Vanda Pharmaceuticals Inc. v. Teva Pharmaceuticals USA, Inc. ( 2023 )

Case: 23-1247 Document: 48 Page: 1 Filed: 05/10/2023
NOTE: This disposition is nonprecedential.
United States Court of Appeals
for the Federal Circuit
______________________
VANDA PHARMACEUTICALS INC.,
Plaintiff-Appellant
v.
TEVA PHARMACEUTICALS USA, INC., APOTEX
INC., APOTEX CORP.,
Defendants-Appellees
______________________
2023-1247
______________________
Appeal from the United States District Court for the
District of Delaware in Nos. 1:18-cv-00651-CFC, 1:18-cv-
00689-CFC, 1:19-cv-00560-CFC, 1:19-cv-00685-CFC, 1:19-
cv-02202-CFC, 1:19-cv-02375-CFC, 1:20-cv-00083-CFC,
1:20-cv-00093-CFC, 1:20-cv-01104-CFC, 1:20-cv-01333-
CFC, 1:21-cv-00121-CFC, 1:21-cv-00282-CFC, Chief Judge
Colm F. Connolly.
______________________
Decided: May 10, 2023
______________________
NICHOLAS P. GROOMBRIDGE, Groombridge, Wu, Baugh-
man & Stone LLP, New York, NY, argued for plaintiff-ap-
pellant. Also represented by ERIC ALAN STONE, JOSEPHINE
YOUNG; JENNIFER REA DENEAULT, DANIEL KLEIN, MICHAEL
F. MILEA, Cold Spring, NY.
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2 VANDA PHARMACEUTICALS INC. v.
TEVA PHARMACEUTICALS USA, INC.
JOHN CHRISTOPHER ROZENDAAL, Sterne Kessler Gold-
stein & Fox, PLLC, Washington, DC, argued for defendant-
appellee Teva Pharmaceuticals USA, Inc. Also represented
by WILLIAM MILLIKEN, BYRON LEROY PICKARD, SASHA RAO,
DEIRDRE M. WELLS.
AARON S. LUKAS, Cozen O'Connor P.C., Washington,
DC, argued for defendants-appellees Apotex Inc., Apotex
Corp. Also represented by WILLIAM BLAKE COBLENTZ; KERI
SCHAUBERT, New York, NY.
______________________
Before DYK, BRYSON, and PROST, Circuit Judges.
DYK, Circuit Judge.
Vanda Pharmaceuticals Inc. sued Apotex Inc. and Apo-
tex Corp. (collectively, “Apotex”) and Teva Pharmaceuti-
cals USA, Inc. alleging that their abbreviated new drug
applications (“ANDAs”) infringed claims in four patents
owned by Vanda. Those claims relate to a method of treat-
ing Non-24-Hour Sleep-Wake Disorder (“Non-24”) with
tasimelteon. The district court held that all of the asserted
claims were invalid as obvious. We affirm.
BACKGROUND
Non-24 is a circadian rhythm disorder that occurs in
individuals whose biological clocks are not synchronized,
that is, entrained, to the 24-hour day. Non-24 causes too
little nighttime sleep and too much daytime sleep. It can
be treated by causing entrainment, i.e., synchronizing a
person’s circadian rhythm to the 24-hour day. “Approxi-
mately 55 to 70 percent of totally blind individuals . . . suf-
fer from Non-24.” J.A. 11.
Vanda sells a tasimelteon drug product (Hetlioz®) that
is approved by the Food and Drug Administration (FDA)
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and indicated for the treatment of Non-24. Vanda owns
patents related to using tasimelteon to treat Non-24.
Appellees Teva and Apotex both filed ANDAs with the
FDA “seeking approval for the commercial manufacture,
use, and sale of tasimelteon.” J.A. 15. At issue in this case
are four claims from four different unexpired Vanda-owned
patents, U.S. Patent No. RE46,604 (the RE604 patent);
U.S. Patent No. 10,149,829 (the ’829 patent); U.S. Patent
No. 9,730,910 (the ’910 patent); and U.S. Patent
No. 10,376,487 (the ’487 patent), all of which are listed in
the FDA’s Orange Book (Approved Drug Products with
Therapeutic Equivalence Evaluations) for Hetlioz®. Teva’s
and Apotex’s ANDAs both included certifications pursuant
to 21 U.S.C. § 355(j)(2)(a)(vii)(IV) (“Paragraph IV Certifi-
cations”) alleging that the asserted claims are invalid and
that all or most of the claims will not be infringed by the
ANDA products. 1
Vanda sued Teva and Apotex in the District of Dela-
ware alleging that their ANDA submissions constituted in-
fringement of claim 3 of the RE604 patent; claim 14 of the
’829 patent; claim 4 of the ’910 patent; and claim 5 of the
’487 patent. Teva and Apotex stipulated to infringement of
claim 5 of the ’487 patent, denied infringement as to the
other claims, and alleged that all asserted patent claims
were invalid.
In a thorough opinion, the district court held that all
four claims were invalid for obviousness. The court also
held that Teva and Apotex did not infringe claim 3 of the
RE604 patent, but did not make infringement findings for
the asserted claims in the ’829 patent or ’910 patent.
1 Teva’s certification alleged that no asserted claims
would be infringed, and Apotex’s alleged that three of the
four asserted claims would not be infringed.
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Vanda appealed the district court’s obviousness and in-
fringement determinations.
We have jurisdiction under 28 U.S.C. § 1295(a)(1).
DISCUSSION
“[W]e review a district court’s conclusions of law de
novo and its findings of fact for clear error.” Merck Sharp
& Dohme Corp. v. Hospira, Inc., 874 F.3d 724, 728 (Fed.
Cir. 2017). “Obviousness is a question of law, based on un-
derlying factual findings . . . .” Id.I. RE604 Patent
Vanda alleged that Teva and Apotex infringed claim 3
of the RE604 patent, which depends from claims 1 and 2:
1. A method of entraining a patient suffering from
Non-24 to a 24 hour sleep-wake cycle in which the
patient awakens at or near a target wake time fol-
lowing a daily sleep period of approximately 7 to 9
hours, and maintaining said 24 hour sleep-wake
cycle said method comprising: treating the patient
by orally administering to the patient 20 mg of
tasimelteon once daily before a target bedtime.
2. The method of claim 1 wherein the patient is to-
tally blind.
3. The method of claim 2 wherein the tasimelteon
is administered 0.5 to 1.5 hours before the target
bedtime.
J.A. 117 (RE604 patent, col. 38, ll. 25–36). The district
court held that claim 3 would have been obvious over two
combinations of prior art references: Hack, 2 the
2 Lisa M. Hack et al., The Effects of Low-Dose 0.5-mg
Melatonin on the Free-Running Circadian Rhythms of
Blind Subjects, 18 J. Biological Rhythms 420 (2003).
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’244 Publication, 3 and Lankford; 4 and, alternatively, Hack,
the ’244 Publication, and Hardeland. 5
Vanda claims that the district court made several er-
rors in determining that claim 3 was obvious. Vanda first
argues that the district court erred in stating that a skilled
artisan would look to Hack, a prior art reference that ex-
plains that melatonin can be used to entrain blind patients
with Non-24, when considering whether there would have
been a reasonable expectation that tasimelteon would en-
train. The district court did not err.
Of course, tasimelteon and melatonin are not identical.
See J.A. 19,299–300 (Emens 858:21–859:9) (testimony that
melatonin and tasimelteon have different binding affinities
for melatonin receptors); J.A. 20,525–26 (Hardeland) (not-
ing that melatonin and tasimelteon have some structural
differences). However, as Lankford explains, “tasimelteon
has high affinity for both the [melatonin] receptors, both in
ranges similar to that of melatonin.” J.A. 20,539. The dis-
trict court noted that prior art references concluded that
tasimelteon and melatonin are similar, and, because of
their similarities, “tasimelteon could . . . potentially en-
train patients suffering from circadian rhythm sleep disor-
ders.” J.A. 25 (citing J.A. 20,523 (Hardeland); J.A. 20,539
(Lankford)). There was no error in the district court’s
choice to credit statements in the prior art explaining the
similarities between tasimelteon and melatonin and why
3 Int’l Pat. Application No. WO 2007/137244.
4 D. Alan Lankford, Tasimelteon for Insomnia, 20
Expert Op. Investigational Drugs 987 (2011).
5 Rüdiger Hardeland, Tasimelteon, a Melatonin Ag-
onist for the Treatment of Insomnia and Circadian Rhythm
Sleep Disorders, 10 Current Op. Investigational Drugs 691
(2009).
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those similarities would have made data for melatonin rel-
evant to tasimelteon.
Vanda’s second argument is that, contrary to the dis-
trict court’s conclusion, none of the prior art references
“would give a skilled artisan a reasonable expectation of
success in using 20mg of tasimelteon . . . to entrain.” Ap-
pellant’s Br. 36. Vanda is incorrect.
The district court found that the claim element “orally
administering to the patient 20 mg of tasimelteon” was dis-
closed in Hardeland, the ’244 Publication, and Lankford.
Hardeland summarizes a phase II clinical trial by Ra-
jaratnam et al. 6 that looked at the effect of tasimelteon on
phase shifting, which is necessary for and related to en-
trainment. In that study, trial participants were given ei-
ther a placebo or 10mg, 20mg, 50mg, or 100mg of
tasimelteon after having their bedtimes shifted by five
hours. Only the 100mg dose produced a statistically sig-
nificant phase shift compared to the placebo. However, the
20mg dose produced a phase shift of over one hour, which
was greater than the shift of about thirty minutes observed
with the placebo (although the difference was not statisti-
cally significant). Based on this and other data, Hardeland
concluded that the prior art showed that tasimelteon “may
be useful in the treatment of sleep disturbances related to
circadian rhythm sleep disorders, such as . . . entrainment
difficulties” and stated that “[t]he most effective doses of
6 Shantha M. W. Rajaratnam et al., Melatonin Ago-
nist Tasimelteon (VEC-162) for Transient Insomnia After
Sleep-Time Shift: Two Randomised Controlled Multicentre
Trials, Lancet (Dec. 2, 2008).
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tasimelteon were in the range of 20 to 50 mg/day.” 7
J.A. 20,529.
Relying on the Rajaratnam study, Dr. Jonathan
Emens, one of Teva and Apotex’s expert witnesses, testi-
fied: “You would never really need a shift of more than an
hour, and so [a phase shift of over an hour caused by a
20mg dose of tasimelteon] would be a sufficient shift to
treat any individual with Non-24. ” J.A. 19,267 (Emens
729:16–18). While Dr. Emens recognized that a 20mg dose
of tasimelteon did not have a statistically significant effect
on phase shifting, J.A. 19,302–03 (Emens 870:4–871:23);
J.A. 19,304 (Emens 877:11–16); J.A. 19,306 (Emens
884:17–21), he still concluded that Rajaratnam suggested
that 20mg of tasimelteon can cause entrainment, see
J.A. 19,267 (Emens 729:9–18). The district court found
Dr. Emens to be “very credible” and “found his testimony
to be compelling.” J.A. 10 (citation omitted).
The ’244 Publication, an international patent applica-
tion filed by Vanda, also summarized the Rajaratnam
study. Based largely on that study, the ’244 Publication
stated that “[a]n oral dose of about 20 to about 50 mg is
effective in treating sleep disorders when administered
about 1/2 hour before sleep time.” J.A. 20,629. The ’244
Publication also claimed using 20mg of tasimelteon to treat
7 Vanda is incorrect in saying that “Hardeland was
flat-out wrong” in its interpretation of Rajaratnam. Appel-
lant’s Reply Br. 10. Vanda argues that “Hardeland wrote
that Rajaratnam had not tested doses below 100mg.” Ap-
pellant’s Reply Br. 10. While the sentence in Hardeland
that Vanda relies on for that assertion is admittedly poorly
worded, see J.A. 20,529, Vanda has not shown that
“Hardeland was flat-out wrong” in its interpretation of Ra-
jaratnam. It is clear reading Hardeland that Rajaratnam
tested a 20mg dose of tasimelteon. See J.A. 20,527–28.
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a circadian rhythm disorder. J.A. 20,630. Dr. Emens
stated that the ’244 Publication “says [tasimelteon] . . . can
. . . cause entrainment . . . specifically at doses of about . . .
20 to 50 milligrams.” J.A. 19,267 (Emens 727:17–21).
Thus, Vanda’s own patent application found significance in
the 20mg result from the Rajaratnam study.
Lankford, another prior art reference, stated that a
then-ongoing phase III trial of tasimelteon in blind people
with Non-24 was “designed to assess the effectiveness of 20
mg of tasimelteon, compared with placebo, in improving
nighttime sleep.” J.A. 20,539. Vanda argues that “the
court erred in finding that Vanda’s ongoing clinical trial
[mentioned in Lankford] would give an ordinary artisan an
expectation of success.” Appellant’s Br. 40 (capitalization
changed). Contrary to Vanda’s characterization, the dis-
trict court did not find that Vanda’s ongoing clinical trial
would have given a POSA an expectation of success in us-
ing tasimelteon to treat Non-24 in and of itself. Instead,
the district court found “Lankford’s disclosure of Vanda’s
Phase III trial would also have contributed to a skilled ar-
tisan’s expectation of success.” J.A. 43. There is no error
in the district court’s use of the then-ongoing clinical trial
as one piece of evidence, combined with other prior art ref-
erences, to support an obviousness determination.
Taken together, the evidence is sufficient to support
the district court’s finding that the tasimelteon prior art
would have given a skilled artisan a reasonable expectation
of success of entrainment with 20mg. 8
8 Vanda also argued that the district court erred in
concluding, as part of its analysis of objective indicia of
non-obviousness, that success in entrainment with 20mg of
tasimelteon would not have been unexpected. For the rea-
sons explained above, we find no error.
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Vanda’s final argument is that the district court erred
in its assessment of the objective indicia of non-obvious-
ness. First, Vanda argues that the district court “disre-
garded the contrary evidence” of long-felt need, Appellant’s
Reply Br. 14, namely “the Reexamination Specialists’ find-
ing [in reexamination] that Vanda had ‘provided evidence
that the invention satisfies a long felt need,’” Appellant’s
Br. 43 (quoting J.A. 22,842). Vanda argues that the dis-
trict court was required to weigh such evidence as part of
secondary considerations concerning obviousness. How-
ever, “[t]he fact that the district court did not in its opinion
recite every piece of evidence does not mean that the evi-
dence was not considered.” Plant Genetic Sys., N.V. v. DeK-
alb Genetics Corp., 315 F.3d 1335, 1343 (Fed. Cir. 2003)
(citation omitted).
Vanda also argues that the district court disregarded
evidence from Non-24 sufferers that “until tasimelteon
nothing worked for them.” Appellant’s Reply Br. 14; see
also Appellant’s Br. 43. The district court did not disregard
this evidence. It explained that Vanda cited one article
that “recounts the successful treatment of one adolescent
Non-24 patient who had previously been treated unsuc-
cessfully with melatonin” and that the remaining evidence
cited by Vanda was “cursory at best.” J.A. 57. We find no
error in the district court’s determination that evidence of
the successful treatment of one person does not constitute
evidence of long-felt need and that the remaining evidence
was cursory. The district court correctly found that long-
felt need was not established.
Vanda finally argues that the district court erred by
“dismiss[ing] the praise that Vanda has received because it
was not ‘praise specifically directed at the treatment
method claimed in the RE604 patent.’” Appellant’s Br. 43
(quoting J.A. 57). This was not an error. “[O]bjective evi-
dence of non-obviousness fails [when] it is not ‘commensu-
rate in scope with the claims which the evidence is offered
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to support.’” Therasense, Inc. v. Becton, Dickinson & Co.,
593 F.3d 1325, 1336 (Fed. Cir. 2010) (quoting In re
Grasselli, 713 F.2d 731, 743 (Fed. Cir. 1983)).
In sum, we find no error in the district court’s determi-
nation that claim 3 of the RE604 patent is invalid for obvi-
ousness.
II. ’487 Patent
Vanda alleged that Teva and Apotex infringed claim 5
of the ’487 patent, which depends from claims 1 and 4:
1. A method of treating a human patient suffering
from a circadian rhythm disorder or a sleep disor-
der that comprises orally administering to the pa-
tient an effective dose of tasimelteon without food,
wherein the effective dose is 20 mg/d.
...
4. The method of claim 1, wherein the patient is
suffering from a circadian rhythm disorder.
5. The method of claim 4, wherein the circadian
rhythm disorder is Non-24 Disorder.
J.A. 198 (’487 patent, col. 4, ll. 2–16).
The district court held that claim 5 would have been
obvious. At issue is the claim element that tasimelteon is
administered “without food.” We agree with the district
court because it would have been obvious to try adminis-
tering tasimelteon without food.
“When there is a design need or market pressure to
solve a problem and there are a finite number of identified,
predictable solutions, a person of ordinary skill has good
reason to pursue the known options within his or her tech-
nical grasp.” KSR Int’l Co. v. Teleflex Inc., 550 U.S. 398,
421 (2007). “If one of these predictable solutions leads to
the anticipated success, the combination was obvious to
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try.” Valeant Pharms. Int’l, Inc. v. Mylan Pharms. Inc., 955
F.3d 25, 34 (Fed. Cir. 2020).
In this case, there was market pressure (regulatory ad-
vice) to determine if food would have an effect on the effi-
cacy of a drug, such as tasimelteon. At the time Vanda’s
tasimelteon product was being developed, the FDA recog-
nized that “[f]ood can change the [bioavailability] of a drug
. . . [and f]ood effects on [bioavailability] can have clinically
significant consequences.” U.S. Food & Drug Admin.,
Guidance for Industry: Food-Effect Bioavailability and Fed
Bioequivalence Studies 2 (2002). 9 Therefore, a POSA
would have understood that administering a drug with or
without food could make it more or less effective. The guid-
ance document also states that “[f]ood effect [bioavailabil-
ity] studies are usually conducted for new drugs,” id. at 1,
and that “[f]ood-effect [bioavailability] information should
be available to design clinical safety and efficacy studies
and to provide information for the CLINICAL
PHARMACOLOGY and/or DOSAGE AND
ADMINISTRATION sections of product labels.” Id. at 3. 10
Based on this language, it is clear that food-effect studies
were expected to be performed on new drugs, meaning cli-
nicians and others who purchased or prescribed the drug
would have expected food effect information about the drug
to have been developed.
9 Vanda cited this guidance document in its clinical
study report on tasimelteon. J.A. 23,145.
10 In a later publication, the FDA clarified its posi-
tion. See U.S. Food & Drug Admin., Bioavailability Studies
Submitted in NDAs or INDs – General Considerations:
Guidance for Industry 8 (2022) (noting that “[t]he effect of
food on the [bioavailability] of the test product should also
be assessed” when describing study design considerations
for bioavailability studies for new drug applications).
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Here, as the specification appears to recognize, see J.A.
197 (’487 patent, col. 2, ll. 18–19), there were only two per-
mutations for the food variable: tasimelteon could have
been administered with food or without food. In other
words, there were two identifiable and predictable options.
As the district court recognized, “[w]hether to administer
tasimelteon with food is a binary choice.” J.A. 72. Under
these circumstances, given the FDA guidance, it would
have been obvious to try administering tasimelteon with-
out food. Therefore, we agree with the district court that
claim 5 of the ’487 patent is invalid for obviousness.
III. ’910 Patent
Vanda alleged that Teva and Apotex infringed claim 4
of the ’910 patent, which depends from claims 1, 2, and 3:
1. A method of treating a patient for a circadian
rhythm disorder wherein the patient is being
treated with rifampicin, the method comprising:
(A) discontinuing the rifampicin treatment
and then
(B) treating the patient with tasimelteon,
thereby avoiding the use of tasimelteon in
combination with rifampicin and also
thereby avoiding reduced exposure to
tasimelteon caused by induction of
CYP3A4 by rifampicin.
2. The method of claim 1 that comprises treating
the patient for Non-24-Hour Sleep-Wake Disorder.
3. The method of claim 2 wherein the patient is
light perception impaired (LPI).
4. The method of claim 3 wherein treating the pa-
tient with tasimelteon comprises orally
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administering to the patient 20 mg of tasimelteon
once daily before a target bedtime.
J.A. 159 (’910 patent, col. 40, ll. 7–22).
The district court found claim 4 would have been obvi-
ous. With respect to obviousness, the only additional limi-
tation at issue here with respect to claim 4 is the limitation
in claim 1 of: “(A) discontinuing the rifampicin treatment
and then (B) treating the patient with tasimelteon.”
J.A. 159 (’910 patent, col 40, ll. 10–11). The focus of claim
1 is avoiding the coadministration of rifampicin (an antibi-
otic drug) and tasimelteon. Rifampicin, also known as ri-
fampin, is a strong inducer of CYP3A4. CYP3A4 is an
enzyme that is often involved in drug metabolism. A
CYP3A4 inducer induces the expression of CYP3A4, which
causes CYP3A4 to increase its drug metabolism thereby
decreasing the amount of the metabolized drug in blood
plasma.
As of January 2012, the priority date of the patent, it
was known that ramelteon (a drug similar to tasimelteon)
“undergoes an 80 percent decrease in blood plasma levels
when it is co-administered with the CYP3A4 inducer rifam-
pin” because it is metabolized by CYP3A4. J.A. 29.
The district court found that a POSA “would have
looked to ramelteon to predict tasimelteon drug-drug inter-
actions because of the many known similarities between
ramelteon and tasimelteon.” J.A. 47. Based on the
ramelteon studies, the district court held that if “a skilled
artisan wanted to administer tasimelteon to a patient who
was already taking . . . rifampin, then the artisan would
have expected that tasimelteon should not be co-adminis-
tered with rifampin and would have thought it necessary
and obvious to stop treating the patient with rifampin be-
fore treating the patient with tasimelteon.” J.A. 48 (cita-
tions omitted).
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We see no error in the district court’s finding that a
skilled artisan would have looked to the ramelteon art be-
cause ramelteon and tasimelteon bind to the same recep-
tors, have similar half lives in the body, and are
structurally similar. The district court’s finding that a
POSA “would have looked to ramelteon” is not clearly erro-
neous.
Vanda also argues that the prior art taught away from
there being any problems with administering tasilemteon
with a CYP3A4 inducer. It is true that the only cited prior
art that studied the metabolism of tasimelteon by CYP3A4,
the Vachharajani reference, 11 found that “[n]o metabolism
of [tasimelteon] was observed following incubation with
[CYP3A4].” J.A. 23,857. This conclusion was echoed in
Hardeland, which did not include CYP3A4 in its list of en-
zymes that metabolize tasimelteon. However, these stud-
ies did not look into CYP3A4’s metabolism of tasimelteon
after CYP3A4 had been induced by rifampicin, a require-
ment of the claims.
The evidence in Vachharajani and Hardeland does not
refute the conclusion that a skilled artisan would recognize
that tasimelteon and ramelteon have similar properties,
nor does it suggest that the metabolism of tasimelteon by
CYP3A4 in its induced and uninduced (natural) states
would be the same. Induction of CYP3A4 by rifampicin
causes a large increase in CYP3A4 activity. So, it is possi-
ble for CYP3A4 to metabolize a drug after being induced
even if CYP3A4 does not metabolize that drug in its unin-
duced state. See J.A. 19,412 (Greenblatt 1,116:17–20). A
credible Teva/Apotex expert testified that, for this reason,
a skilled artisan who knew about the Vachharajani
11 Nimish N. Vachharajani et al., Preclinical Pharma-
cokinetics and Metabolism of BMS-214778, a Novel Mela-
tonin Receptor Agonist, 92 J. Pharm. Scis. 760 (2003).
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reference could not have ruled out an interaction between
tasimelteon and a CYP3A4 inducer, like rifampicin—i.e.,
could not have ruled out that coadministration of
tasimelteon and a CYP3A4 inducer such as rifampin would
cause tasimelteon to be metabolized too quickly. J.A. 54;
see also J.A. 19,412 (Greenblatt 1,116:17–20) (“[I]nduction
causes a massive increase in the amount of enzymes, and
you cannot exclude a major role of CYP3A4 [in metaboliz-
ing tasimelteon] in the induced state even if you can’t de-
tect it in the uninduced state.”). We therefore find no error
in the district court’s finding that it was obvious to avoid
coadministration of rifampicin and tasimelteon, and that
claim 4 would have been obvious.
IV. ’829 Patent
Vanda alleged that Teva and Apotex infringed claim 14
of the ’829 patent, which depends from claim 13:
13. A method of treating a patient for a circadian
rhythm disorder or for a sleep disorder wherein the
patient is being treated with a strong CYP1A2 in-
hibitor selected from a group consisting of fluvox-
amine, ciprofloxacin, and verapamil, the method
comprising:
(A) discontinuing treatment with the
strong CYP1A2 inhibitor and then
(B) treating the patient with 20 mg of
tasimelteon once daily.
14. The method of claim 13, that comprises treat-
ing the patient for Non-24-Hour Sleep-Wake Dis-
order.
J.A. 194 (’829 patent, col. 38, ll. 52–62). The claim ele-
ments at issue here are “(A) discontinuing treatment with
the strong CYP1A2 inhibitor and then (B) treating the
Case: 23-1247 Document: 48 Page: 16 Filed: 05/10/2023
16 VANDA PHARMACEUTICALS INC. v.
TEVA PHARMACEUTICALS USA, INC.
patient with . . . tasimelteon.” J.A. 194 (’829 patent,
col. 38, ll. 57–59).
The district court relied on Hardeland and, as with
claim 4 of the ’910 patent, a ramelteon study in finding
that claim 14 of the ’829 patent would have been obvious.
CYP1A2 is another enzyme that is often involved in drug
metabolism. A CYP1A2 inhibitor decreases CYP1A2’s abil-
ity to metabolize drugs, leading to a higher concentration
of drugs metabolized by CYP1A2 in blood plasma. The
Hardeland reference states that “[a]s tasimelteon is metab-
olized by [CYP1A2] . . . , coadministration of any drug that
inhibits [this enzyme] should be regarded with caution.”
J.A. 20,528. The ramelteon study showed that “ramelteon
underwent a 100-fold increase in blood plasma levels when
it was co-administered with the CYP1A2 inhibitor fluvox-
amine.” J.A. 29 (citations omitted). The district court ex-
plained that, as with claim 4 of the ’910 patent, the
ramelteon study is relevant to tasimelteon and “[a] skilled
artisan would have known that any drug-drug interaction
resulting in a five-fold change in blood plasma levels is con-
sidered ‘large’ by FDA standards, and therefore a skilled
artisan would have viewed the ramelteon-fluvoxamine
drug-drug interaction as a ‘huge interaction’ and clearly
significant.” J.A. 29 (citation omitted).
Vanda argues that the prior art does not tell a skilled
artisan not to prescribe tasimelteon with a CYP1A2 inhib-
itor and notes that the testing that explicitly showed that
coadministration of tasimelteon and a CYP1A2 inhibitor
renders tasimelteon ineffective was done after the priority
date. This argument misunderstands the standard for ob-
viousness.
Obviousness does not require certainty—it requires a
reasonable expectation of success. Pfizer, Inc. v. Apotex,
Inc., 480 F.3d 1348, 1364 (Fed. Cir. 2007). Taken together,
Hardeland’s warning and the ramelteon study supported
Case: 23-1247 Document: 48 Page: 17 Filed: 05/10/2023
VANDA PHARMACEUTICALS INC. v. 17
TEVA PHARMACEUTICALS USA, INC.
the district court’s finding that a skilled artisan would have
expected that taking a CYP1A2 inhibitor with tasimelteon
would have negatively impacted the efficacy of tasimelteon
and so the two should not be given together. Appellees did
not need to show that coadministration would have nega-
tively impacted tasimelteon’s efficacy, just that it would
have been reasonable to expect it to do so. The district
court did not err in finding that claim 14 would have been
obvious.
CONCLUSION
The district court did not err in finding all of the chal-
lenged claims obvious. In light of our invalidity conclusion,
we do not reach the question of infringement.
AFFIRMED