaining the decision
lacks adequate fact-findings, meaningful review is not
possible, frustrating the very purpose of appellate review
as well as this court’s compliance with its statutory man-
date.” Gechter v. Davidson, 116 F.3d 1454, 1457 (Fed.
Cir. 1997) (citation omitted). Findings of fact are ade-
quate when “they are sufficiently comprehensive and
pertinent to the issue to form a basis for the decision.”
Medtronic, Inc. v. Daig Corp., 789 F.2d 903, 906 (Fed. Cir.
1986) (quoting Loctite Corp. v. Ultraseal Ltd., 781 F.2d
861, 873 (Fed. Cir. 1985)). Although Rule 52(a)(1) does
TRIS PHARMA, INC. v. ACTAVIS LABORATORIES FL, INC. 11
not require detailed factual findings on every issue raised,
it does require findings on “as many of the subsidiary
facts as are necessary to disclose to the appellate court
the steps by which the trial court determined factual
issues and reached its ultimate conclusions.” Atlantic
Thermoplastics Co., Inc. v. Faytex Corp., 5 F.3d 1477,
1479 (Fed. Cir. 1993).
Tris raises three primary issues on appeal. First, Tris
argues that a skilled artisan would not have reasonably
expected to successfully combine the claimed single mean
peak PK profile with the claimed 45-minute onset of
action and 12-hour duration of effect (PD characteristics)
because the PK-PD relationship was unknown. 3 Second,
3 On appeal, Tris cites In re Cyclobenzaprine Hy-
drochloride Extended-Release Capsule Patent Litigation,
as being on all fours with this case. 676 F.3d 1063 (Fed.
Cir. 2012). In Cyclobenzaprine, we reversed the district
court’s judgment of obviousness, holding that its “failure
to appreciate the lack of a known PK/PD relationship for
any formulation of cyclobenzaprine rendered deficient its
analysis of the evidence . . . and its analysis of the impli-
cations of that evidence on its legal conclusions of obvi-
ousness.” Id. at 1071. However, in Cyclobenzaprine, no
extended release formulation of the drug was present in
the prior art, and we found that without a known PK/PD
relationship, “immediate-release PK values are of little
use in calculating extended-release values, because there
is no proof that a skilled artisan would expect the extend-
ed release values to produce a therapeutic effect solely
because they are drawn from immediate-release values.”
Id. The present case is different because the prior art
disclosed numerous existing extended-release formula-
tions, some with one or a combination of single mean peak
PK profile, extended duration, early onset, and early Tmax.
12 TRIS PHARMA, INC. v. ACTAVIS LABORATORIES FL, INC.
Tris contends that the district court failed to address why
the combination of an early Tmax and a 12-hour duration
of effect would have been obvious. Third, Tris claims the
district court mistakenly disregarded Tris’s evidence of
unexpected results based on a belief that Tris’s experts
did not compare the claimed invention to the closest prior
art. Rather, Tris compared the Quillivant XR® formula-
tion with the commercially available prior art formula-
tions identified by the parties.
As we explain below, the district court failed to make
the necessary factual findings and provide sufficient
analysis of the parties’ arguments to permit effective
appellate review. Specifically, the district court’s opinion
merely recites the parties’ arguments but fails to explain
or identify which arguments it credits or rejects. We thus
cannot reach the merits of whether the Quillivant XR®
formulation would have been obvious over the prior art.
Rather, we identify gaps in the district court’s opinion and
remand for the district court to conduct further fact-
findings and detailed analysis consistent with this opin-
ion.
A. Single Mean Peak PK Profile, 45-Minute Onset, and
12-Hour Duration of Effect
Claim 10 of the ’033 patent and claim 20 of the ’765
patent require a liquid MPH formulation with (1) a single
mean peak PK profile, (2) a 45-minute onset of action, and
(3) a 12-hour duration of effect. ’033 patent col. 38 ll. 34–
35; ’765 patent col. 39 ll. 16–17. The district court held
that a skilled artisan would have found it obvious to use a
formulation with a single mean peak PK profile to achieve
a 45-minute onset of action and a 12-hour duration of
Cyclobenzaprine is thus, factually distinguishable from
this case.
TRIS PHARMA, INC. v. ACTAVIS LABORATORIES FL, INC. 13
effect. But the district court failed to make adequate
findings of fact to support this holding.
First, while the district court found that one would
have expected from the prior art that a single mean peak
PK profile could provide for rapid onset of action and
extended duration of effect, J.A. 46, it never articulated
which prior art references do so and how. The district
court’s only clear finding on this point was its statement
that formulations in the prior art such as Daytrana®
exhibit a single mean peak PK profile. J.A. 37. The
district court also recited Actavis’s expert’s testimony that
Concerta® and Metadate CD® also have a single mean
peak PK profile, despite having a slight initial peak or
shoulder in their plasma concentration profiles followed
by a larger single peak, and that Scicinski also teaches a
single mean peak PK profile. J.A. 37, 41.
But it is unclear if these statements amount to actual
fact-findings as opposed to a mere recounting of Actavis’s
arguments. Even if we were to interpret these statements
as findings of fact, there are still holes in the district
court’s analysis. For instance, the district court never
made explicit findings that Daytrana®, Concerta®, Meta-
date CD®, and/or Scicinski also teach a 45-minute onset of
action or 12-hour duration of effect. And with respect to
the 45-minute onset of action limitation, the district court
cited a concession by Tris’s expert that second-generation
MPH formulations could have an onset of action in as
early as 30 minutes, but it did not explain the significance
of this concession. 4 J.A. 47. And the district court did not
4 Actavis argues that the Biederman article, a prior
art reference relied upon by Tris’s expert, describes Con-
certa® as having an onset of action in as early as 30
minutes and a 12-hour duration of effect. J.A. 3446
(Biederman, J. “New-Generation Long-Acting Stimulants
14 TRIS PHARMA, INC. v. ACTAVIS LABORATORIES FL, INC.
specifically identify which second-generation products
have an onset of action around 30 minutes or state
whether it believed that all second-generation MPH
products, except Daytrana®, had this onset of action time.
As for the 12-hour duration of effect limitation, the dis-
trict court’s opinion is vague as to whether any of the
prior art formulations actually teach the 12-hour duration
of effect limitation. Throughout its analysis, the district
court imprecisely states that certain prior art discloses
“efficacy that last[s] throughout the day,” a “long duration
of effect,” or an “extended duration of action.” See e.g.,
J.A. 16, 36, 46. It is unclear, however, whether the dis-
trict court intended this language to equate to the claimed
12-hour duration of effect. We identify these issues
because whether a particular prior art formulation
achieves a 45-minute onset of action and/or a 12-hour
duration of effect are central, disputed issues on appeal.
And it is the role of the district court to resolve these
specific fact issues with an explanation to support those
findings.
Second, and importantly, the district court does not
address a fundamental aspect of the obviousness in-
for the Treatment of Attention-Deficit/Hyperactivity
Disorder,” Medscape Psychiatry 8(2) (Nov. 2003)). How-
ever, the district court never cited this passage in its
opinion. Also, the record is unclear as to whether Scicin-
ski actually teaches the 45-minute onset of action limita-
tion. Scicinski reports that its formulation would be
effective “within about 1 to 1.5 hours post administra-
tion.” ’844 application ¶ 0016. While Actavis’s expert
testified that a skilled artisan would have viewed this
disclosure as consistent with a 45-minute onset, the
district court never directly made this fact-finding. J.A.
2102.
TRIS PHARMA, INC. v. ACTAVIS LABORATORIES FL, INC. 15
quiry—i.e. why a skilled artisan would have been moti-
vated to use a single mean peak PK profile to achieve a
formulation with a 45-minute onset of action and/or a 12-
hour duration of effect with a reasonable expectation of
success. 5 Tris argued below and to us on appeal that the
acute tolerance theory as well as the prior art taught
away from using a single mean peak PK profile to achieve
a 45-minute onset and a 12-hour duration of effect.
According to Tris, the prior art extended release products
with a single mean peak PK profile do not achieve either
a 45-minute onset of action, a 12-hour duration of effect,
or both. Tris argues that this is due to the acute tolerance
theory, which postulates that the plasma concentration of
a drug must be higher in a patient as the day progresses
to achieve therapeutic efficacy, and therefore a bimodal
(two-peak) plasma concentration curve is required. On
appeal, Actavis argues that the acute tolerance theory is
irrelevant to whether a drug has a single or bimodal peak
PK profile, attempts to discredit the theory, and asserts
that skilled artisans did not regard the number of peaks
as important when formulating a drug. But the district
court made none of these findings below. Other than
explaining what the acute tolerance theory is, J.A. 38 n.8,
5 We understand that one of Actavis’s arguments on
appeal is that Quillivant XR®’s single mean peak PK
profile and early Tmax range are incidental properties of
the formulation. That is, these PK limitations played no
role in Quillivant XR®’s development. The PK character-
istics are specifically claimed in the patents-in-suit,
however, and Actavis has not suggested that these limita-
tions are not entitled to patentable weight. Thus, Actavis
needs to demonstrate that a skilled artisan would have
been motivated to create a liquid formulation of MPH
with these claimed PK characteristics and specific PD
properties.
16 TRIS PHARMA, INC. v. ACTAVIS LABORATORIES FL, INC.
and reciting Tris’s expert testimony explaining why acute
tolerance was one of the reasons a first-generation MPH
formulation like Ritalin-SR® could not achieve the desired
clinical effects of a fast onset and extended duration, J.A.
38, the district court did not address the acute tolerance
theory. It is thus unclear whether the district court found
that (1) the theory is not applicable because it does not
affect the shape of the plasma concentration curve; (2) the
theory is unreliable; or (3) the theory is applicable, but
even acknowledging it, a skilled artisan would have a
reasonable expectation of success to combine a single
mean peak curve with a 45-minute onset of action and a
12-hour duration of effect. And we decline to guess at
what the district court meant.
Without the requisite factual findings and adequate
explanation for such findings, we cannot affirm the dis-
trict court’s conclusion that a formulation with (1) a single
mean peak PK profile, (2) 45-minute onset of action, and
(3) 12-hour duration of effect would have been obvious
over the prior art. See Golden Blount, Inc. v. Robert H.
Peterson Co., 365 F.3d 1054, 1061 (Fed. Cir. 2004) (“Be-
cause the district court’s sparse opinion provides this
court with only bald conclusions for review, we conclude
that the district court’s judgment . . . is insufficient under
Rule 52(a). We thus vacate those portions of the district
court’s opinion and remand those issues to the district
court for specific factual findings.”); see also Atlantic
Thermoplastics Co., 5 F.3d at 1479 (finding the court’s
opinion too conclusory and sparse to provide a factual
basis for determining whether the invention was on sale
within the meaning of 35 U.S.C. § 102(b)). Accordingly,
we remand this issue to the district court for further fact-
finding.
B. Early Tmax and 12-Hour Duration of Effect
Claims 4 and 10 of the ’033 patent; claim 6 of the ’765
patent; and claims 15, 16, and 20 of the ’390 patent recite
TRIS PHARMA, INC. v. ACTAVIS LABORATORIES FL, INC. 17
a liquid formulation of MPH with a single Tmax of about 4
to 5.25 hours and a 12-hour duration of effect. ’033 patent
col. 38 ll. 3–5, 34–35; ’765 patent col. 38 ll. 4–13; ’390 at
col. 39 ll. 3–11, 27–29. On appeal, Tris argues that the
district court never provided its assessment of the obvi-
ousness of a MPH formulation with both an early Tmax
and 12-hour duration of effect. We agree.
The district court’s analysis with respect to Tmax is
very cursory. The entirety of the district court’s discus-
sion of Tmax appears amounts to a mere recitation of
Actavis’s experts’ testimony regarding how (1) Tmax does
not control the onset or duration of effect and (2) Tmax
ranges in the prior art formulations overlap with the
claimed Tmax range of 3.6 to 5.78 hours (factoring in the
district court’s construction of “about”). J.A. 41. And, yet
again, the district court fails to articulate whether it
credited this testimony or explain why and how the
testimony supports its conclusion. Even if we were to
assume that these statements were actual findings of fact,
the district court’s analysis still fails to explain why a
skilled artisan would have reasonably expected to achieve
a formulation with the claimed 12-hour duration of effect
and an early Tmax.
The district court’s opinion lacks any response to
Tris’s argument that formulations with an early Tmax
(such as Metadate CD® and Ritalin LA®) did not achieve
12 hours of effect while those with 12 hours of effect
(Concerta® and Focalin XR®) had later Tmax values. Tris’s
expert explained that this was because oral formulations
only contain a certain amount of any drug; if the formula-
tion releases a substantial amount of the drug to obtain
an early Tmax, then the formulation would not be expected
to achieve extended effects for the whole day. J.A. 2204.
While Actavis’s expert responded to this in his testimony,
J.A. 2101, the district court opinion does not discuss or
cite Tris’s testimony.
18 TRIS PHARMA, INC. v. ACTAVIS LABORATORIES FL, INC.
As with the single mean peak PK profile, 45-minute
onset of action, and 12-hour duration of effect combination
of limitations, we also remand the obviousness of the
combination of an early Tmax with a 12-hour duration of
effect to the district court for further consideration.
C. Objective Indicia of Nonobviousness
Tris argues on appeal that the district court incorrect-
ly rejected Tris’s experts’ testimony on unexpected results
because they purportedly failed to compare the Quillivant
XR® formulation with the closest prior art. We agree.
Tris’s experts compared the Quillivant XR® formulation to
all prior art products whose PK and PD values were cited
by Actavis or known to Tris. J.A. 2708–13. While Kao
stands for the proposition that “when unexpected results
are used as evidence of nonobviousness, the results must
be shown to be unexpected compared with the closest
prior art,” we do not read Kao so rigidly as to require Tris
to identify and focus on just one prior art product when
multiple, similar extended release formulations of MPH
existed or were described in the prior art. 441 F.3d at
970. Because the patents-in-suit claim multiple PK and
PD characteristics, different prior art references are
closer on different PK and PD characteristics, and none of
the parties asserted that one of the references or products
represented the closest art. Under the circumstances
here, the district court should have considered Tris’s
evidence that its claimed invention enjoyed unexpected
properties compared to the known, extended release
formulations.
Moreover, even though the district court went on to
consider the merits of Tris’s unexpected results argument,
the district court’s analysis is deficient because it, at best,
only addresses the single mean peak PK limitation. J.A.
46. The district court does not explain why—separately,
and more importantly together with the single mean peak
PK profile limitation—the Tmax, 45-minute onset, and 12-
TRIS PHARMA, INC. v. ACTAVIS LABORATORIES FL, INC. 19
hour duration of effect limitations were not unexpected.
Thus, we remand the issue of unexpected results to the
district court for further analysis.
Additionally, Tris also argues that the district court
incorrectly rejected its evidence of long-felt need based on
second-generation products that lack one or more of the
long-felt needs Tris identified. Below, Tris argued that
there was a long-felt need for a product having several
desired properties: (1) a liquid MPH product that does not
require swallowing a tablet; (2) a 45-minute onset of
action; and (3) 12-hour duration of effect. None of the
prior art products, Tris contends, satisfied this alleged
long-felt need because none of them possess all three of
these properties.
In rejecting Tris’s long-felt need argument, the dis-
trict court opinion identified various prior art products
that meet each of the three individual needs above, but
never identified a prior art product that contains all three
properties. For instance, Daytrana® can be administered
to individuals without requiring them to swallow a pill;
Metadate CD®, Ritalin LA®, and Concerta® are adminis-
tered once daily. J.A. 44. The district court also found
that second generation prior art products generally have
an onset of action of as early as 30 minutes. Id. But
finding each of the properties in separate prior art prod-
ucts does not adequately address Tris’s specific theory as
to a long-felt need for all three desired properties to be
contained a single product. Actavis contends that any
differences in onset, duration, and formulation between
Quillivant XR® and particular prior art products were too
insignificant to establish any unsolved long-felt need, but
the district court did not make such a finding for us to
review. Accordingly, we remand the long-felt need issue
to the district court for further consideration.
20 TRIS PHARMA, INC. v. ACTAVIS LABORATORIES FL, INC.
In view of the errors we identified above, we invite the
district court to reconsider all the evidence of objective
indicia in its overall determination of obviousness.
CONCLUSION
Because district court’s obviousness decision lacks the
requisite fact-finding, and because the district court erred
in rejecting Tris’s evidence of objective indicia of nonobvi-
ousness, we remand the obviousness analysis to the
district court for further fact-finding. We have considered
the parties’ other arguments and find them unpersuasive.
VACATED AND REMANDED
COSTS
No Costs.