Full opinion text
Opinion dissenting filed by Circuit Judge NEWMAN Opinion for the court filed by Circuit Judge TARANTO. Before us are patents that claim the administration of a medication containing the active ingredient 4-aminopyridine (4-AP) to improve walking in individuals with multiple sclerosis. Acorda Therapeutics, Inc., holds New Drug Application No. 022250, approved by the U.S. Food and Drug Administration (FDA). Pursuant to that approval, Acorda markets, under the name "Ampyra®," 10 milligram 4-AP sustained-release tablets for twice-daily oral administration. In the FDA's Approved Drug Products with Therapeutic Equivalence Evaluations , or Orange Book, Acorda has listed, as claiming methods of using Ampyra, four patents that Acorda owns: U.S. Patent No. 8,007,826 ; No. 8,663,685 ; No. 8,354,437 ; and No. 8,440,703. Those patents ("the Acorda patents") are the main patents at issue on appeal. One additional patent is before us. Acorda holds an exclusive license to an earlier, broader patent, U.S. Patent No. 5,540,938, referred to as "the Elan patent" because it was originally assigned to Elan Corporation, plc (whose successor in interest is Alkermes Pharma Ireland Ltd.). The Elan patent, listed in the Orange Book for Ampyra along with the Acorda patents, claims methods of treating patients having certain conditions, including multiple sclerosis, by administering a drug containing a sustained-release formulation of any of certain agents, one of them 4-AP. The later Acorda patents claim species of the Elan patent's genus claims by adding further, more specific requirements to the Elan patent's claimed methods. While the Elan patent's claims broadly cover administering a sustained-release formulation of 4-AP to individuals with multiple sclerosis, the Acorda patents' claims further specify that such a drug must be administered (1) in a 10 mg dose twice a day (2) at that stable dose for the entire treatment period of at least two weeks (3) to achieve 4-AP serum levels of 15-35 ng/ml and (4) to improve walking. Roxane Laboratories, Inc.; Mylan Pharmaceuticals, Inc.; and Teva Pharmaceuticals USA, Inc., have submitted Abbreviated New Drug Applications seeking FDA approval to market generic versions of Ampyra. In July 2014, Acorda and Alkermes sued those entities ("defendants") in the District of Delaware, alleging infringement of several claims in each of the Elan and Acorda patents. The defendants stipulated to infringement but challenged the validity of the asserted claims. The district court held that the asserted claims in the Acorda patents are invalid for obviousness. But the court upheld the asserted claims of the Elan patent against invalidity challenges and enjoined the defendants from activity infringing that patent until it expired on July 30, 2018. Acorda appealed the invalidity ruling regarding the Acorda patents. The defendants cross-appealed the validity ruling regarding the Elan patent and the resulting injunction. We now affirm the judgment that the asserted Acorda patent claims are invalid. We dismiss the cross-appeal as moot. I A In view of our decision that the issues concerning the Elan patent are moot, we focus on the background of the Acorda patents. Essential to understanding the obviousness issue is an understanding of the prior art. 4-AP, also called "dalfampridine" and "fampridine," was first identified in 1902. Acorda Therapeutics, Inc. v. Roxane Labs., Inc. , No. 1:14-cv-00882-LPS, 2017 WL 1199767, at *3, *5 (Mar. 31, 2017) ( Dist. Ct. Op. ). Belonging to a class of compounds that function as potassium-channel blockers, 4-AP "has been found to slow the potassium flow in nerve impulse transmission" and, by doing so, help "restor[e] conduction in blocked and demyelinated nerves," '826 patent, col. 2, lines 5-11, i.e. , nerves whose myelin insulation has been damaged. 4-AP was first used in human studies in the 1970s to investigate its effect on neurological diseases resulting in muscle weakness. Dist. Ct. Op. at *5. For several decades, 4-AP has been the focus of research regarding the treatment of multiple sclerosis in particular. See, e.g. , id. at *5-7 (reciting studies); J.A. 6697 (paper published in 1987 describing study of the effect of 4-AP on subjects with multiple sclerosis ). Multiple sclerosis causes the demyelination, or loss of myelin, of nerves in the central nervous system and results in a wide variety of symptoms, including walking impairment, tingling or pain, brain scarring, cognitive changes, visual impairments, and fatigue. See '826 patent, col. 1, lines 36-42; Dist. Ct. Op. at *2. Eventually, 4-AP research led to the development, patenting, and FDA approval of Ampyra. 1 In the 1980s, researchers at the Rush Medical School conducted a study on 12 patients with multiple sclerosis, and 5 without, to determine whether intravenous administration of 7 to 35 mg of 4-AP had any therapeutic effect on multiple sclerosis. J.A. 6697 (Dusan Stefoski et al., 4-Aminopyridine Improves Clinical Signs in Multiple Sclerosis , 21 Annals of Neurology 71 (1987) ). According to the published paper reporting that study (Stefoski), 10 of the 12 patients with multiple sclerosis"showed mild to marked improvement"; "[v]ision improved in 7 patients, oculomotor function in 5, and motor function (power, coordination, gait) in 5." J.A. 6697. Improvements were seen at doses as low as 2 mg: In one patient, gait improvement occurred within 25 minutes of administration of a total dose of 2 mg. J.A. 6699. Stefoski also reported: [W]e observed no serious or bothersome side effects at total doses below 30 to 35 mg injected not less than 20 minutes apart for aliquots up to 3 mg. Moreover, the clinical improvements in many of our patients were of sufficient magnitude to represent a functionally noteworthy therapeutic benefit. Studies are currently in progress to determine the clinical usefulness of oral 4-AP as a symptomatic treatment. J.A. 6701; accord J.A. 6697. In 1990, an overlapping group of researchers published a paper (Davis) reporting another study on 4-AP's effect on symptoms of multiple sclerosis. J.A. 6327 (Floyd A. Davis et al., Orally Administered 4-Aminopyridine Improves Clinical Signs in Multiple Sclerosis , 27 Annals of Neurology 186 (1990) ). In that study, 20 patients with multiple sclerosis were given either a single oral dose of 4-AP (15 patients) or a placebo (5 patients). J.A. 6327. Of those in the active treatment group, 4 patients were given a 10 mg dose of 4-AP, 2 were given 12.5 mg, 4 were given 15 mg, 4 were given 20 mg, and 1 was given 25 mg. Davis at 187 tbl.1. Davis states that "[m]ild to marked improvements occurred in all of the 15 [multiple sclerosis] patients given 4-AP." J.A. 6329; accord J.A. 6327. "Improvements developed gradually with doses as low as 10 mg 4-AP, usually beginning within 60 minutes after drug administration." J.A. 6329. Motor function improved in 9 of 13 patients in the active treatment group (motor function was not measured in 2). Davis at 187 tbl.1; J.A. 6329. The improvements were "most striking[ ] with respect to power and coordination" and "were apparent with both simple function tests and the performance of complex motor tasks such as gait and repetitive movements." J.A. 6329. Finally, Davis notes, no "serious or bothersome side effects," including seizures, were observed at single oral doses up to 25 mg. J.A. 6332. A few years later, researchers at a university hospital in the Netherlands published a paper (Van Diemen) reporting a randomized, double-blind, placebo-controlled crossover study that "demonstrated efficacy of [4-AP] in improving disability of patients with multiple sclerosis." J.A. 7037 (Harriët A. M. Van Diemen et al., 4-Aminopyridine in Patients with Multiple Sclerosis : Dosage and Serum Level Related to Efficacy and Safety , 16 Clinical Neuropharmacology 195 (1993) ). In the second phase of the study lasting 12 weeks, 69 patients were orally administered 10-20 mg 4-AP per day, split into two or three doses. J.A. 7038, 7042. The doses were escalated during the second week, and again during the sixth week, by 5-15 mg. J.A. 7038-39. The paper reports improvements in certain measures of eye functioning. J.A. 7042. And it reports that "side effects were mild" for those patients given oral doses of 4-AP (versus intravenous 4-AP). J.A. 7045; see also Van Diemen at 200-01 (no seizures). Soon thereafter, some of the same researchers published a second paper (Polman) about the long-term efficacy and safety of 4-AP given to patients with multiple sclerosis. J.A. 6654 (Chris H. Polman et al., 4-Aminopyridine in the Treatment of Patients with Multiple Sclerosis , 51 Archives of Neurology 292 (1994) ). Polman reports a study of 31 patients with multiple sclerosis, 19 of whom took a stable dose of 4-AP between 10-50 mg per day (the exact dose for each patient is unknown), and 12 of whom initially took 10-15 mg per day and then took increasing doses in 4 to 8 weeks. J.A. 6655; see J.A. 7042. In the first group, 18 of the 19 patients "had a favorable response to the medication" and "reported a subjective improvement in the ability to perform the activities of normal daily life, which was mainly owing to improved ambulation and reduction in severity of fatigue." J.A. 6655. In 3 patients, the subjective improvement was significant on the Expanded Disability Status Scale (EDSS), id. -a composite measure of function in multiple sclerosis patients, including a walking component, that is "widely accepted in the [multiple sclerosis ] community," Dist. Ct. Op. at *8 ; see id. at *30 ; J.A. 6681. In the second group, 6 patients reported a "favorable response" to 4-AP treatment, "as defined by the ability to perform activities of normal daily life." J.A. 6655-56. One patient demonstrated a significant improvement in EDSS score. J.A. 6656. Overall, 23 patients (17 in the first group; 6 in the second group) continued active treatment for 6 to 32 months, with daily doses ranging from 15-40 mg. J.A. 6655-56. Those patients "indicated the drug to be beneficial because, by improving several neurologic functions, it increased their capability to perform the activities of normal daily life," including-for 13 of the 23 patients-a reported improvement in ambulation and fatigue. J.A. 6656 & tbl.1; see J.A. 6654. The paper states: Although a placebo effect cannot be excluded, the dynamics of the response in relation to the intake of the medication and the deterioration and subsequent improvement in functioning during a drug-free interval and subsequent restarting of the therapy are, in our view, highly suggestive of a real effect being induced by the 4-[AP]. Improvements in fatigue and ambulation were mentioned quite often by the patients as being responsible for the favorable overall effect .... J.A. 6657. The paper thus reports improvements in specific measures, while few patients experienced a significant change in EDSS, the overall composite measure. Id. As for adverse effects, two patients experienced a seizure-one on the second day of treatment and the other after 18 months of treatment. J.A. 6656-57. Otherwise, the subjective side effects reported by the patients "never were reported to be very troublesome." J.A. 6657. Polman states several conclusions and suggestions for further research. First, the study "demonstrates that 4-[AP] therapy, in the majority of patients who favorably respond to it, results in responses that can continue for periods of up to 32 months or more without interfering with the course of the disease." Polman at 296. Second, the fact that "three major, though not life-threatening, side effects" occurred (including 2 seizures) "indicates that careful medical supervision is warranted during 4-[AP] therapy." Id. Third, based on the study data, the authors "suggest that approximately 30% of patients with [multiple sclerosis ] will report a significant clinical response when they begin treatment with 4-[AP] and that 80% to 90% of these responders will benefit from long-term administration. More studies are needed for further elaboration of the exact value of 4-[AP] in the long-term treatment of patients with [multiple sclerosis ]." Id. Around the same time, researchers at the University of Maryland, the Baltimore VA Medical Center, and Elan published a paper (Bever I) reporting the results of a randomized, placebo-controlled, double-blind, concentration-controlled, crossover trial in 8 patients with multiple sclerosis. Christopher T. Bever, Jr., et al., The effects of 4-aminopyridine in multiple sclerosis patients: Results of a randomized, placebo-controlled, double-blind, concentration-controlled, crossover trial , 44 Neurology 1054 (1994); see J.A. 6180 (excerpt of Bever I). Noting that 4-AP has a "narrow toxic-to-therapeutic range[ ]," the study aimed to evaluate the toxicity and efficacy of 4-AP when the resulting peak concentration in blood was low (30-59 ng/ml) versus when it was high (60-100 ng/ml). Bever I at 1055. Regarding toxicity, the report states that "[a]ll patients experienced side effects" when serum concentration was high, with two serious adverse events: a seizure when serum 4-AP peaked at 104 ng/ml, and an episode of encephalopathy when serum 4-AP peaked at 114 ng/ml. Id. at 1054, 1056. Regarding efficacy, "[i]mprovements were seen in lower extremity strength," including significant improvement in mean videotape scores of lower extremity strength (scoring muscle strength, reflexes, and ambulation) in both the low- and high-serum concentration ranges, although no significant changes were seen in EDSS scores or ambulation index (AI) scores. Id. at 1056-57 & tbl.4; but see id. at 1058 (commenting that the increased side effects from the short treatment duration "may have contributed to the lack of improvement in overall function (EDSS and AI scores)"). Bever I concludes that the therapeutic response was not concentration-related as between the two ranges tested and, therefore, that "[t]he lower serum concentration range of 30 to 59 ng/ml may ... be adequate for inducing improvement of some neurologic deficits." Bever I at 1058; see id. ("Because the high-serum-concentration arm produced much greater toxicity than the low without any obvious therapeutic advantage, it seems likely that clinically useful serum concentrations would be in the 30 to 59 ng/ml range."). Bever I also states that the "rates of treatment-related improvements in visual and lower extremity motor function ... were similar to those reported in similar short-term trials of [4-AP]," including Stefoski and Davis. Bever I at 1057-58. The article notes the limitations of the earlier trials' designs, including "questions about blinding, failure to randomize treatment, and failure to either use prospectively defined neurologic deficits or adjust significance levels to compensate for multiple comparisons." Id. at 1058. Bever I then observes that another study "addressed some of the design weaknesses in earlier studies and suggested that not only can AP treatment improve specific residual deficits, but it can also improve overall function." Id. The same year as Bever I appeared, Dr. Bever, with the University of Maryland and the Baltimore VA Medical Center, published a review article on studies of the effect of 4-AP on multiple sclerosis (Bever II). Christopher T. Bever, Jr., The Current Status of Studies of Aminopyridines in Patients with Multiple Sclerosis , 36 Annals of Neurology S118 (1994); see J.A. 6172 (excerpt of Bever II). The article states: "Recently completed randomized, double-blind, placebo-controlled trials show that treatment with the potassium channel blockers 4-aminopyridine (AP) or 3,4-diaminopyridine (DAP) can improve residual neurological deficits in some multiple sclerosis (MS) patients." Bever II at S118; accord id. at S120. As to efficacy, "[t]hese studies suggest that aminopyridines may provide a new approach to the symptomatic treatment of [multiple sclerosis ]." Id. at S118. As to toxicity, "seizures are common at higher doses," but 4-AP "rarely cause[s] seizures at the doses used in [multiple sclerosis ] trials." Id. at S120; see also id. at S118 ("Both agents [4-AP and DAP] have rarely caused seizures."). The paper notes that one 4-AP study "showed that side effects correlated with peak serum concentrations, while efficacy correlated with total drug exposure, suggesting that controlled release formulations may be useful in minimizing toxicity." Id. at S120. 2 The foregoing studies involved immediate-release, rather than sustained-release, formulations of 4-AP. See Dist. Ct. Op. at *4 ; J.A. 761, 763, 767, 769, 774 (testimony of Acorda's expert, Dr. Andrew Goodman). By 1990, Elan, which was known for its work on sustained-release formulations, entered into an agreement with the researchers at Rush Medical School to obtain their work on 4-AP pharmaceutical formulations. Dist. Ct. Op. at *4. According to Dr. Michael Myers, who worked at Elan at that time and is a named inventor on the Elan patent, Elan was interested in developing a sustained-release formulation of 4-AP to "potentially reduce or eliminate some of th[e] side effects" associated with the immediate-release formulation. Sept. 19, 2016 Trial Tr. at 149, 155-56, Acorda Therapeutics, Inc. v. Alkem Labs. Ltd. , No. 1:14-cv-00882-LPS (D. Del. Oct. 21, 2016), ECF No. 266. Elan developed a 4-AP sustained-release formulation in approximately a month's time. Dist. Ct. Op. at *4. The inventors then filed for what became the Elan patent, which claims, among other things, administration of a sustained-release formulation of 4-AP once or twice daily for the treatment of neurological diseases, including multiple sclerosis. Elan patent, col. 22, lines 16-25, 29-30, 50-51 (independent claim 1 and dependent claims 3 and 8). The Elan patent has a priority date of November 1, 1991; issuance date of July 30, 1996; and expiration date of July 30, 2018. In 1994, Elan conducted a double-blind, randomized, placebo-controlled clinical trial involving 161 patients with multiple sclerosis to study the safety and efficacy of the sustained-release 4-AP formulation. Dist. Ct. Op. at *8. Patients were administered 12.5 mg 4-AP twice a day, which was later increased to 17.5 mg twice a day and finally to 22.5 mg twice a day. Id. One of the primary endpoints measured was the EDSS composite measure of function. See id. For the primary endpoints and most of the secondary endpoints, including ambulation, the trial revealed no statistically significant improvements for 4-AP versus placebo. Id. But it did show a statistically significant improvement in the secondary outcome of lower extremity motor score, a measure of muscle strength in the legs. Id. The 1994 Elan study was not published. Elan also sponsored a smaller, double-blind, placebo-controlled, crossover study in ten patients with multiple sclerosis. That study was reported in a paper published in 1997 (Schwid), on which Dr. Goodman, Acorda's expert at trial, was the senior author. J.A. 6681-84 (Steven R. Schwid et al., Quantitative assessment of sustained-release 4-aminopyridine for symptomatic treatment of multiple sclerosis , 48 Neurology 817 (1997) ). In the background section, Schwid reports that an earlier, 161-patient study had been conducted to test improvement in EDSS for multiple sclerosis patients (the unpublished 1994 Elan study), but that it did not detect a significant improvement in that measure. J.A. 6681. Schwid notes, however, that the EDSS "may have been an inadequate outcome variable for [the 1994 Elan] trial." Id. The paper explains: [The EDSS] is imprecise due to substantial intrarater and inter-rater variability, and relatively insensitive to change due to its ordinal nature. For example, a patient who needed a cane to walk 100 meters would need to improve enough to walk without the cane before the EDSS score would change. Lesser improvements in gait would not be reflected by the EDSS, and notable changes in strength or other deficits could also be overlooked. We planned the present pilot study to assess the effect of 4AP [sustained release] on more sensitive, quantitative measures of function in [multiple sclerosis ]. Id. (internal references omitted). In the Schwid study, ten patients were each given 17.5 mg sustained-release 4-AP twice a day for a week and placebo for a week. Id. The study measured (1) time to walk 8 meters (timed gait), (2) time to climb four stairs, (3) maximum voluntary isometric contraction measured quantitatively, (4) manual muscle testing, (5) grip strength, (6) EDSS, and (7) the patient's global impression. Id. Schwid reports that the administered drug demonstrated a statistically significant improvement over placebo for timed gait in 9 of 10 patients, with p = 0.02. Id. In addition to that result, Schwid observes that "most of the other outcomes showed trends favoring 4AP [sustained-release]." J.A. 6684. Schwid concludes that, in the reported study, "4AP [sustained-release] improved motor function in [multiple sclerosis ] patients." J.A. 6681. The article notes that the results of the Schwid study are consistent with "[p]revious double-blind, placebo-controlled studies" using an immediate-release formulation of 4-AP, including another study reported by Stefoski (13 of 17 patients "showed 'clinically important' improvements"), Bever I (reporting that 4-AP "improved lower-extremity strength" and "a composite score of leg strength, spasticity, and ambulation"), and another study reported by Van Diemen (improvement in neurologic deficits, as measured by the EDSS). J.A. 6684. Schwid also states: "The quantitative outcomes used in this study permit more sensitive evaluation of the therapeutic effect and promise to be useful in future trials of symptomatic treatments for [multiple sclerosis ]." J.A. 6681. It notes particularly that timed gait showed improvement where the EDSS did not. Id. ; J.A. 6684. Schwid advises that future studies evaluate the more sensitive outcome measures, "establish[ ] efficacy in larger trials," and "examine long-term efficacy and tolerability as well as further refine dosing regimens to optimize delivery despite a relatively narrow therapeutic window." J.A. 6684. 3 While Elan was conducting those studies, Acorda was exploring the use of 4-AP in patients with spinal cord injuries. Dist. Ct. Op. at *8. In 1997, Elan granted Acorda an exclusive license to the Elan patent for the use of Elan's sustained-release formulation of 4-AP in patients with spinal cord injuries. Id. Acorda conducted two studies to evaluate the pharmacokinetic and safety profile of the sustained-release formulation, and the results of both studies are reported in a paper published in 2003 (Hayes). J.A. 6433-40 (Keith C. Hayes et al., Pharmacokinetic Studies of Single and Multiple Oral Doses of Fampridine-SR (Sustained-Release 4-Aminopyridine) in Patients With Chronic Spinal Cord Injury , 26 Clinical Neuropharmacology 185 (2003) ). In the second study, Acorda tested doses of 10 mg, 15 mg, 20 mg, and 25 mg of the sustained-release formulation of 4-AP administered twice daily in patients with spinal cord injuries. J.A. 6434. The average serum concentration level (at steady state) for the 10 mg twice-daily dose was 20.8 ± 5.7 ng/ml. J.A. 6439; accord '826 patent, col. 25, lines 1-28 (Table 7); '685 patent, col. 25, lines 5-32 (Table 7). Acorda also conducted clinical trials to evaluate the efficacy of that sustained-release formulation of 4-AP in patients with spinal cord injuries, but those studies failed. Soon after, Acorda learned that Elan was "no longer interested in pursuing or supporting" research into use of Elan's sustained-release formulation of 4-AP for treatment of multiple sclerosis. J.A. 596 (testimony of Dr. Ron Cohen, Acorda founder). Acorda told Elan that it wished to take over that research. Id. In 1998, Elan agreed to expand the earlier license to Acorda; it granted Acorda exclusive rights over the 4-AP sustained-release formulation for use in the treatment of multiple sclerosis. Dist. Ct. Op. at *8. Acorda reviewed Elan's research, including Elan's pharmacokinetic data and clinical study reports of the 1994 Elan study. Acorda then conducted its own clinical trials. Id. at *9. a In 2000 and 2001, Acorda ran a study-the MS-F201 study-which involved 36 patients with multiple sclerosis and whose results were published only in part. Id. After one week of a placebo lead-in, a group of 25 patients received 10 mg 4-AP twice daily for a week, then higher dosages, which increased weekly in 5 mg increments up to 40 mg twice daily at week 7. Id. The rest of the patients consistently received a placebo. See id. The outcome measures included fatigue, a lower extremity muscle test, a multiple sclerosis functional composite (timed 25-foot walk; nine-hole peg test; cognitive test), and subjective measures. Id. Only the lower extremity muscle test showed a statistically significant difference-"when comparing the seven week range [4-AP] group against placebo." J.A. 604-05. The results were not statistically significant for the timed 25-foot walk for any particular dose of 4-AP; and in 3 of the 7 weeks, the placebo group did better in the timed walk than the 4-AP group taking 10 mg twice daily. Dist. Ct. Op. at *9. After the study was completed, Acorda conducted a post-hoc analysis of the data on walking speed-which, unlike timed 25-foot walk, was not an endpoint the study was designed to test-and identified a statistically significant difference between the placebo and 4-AP groups considering all doses in the aggregate. Id. Most but not all of the just-described results of the MS-F201 study were published. Dr. Goodman published two nearly identical abstracts in early 2003 (Goodman I, J.A. 6371-72, and Goodman II, J.A. 6370) and presented a poster in connection with those abstracts in late 2002 (Goodman Poster, J.A. 6497-504). Goodman I explains that "[t]he primary aim" of the randomized, placebo-controlled, double-blinded Phase II dose-ranging study was to "determine the safety and tolerability of escalating doses of a sustained release (SR) formulation [of 4-AP], given orally to patients with [multiple sclerosis ]," and that "[t]he secondary aim was to explore efficacy over a broad dose range using measures of fatigue and motor function." J.A. 6371; see Dist. Ct. Op. at *14. The abstract discloses that the study involved 36 patients, 25 in the active-treatment and 11 in the placebo group, and that the active-treatment group received 20 mg/day 4-AP, with doses escalating 10 mg/day to reach a maximum of 80 mg/day during week 8 of the study. J.A. 6371-72; see Dist. Ct. Op. at *14. In the "Results" section, Goodman I reports that five subjects withdrew as a result of adverse effects, including two seizures, and that adverse effects were "more severe at doses of 50 mg/day and higher," including the two seizures that occurred at doses of 60 and 70 mg/day. J.A. 6372; see Dist. Ct. Op. at *14. Another reported result is that the 4-AP sustained-release treatment "group showed statistically significant improvement from baseline compared to placebo in functional measures of mobility (timed 25 walking speed; p=0.04) and lower extremity strength (manual muscle testing; p=0.01). Dose-response curves showed increasing benefit in both measures in the 20 to 50 mg/day range." J.A. 6372; see Dist. Ct. Op. at *14. The abstract clarifies that "[n]o other measures showed significant treatment effects." J.A. 6372; see Dist. Ct. Op. at *14. The "Conclusions" section reads: The safety profile of [4-AP sustained-release] was consistent with previous experience. Doses above 50 mg [per day] added little benefit and increased adverse effects. There was significant improvement in measures of mobility and muscle strength. J.A. 6372. The Goodman Poster is similar. It reproduces almost all of the material in Goodman I in the "Abstract" section at the upper-left-hand corner of the poster. J.A. 6502 (capitalization altered). The Poster contains more detail in the "Background" section, which notes that "[r]ecent clinical studies have indicated that [4-AP] promotes improvement in motor strength, walking, fatigue, and endurance in people with [multiple sclerosis ]"; that observed adverse events, including seizures, were associated with higher peak plasma concentrations and rapid plasma concentration changes caused by immediate-release 4-AP; and that sustained-released formulations were developed to address those problems. Id. (capitalization altered). The study objectives were defined as: (1) "[d]etermine safety of multiple doses of [sustained-release 4-AP] (one week each of 20 mg/day, 30 mg/day, 40 mg/day, 50 mg/day, 60 mg/day, 70 mg/day, and 80mg/day)"; and (2) "[o]btain evidence of efficacy and dose-response using several outcome measures." Id. ; accord id. (Methods section). The Goodman Poster notes that, because individuals taking 4-AP "frequently report" improvements in activity and fatigue levels, the study focused on outcomes associated with such effects-namely, timed ambulation, manual muscle testing, and patients' self-reports of fatigue-rather than the EDSS, because "it was not clear whether" the EDSS "would adequately reflect this type of improvement." Id. (Methods section). As to the study's results concerning safety, the Goodman Poster provides, in the "Results Summary," that "more severe adverse events," including seizures, occurred "[a]t doses above 40 mg/day." J.A. 6504 (capitalization altered). The Poster states that "the risk of seizure requires further study and characterization[,] particularly in the anticipated dose range." Id. As to the results concerning efficacy, the Goodman Poster includes a graph of a dose-response curve for the 25-foot walk: J.A. 6503. The graph shows that the total time for the walk decreased significantly between the placebo dose (run-in) and the 20 mg/day dose. Id. The total time seems to have plateaued at higher doses. Id. (total time remained between approximately 12.5 and 14 seconds as doses increased from 20 mg/day to 80 mg/day); see also Sept. 19, 2016 Trial Tr. at 102-03, 137 (testimony of defendants' expert Dr. Peroutka, observing a walk time between 12 and 14 seconds for a "stable clinical effect at 20 to 40" mg/day in the "flat part of the dose response curve"). The results section also provides bar graphs showing changes in individual patients' speed on the 25-foot walk. J.A. 6503. The upper bar graph shows, on average, improvements in speed for patients in the active-treatment group, aggregated for doses ranging from 20-50 mg/day. Id. ; see J.A. 416. It appears that a few of those patients' speed decreased by approximately 0-10%, while more than a dozen patients' speed increased by more than 10%-nine by more than 20%, four by more than 40%, and one by more than 60%. J.A. 6503. The lower bar graph shows, on average, zero or slight improvement in speed for patients in the placebo group, with no patient's speed having improved by more than 20% and one patient's speed having decreased by more than 20%. Id. The results for improvements in leg strength between the active-treatment group (aggregating the doses of 20-50 mg/day) and placebo group showed a similar trend: Id. In the "Results Summary," the Goodman Poster states that "[s]ignificant improvement in walking speed was observed in the [4-AP sustained-release] treated group (p=0.04*)," where the p-value reflects a "*repeated measure ANOVA (weeks 1-7)"-i.e. , the walking speed for the active-treatment group, aggregating the dose levels. J.A. 6504; see Dist. Ct. Op. at *14 n.11 (noting that Dr. Goodman explained that the p-value reflects "the aggregated value for the treatment group as a whole, including all dosages, and did not reflect the results associated with any single dosage" (emphasis omitted) ). More specifically, the Goodman Poster reports that (1) "[t]he average improvement in walking speed [in the 25-foot walk] during the low dose period (20-50 mg/day) included > 20% increase for 9 of the 25 subjects" and (2) "[c]hanges in the placebo-treated group were equally distributed between increases and decreases in walking speed and none of the 11 subjects showed increases > 18% during the low dose period." J.A. 6504. The Poster also reports, for the lower extremity manual muscle test (LEMMT), a "[s]tatistically significant improvement in the [4-AP sustained-release] treated group (p=0.01*)." Id. The Conclusions section contains six bullet points. The first states that the "[s]afety profile [is] consistent with previous experience." J.A. 6503. The next few bullet points report a "[s]ignificant benefit on timed walking," "[s]ignificant benefit on lower extremity strength," "[n]o evidence of benefit on overall fatigue-susceptibility of fatigue to placebo effect," and "[e]vidence of dose-response in 20-40 mg/day range." Id. Finally, there was "[l]ittle added benefit, and increased [adverse events,] at doses above 50 mg/day."Id. This Goodman prior art-which post-dates Elan's transfer of the research project to Acorda and which added significantly to the teachings of the earlier prior art-became the most important prior art in the obviousness analysis in this case. b In 2003, after completion of the MS-F201 study, Acorda conducted another placebo-controlled Phase II study (MS-F202 study) to test 4-AP's effect on walking speed. Dist. Ct. Op. at *9. After a two-week up-titration period beginning with a 10 mg dose, patients were administered a stable dose of 10 mg, 15 mg, or 20 mg sustained-release 4-AP twice daily for twelve weeks. Id. Although none of the 4-AP groups demonstrated a statistically significant improvement in walking speed relative to placebo, another post-hoc analysis showed that responders were in the 4-AP group (p < 0.0001) and that there was no meaningful difference in efficacy among the tested 4-AP doses. Id. ; see also J.A. 612-14 (Acorda founder Dr. Cohen explaining that isolating responders in the study-those patients with improved walking-showed that responders were overwhelmingly in the active treatment groups and that there was no meaningful difference in efficacy among the responders in those treatment groups taking 10 mg, 15 mg, or 20 mg twice daily). Acorda then conducted two Phase III studies to evaluate the effect of 10 mg sustained-release 4-AP twice daily, with walking improvement responder analysis as the primary outcome measure. Id. Both studies were successful, with p < 0.0001. Id. Neither the results of the MS-F202 study nor the results of the Phase III studies constitute publicly available prior art to the Acorda patents in this case. 4 On April 9, 2004, Acorda employees filed a provisional patent application; that date is undisputedly the priority date of the Acorda patents. Id. at *9 n.8. The Acorda patents issued between August 2011 and March 2014. The parties treat the Acorda patents' claims, for purposes of the invalidity issue on appeal, as involving methods of administering to a patient with multiple sclerosis a sustained-release 4-AP formulation (1) in a 10 mg dose twice daily, (2) at that stable dose for the entire treatment period of at least two weeks, (3) maintaining 4-AP serum levels of 15-35 ng/ml, (4) with walking improved. The parties treat claim 7 of the '826 patent and claim 22 of the '437 patent as representative. Claim 7 of the '826 patent depends on claim 6, which reads: 6. A dosing regimen method for providing a 4-aminopyridine at a therapeutically effective concentration in order to improve walking in a human with multiple sclerosis in need thereof, said method comprising: initiating administration of 4-aminopyridine by orally administering to said human a sustained release composition of 10 milligrams of 4-aminopyridine twice daily for a day without a prior period of 4-aminopyridine titration, and then, maintaining administration of 4-aminopyridine by orally administering to said human a sustained release composition of 10 milligrams of 4-aminopyridine twice daily; without a subsequent period of 4-aminopyridine titration, whereby an in vivo CmaxSS:CminSS ratio of 1.0 to 3.5 and a CavSS of 15 ng/ml to 35 ng/ml are maintained in the human. '826 patent, col. 27, lines 41-57. Claim 7 covers "[t]he method of claim 6, whereby an increase in walking speed is obtained in said human." Id. , col. 27, lines 58-59. Claim 22 of the '437 patent depends on claim 18, which depends on claim 1. Claim 1 of the '437 patent reads: 1. A method of increasing walking speed in a human multiple sclerosis patient in need thereof comprising orally administering to said patient a sustained release composition of 10 milligrams of 4-aminopyridine twice daily for a time period of at least two weeks, wherein said 10 milligrams of 4-aminopyridine twice daily are the only doses of 4-aminopyridine administered to said patient during said time period. '437 patent, col. 27, lines 55-61. Claim 18 requires that the sustained release composition in claim 1 be "a tablet," id. , col. 28, lines 47-48; and claim 22 requires that the tablet of claim 18 "exhibit[ ] a release profile to obtain a CavSS of about 15 ng/ml to about 35 ng/ml," id. , col. 28, lines 55-57. The parties have not distinguished the claims for purposes of the invalidity issue before us. 5 Acorda submitted New Drug Application No. 022250 to the FDA for the use of 10 mg 4-AP extended-release tablets (Ampyra). The FDA granted priority review to that application and approved it on January 22, 2010. According to the approved FDA label, Ampyra " 'is indicated as a treatment to improve walking in patients with multiple sclerosis (MS). This was demonstrated by an increase in walking speed.' " Dist. Ct. Op. at *4 (citation omitted). "Improvement in walking in MS patients is [the] only approved use" of Ampyra. Id. The "Description" section of the label states that " 'Ampyra (dalfampridine) is a potassium channel blocker, available in a 10 mg tablet strength ..., formulated as an extended release tablet for twice-daily oral administration.' " Id. (capitalization altered). The "Dosage and Administration" section explains that " '[t]he maximum recommended dose of Ampyra is one 10 mg tablet twice daily, taken with or without food, and should not be exceeded. ... No additional benefit was demonstrated at doses greater than 10 mg twice daily and adverse reactions and discontinuations because of adverse reactions were more frequent at higher doses.' " Id. (capitalization altered). Between the time of FDA approval in 2010 and the end of 2015, total sales of Ampyra were $1.7 billion and net income was $998.7 million. Id. at *16. Net sales of Ampyra, in dollars, increased at an average rate of 20% per year, and the volume of tablets sold increased at an average rate of 8% per year, despite an increasing price per tablet over that period (2010 to 2015). Id. Acorda also receives royalty payments from licenses to sell Ampyra outside the United States; it has collected at least $135 million from those licenses. Id. Commercial opportunity, however, is constrained because Ampyra is indicated only for improvement of walking. Id. at *16-17. Ampyra sales revenue is approximately 2-3% of the total sales revenue from the top ten multiple sclerosis drugs. Id. at *17. Not all multiple sclerosis patients respond to Ampyra. Among multiple sclerosis patients who experience walking difficulties, 15-20% of those patients are prescribed Ampyra. Id. On the other hand, Ampyra is the first and only drug approved for improving walking in multiple sclerosis patients. Id. When Sanofi-Aventis in 2008 conducted a Phase III study to test whether a different potassium-channel blocker, nerispirdine, would improve walking in patients with multiple sclerosis, it did not find evidence of a "specific significant difference between the responders [and] non-responders that received nerispirdine or placebo" in a timed 25-foot walk. J.A. 726-28 (testimony of Acorda's expert Dr. Fred Lublin); see Dist. Ct. Op. at *17. B In 2014, the defendants notified Acorda and Alkermes of the defendants' submission of Abbreviated New Drug Applications seeking FDA approval to market generic versions of Ampyra. In mid-July 2014, Acorda and Alkermes filed suits against Roxane, Mylan, and Teva, among others, in the District of Delaware for the alleged infringement of several claims in each of the Elan and Acorda patents under 35 U.S.C. § 271(e). The cases were consolidated in 2015. The defendants stipulated to infringement of the asserted claims-claims 3 and 8 of the Elan patent; claims 1, 7, 38, and 39 of the '826 patent ; claims 3 and 5 of the '685 patent ; claims 1, 2, 5, 22, 32, 36, and 37 of the '437 patent ; and claims 36, 38, and 45 of the '703 patent. Dist. Ct. Op. at *9-12, *18. The defendants, however, challenged the validity of the asserted claims of all five patents for obviousness under 35 U.S.C. § 103. The defendants also challenged the validity of the asserted claims of the Elan patent for insufficient written description and enablement under 35 U.S.C. § 112, ¶ 1. After a bench trial held in September 2016, the district court determined that the defendants had not proven invalidity of the Elan patent. Dist. Ct. Op. at *20-29. But the court held that the defendants had proven that the asserted claims of the Acorda patents are invalid for obviousness. Id. at *29-41. As to the Acorda patents: Based on the publications discussed above, as well as expert testimony, the court found that, as of 2004 (the priority date), a relevant skilled artisan would have been motivated to administer a stable dose of 10 mg of 4-AP twice daily and had a reasonable expectation of success in the objective of improving the walking ability of multiple sclerosis patients. Id. at *30-35. The court also found that the Acorda patents' claim limitations regarding serum levels (the pharmacokinetic limitations) were inherent in the dosing claimed. Id. at *35-36. Finally, the court, while finding certain facts in Acorda's favor regarding objective indicia of obviousness, ultimately discounted such indicia, relying on the fact that the Elan patent was a "blocking patent" for the claimed methods of the Acorda patents: any marketer of a drug for uses practicing those methods would need a license to the Elan patent-to which Acorda, for years preceding the 2004 priority date, had an exclusive license from Elan. Id. at *36-40. On April 25, 2017, the court entered final judgment in favor of the defendants as to the Acorda patents and in favor of Acorda as to the Elan patent. The court set the effective date of any final FDA approval of the defendants' Abbreviated New Drug Applications no earlier than the expiration date of the Elan patent-July 30, 2018-and enjoined the defendants from any infringing activity before that date. Acorda and the defendants timely appealed and cross-appealed, respectively. We have jurisdiction under 28 U.S.C. § 1295(a)(1). II Acorda makes essentially three arguments on appeal regarding the district court's ruling that the Acorda patent claims are invalid for obviousness. First, Acorda contends, on a number of grounds, that the district court erred in finding that a person of skill would have had a motivation to combine the prior art to arrive at the Acorda invention and a reasonable expectation of success in doing so. Second, Acorda challenges the court's determination that the claim limitations relating to pharmacokinetics-i.e. , achieving 4-AP serum levels of 15-35 ng/ml-are inherent in the claimed invention and therefore obvious. Third, Acorda argues that the court improperly applied a categorical rule that a blocking patent (the Elan patent) negates any findings in favor of Acorda on the objective indicia of commercial success, failure of others, and long felt but unmet need. Under 35 U.S.C. § 103(a), obviousness is a question of law based on underlying questions of fact, including the level of ordinary skill in the art, the scope and content of the prior art, the differences between the claims and the prior art, motivation to modify or combine with a reasonable expectation of success, and objective indicia of nonobviousness. See KSR Int'l Co. v. Teleflex Inc. , 550 U.S. 398, 406, 127 S.Ct. 1727, 167 L.Ed.2d 705 (2007) ; In re Stepan , 868 F.3d 1342, 1345-46 (Fed. Cir. 2017) ; PAR Pharm., Inc. v. TWI Pharm., Inc. , 773 F.3d 1186, 1193-94, 1196-97 (Fed. Cir. 2014). We review the district court's determination of obviousness de novo and its underlying factual findings for clear error. In re Cyclobenzaprine Hydrochloride Extended-Release Capsule Patent Litig. , 676 F.3d 1063, 1069 (Fed. Cir. 2012). A Acorda challenges the district court's findings about the relevant skilled artisan's motivations and expectations regarding the administration of a stable 10 mg 4-AP dose twice daily to improve walking. It presents two relatively focused arguments: that Schwid teaches away from the claimed invention; and that the prior art teaches the administration of sustained-release 4-AP in a titrated-dosing regimen rather than a stable-dosing regimen. More broadly, Acorda argues that neither the Goodman Poster nor the prior art collectively teaches the efficacy of a stable 10 mg twice-daily dose or indicates that such a dose is among the small number of options that a skilled artisan would have been motivated to test with a reasonable expectation of success to improve walking. We reject these challenges. 1 Acorda contends that Schwid "affirmatively teaches away from Acorda's invention." Acorda Br. 36. The district court considered Schwid, as Acorda urged, among the teachings of the overall art available at the 2004 priority date, and it made findings as to the motivation and expectations of a relevant skilled artisan at that date regarding a stable 10 mg dosage of 4-AP to improve walking. Dist. Ct. Op. at *30-31. Acorda has not shown that Schwid renders the court's findings on those issues clearly erroneous. Schwid supports a motivation to test, with a reasonable expectation of success, a 10 mg twice-daily dose of sustained-release 4-AP to improve walking in multiple sclerosis patients. Schwid itself used a 17.5 mg twice-daily dose, but it found success with that dosage: as stated in Schwid, "[t]he results of this double-blind crossover study provide evidence that 4AP [sustained release] had a therapeutic effect on neurologic deficits from [multiple sclerosis ]." J.A. 6684. In particular, there was a statistically significant improvement for the 17.5 mg 4-AP versus placebo in timed gait (i.e. , in walking ability); and the improvements in other outcomes, while not statistically significant, "showed trends favoring 4AP [sustained release]." J.A. 6681, 6684. Schwid expressly concludes that the study shows "4AP [sustained release] improved motor function in [multiple sclerosis ] patients." J.A. 6681. And, stressing toxicity concerns with high doses, Schwid provides affirmative reason to investigate low doses. See J.A. 6681 ("4AP can provoke seizures and acute encephalopathy"-episodes that "tend to occur when serum 4AP levels peak, suggesting that lower peak levels may increase safety."); J.A. 6684 ("[F]uture studies of 4AP [sustained release] will need to examine long-term efficacy and tolerability as well as further refine dosing regimens to optimize delivery despite a relatively narrow therapeutic window."). Schwid makes certain observations that its study showed favorable results in some outcome measures at high serum levels of 4-AP (60 ng/ml)-levels that, according to evidence emphasized by Acorda, may require the administration of 4-AP doses higher than 10 mg twice a day. See J.A. 445-48 (defendant's expert's testimony that 17.5 mg twice-daily or 25 mg twice-daily could result in serum levels at or above 60 ng/ml); J.A. 823 (Acorda's expert's testimony: similar). But Acorda overstates the significance of this serum-level observation to the issue of a reasonable expectation of success for walking improvement . Schwid found no statistically significant difference between the 4-AP and placebo groups as to patients' subjective global impression of their condition, one of seven outcome measures in the Schwid study. J.A. 6683. As to that outcome measure, Schwid states that "[n]one of the patients with a serum level less than 60 ng/mL felt better (according to their global impressions) on 4AP [sustained release] than placebo." Id. But efficacy in patients' global impression is not the issue-efficacy in timed gait is. Schwid made no such finding as to timed gait. Schwid also observes, as a general matter, that "[t]reatment [with 4AP sustained release] appeared particularly efficacious in subjects who achieved serum 4AP levels above 60 ng/mL, with everyone improving in timed-gait testing and grip strength, and five of six improving by MVICT [maximum voluntary isometric contraction, measured quantitatively] and their own subjective assessment [global impression]." J.A. 6684. But Schwid's measured improvement in timed gait was not limited to patients with high serum levels. See J.A. 6683 (9 of 10 patients improved in timed gait, and only 6 patients achieved serum levels greater than 60 ng/ml). In short, high serum levels were not required, and a dose of 17.5 mg sustained-release 4-AP twice-daily was sufficient, for improvement in timed gait in Schwid. Meanwhile, Acorda has pointed to nothing in Schwid declaring that doses lower than 17.5 mg twice-daily would not be effective in improving walking. Schwid therefore supports a finding that a person of skill would have had a reasonable expectation of success regarding the administration of 17.5 mg of 4-AP twice-daily-or perhaps even a lower dose since 17.5 mg was sufficient-to improve walking in multiple sclerosis patients. And in light of Schwid's warning that seizures may occur at higher doses, the district court did not clearly err in finding that a person of skill would look to lower doses rather than higher ones. See Dist. Ct. Op. at *32 ("While the prior art may have generally suggested that 4-AP would be more effective in higher doses, the art also reduced the set of plausible doses because it suggested that higher doses of 4-AP were more likely to cause adverse events."). 2 Acorda's second argument is that the prior art teaches administering sustained-release 4-AP only in a titrated-dosing regimen to avoid the risk of seizure, and therefore that the district court could not properly find that a person of skill would have been motivated to pursue, or had a reasonable expectation of success concerning, a stable-dosing regimen. We reject this argument. The prior art is not limited to titrated dosing (where doses start low and move higher) but rather contains evidence of stable dosing (where the dose starts and stays at the claimed level). As the district court noted, Polman is evidence of safe and effective long-term oral administration of a stable dose of immediate-release 4-AP. Dist. Ct. Op. at *34 ; see J.A. 6655. Schwid also provides evidence of a stable-dosing regimen of 4-AP, if only for a week. As for the studies that used escalating doses, some of those studies began with 10 mg as the lowest dose before titrating upwards to doses that may increase the risk of seizure. E.g. , Davis at 187 tbl.1; see also Dist. Ct. Op. at *8 (1994 Elan study began with 12.5 mg 4-AP twice daily); id. at *9 (10 mg twice daily was the lowest dose used in the Acorda MS-F202 study); cf. J.A. 6647 (trial in patients with other conditions began with dose of 10 mg 4-AP twice daily and titrated up to 200 mg daily); J.A. 6434 (Acorda's trial in patients with spinal cord injury began with 10 mg twice daily as the lowest dose). Significantly, the most important prior art, the Goodman references, report a start dose of 10 mg twice daily. J.A. 6370, 6372, 6502. Even if many earlier studies used a titrated-dosing scheme to avoid adverse effects caused by starting at higher doses, those studies do not, as the district court found, undermine the other evidence in the prior art that a person of skill would have a reasonable expectation of success for a stable-dosing scheme at low doses. Dist. Ct. Op. at *34. The Bever II prior-art review article reports that while "seizures are common at higher doses," 4-AP "rarely cause[s] seizures at the doses used in [multiple sclerosis ] trials." Bever II at S120. Other published studies say the same: seizures were seen at higher doses, but not lower ones like 10 mg. E.g. , J.A. 6651 (trial in patients with Eaton-Lambert syndrome, congenital myasthenia, and myasthenia gravis starting at dose of 10 mg 4-AP twice daily and escalating to 200 mg daily found that all of the patients who experienced seizures during the study "were receiving 80 mg or more of 4-AP daily"); J.A. 6504 (Goodman Poster "Results Summary": "At doses above 40 mg/day, more severe adverse events were reported, including two cases of seizure (at 60 and 70 mg/day)"). And in Schwid, the authors advise that future studies pursue lower doses for long-term tolerability. See J.A. 6681 ("4AP can provoke seizures and acute encephalopathy," but those episodes "tend to occur when serum 4AP levels peak, suggesting that lower peak levels may increase safety."); J.A. 6684 ("[F]uture studies of 4AP [sustained release] will need to examine long-term efficacy and tolerability as well as further refine dosing regimens to optimize delivery despite a relatively narrow therapeutic window."). Expert testimony supports the district court's finding that a person of ordinary skill in the art would have been motivated to pursue, and had a reasonable expectation of success in pursuing, a stable-dosing regimen of 10 mg 4-AP twice daily. According to Dr. Peroutka, "the general goal of drug development [is] to provide a stable dosing regimen." J.A. 414. He testified that stable dosing was particularly desirable for treating multiple sclerosis because, as a chronic disease that requires long-term treatment, a stable oral dose is much easier to administer. See Sept. 19, 2016 Trial Tr. 110 ("Obviously, it's a lot easier simply to take one pill, the same pill twice a day than to have to figure out, well, this morning I need this much, that much. But with pills, it is almost impossible to titrate easily."). Even Dr. Goodman conceded that "it would be desirable" to have a stable-dosing regimen where "the patient would be prescribed [some dose] to take on a regular basis." J.A. 868. And titration was not required given such a low starting dose: Acorda founder Dr. Cohen testified that, upon recognizing the efficacy of the 10 mg twice-daily dose, "we realized we didn't have to titrate anymore." J.A. 614. Finally, Dr. Peroutka explained that nothing in the prior art suggested that 4-AP could not be used for long-term treatment for a chronic condition. Sept. 19, 2016 Trial Tr. 104. 3 Acorda's most general argument is that the district court improperly found that a relevant skilled artisan "would have formed a reasonable expectation of success based on Schwid and Goodman [in particular, the Goodman Poster], in light of the totality of the prior art," regarding a 10 mg twice-daily dose of 4-AP to improve walking. Dist. Ct. Op. at *31. We reject Acorda's argument. As described above, Schwid reports a statistically significant improvement in timed gait for patients given 17.5 mg 4-AP twice-daily versus placebo. Also as described above, the Goodman Poster reports a statistically significant improvement in walking speed and in lower extremity strength for patients given 10-40 mg 4-AP twice daily versus placebo; an average improvement in walking speed during the low-dose period (10-25 mg 4-AP twice daily) of more than 20% for 9 of 25 subjects; and "more severe adverse events," including seizures, at doses above 20 mg 4-AP twice daily. J.A. 6504. The Goodman Poster also reports a dose response in the timed walk at doses in the range of 10-20 mg 4-AP twice daily. See Dist.Ct. Op. at *33 ("Goodman states that the results showed 'evidence of a dose response in the 20 to 40 milligram per day range,' indicating that patients taking these dosages of 4-AP demonstrated a greater response to treatment than did patients receiving placebo."). The district court did not clearly err in finding that a person of skill would have looked to both of those references, considered their limits, and had a reasonable expectation of success as to the efficacy of 10-20 mg 4-AP twice daily to improve walking. Despite certain identified "shortcomings" in the principal references, "the combined message a [person of skill in the art] would have discerned from Schwid together with the Goodman references was a reasonable expectation of success in treating walking with 4-AP." Id. at *31. Other prior art was consistent with that message. Id. As to dosages, the disclosures of Schwid and the Goodman Poster regarding relevant benefits at doses including or near to the Acorda-claimed range (recounted above), together with the reported concerns about high doses, support the further finding that a relevant skilled artisan would have "consider[ed] 10 mg/twice daily to be among the finite group of doses of sustained-release 4-AP that could reasonably be expected to improve walking in MS patients." Id. at *33 (footnote attached citing further partial support from testimony of Acorda's Dr. Goodman). In a finding reflecting both motivation and reasonable expectation of success, the district court stated: "As the lowest of the range of encouraging doses, 10mg/twice daily would have been an attractive starting point for a [person of skill in the art]." Id. These findings not only have adequate evidentiary support but comport with the guidance of KSR to "take account of the inferences and creative steps that a person of ordinary skill in the art would employ." 550 U.S. at 418, 127 S.Ct. 1727. Expert testimony further supports the district court's findings. The defendants' expert Dr. Peroutka explained that Schwid showed that the claimed formulation was effective at a 17.5 mg twice-daily dose and that the result was statistically significant. J.A. 406-07, 410. Dr. Peroutka also stated that the Goodman abstracts "said that dose response curves showed an increasing benefit in both measures in the 20 to 50 milligram a day range [10-25 mg twice-daily range], meaning timed walking or lower extremity strength." J.A. 414. According to Dr. Peroutka, the study presented in the Goodman abstracts was a dose-ranging study where "the goal" is "to find the most efficacious dose without adverse events." Id. ; accord J.A. 869 (Acorda's expert Dr. Goodman: "[W]hat we really want to find is the most effective dose that can be given safely."). The additional information provided in the bar graph in the Goodman Poster showed that people taking 10-25 mg twice daily did better in walking speed than placebo, and the dose-response curve showed improvement in walking speed at the 10 mg twice-daily dose-a level of improvement that was maintained at higher doses. See J.A. 416; Sept. 19, 2016 Trial Tr. 102 ("They got the 10 milligrams to work at this level and that level of efficacy was maintained through the dose ranges."); id. at 103 ("[I]t's certain stable clinical effect at 20 to 40" milligrams per day (doses of 10 mg, 15 mg, and 20 mg twice-daily).). Dr. Peroutka testified that he would have included the 10 mg dose in a Phase III study because there are "very serious" side effects at higher doses so "you would take the lowest effective dose that was safe." Id. at 104. He also testified that a person of skill might even want to try a lower dose, but "based on the [Goodman] data, 10 is the lowest effective dose." Id . Acorda's expert Dr. Goodman himself stated that the Goodman Poster "suggest[s]"