Court Opinion

ID: 9393465
Source: CourtListenerOpinion
Date Created: 2023-05-10 15:01:03.900379+00
Date Added: 2024-06-11T17:18:53.569549
License: Public Domain

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        NOTE: This disposition is nonprecedential.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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 TEVA PHARMACEUTICALS USA, INC.

 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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 4                            VANDA PHARMACEUTICALS INC. v.
                             TEVA PHARMACEUTICALS USA, INC.

 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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                             TEVA PHARMACEUTICALS USA, INC.

 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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 8                              VANDA PHARMACEUTICALS INC. v.
                               TEVA PHARMACEUTICALS USA, INC.

 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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 TEVA PHARMACEUTICALS USA, INC.

      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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 10                             VANDA PHARMACEUTICALS INC. v.
                               TEVA PHARMACEUTICALS USA, INC.

 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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 VANDA PHARMACEUTICALS INC. v.                                 11
 TEVA PHARMACEUTICALS USA, INC.

 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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 VANDA PHARMACEUTICALS INC. v.                             15
 TEVA PHARMACEUTICALS USA, INC.

 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
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 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
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 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