Full opinion text
OPINION FARNAN, District Judge. ’ This action was brought by Plaintiffs, Alza Corporation (“Alza”) and McNeil-PPC, Inc. (“McNeil”), against Defendants, Andrx Pharmaceuticals, LLC (“Andrx”) and Andrx Corporation (“Andrx Corp.”) (collectively, “Andrx”), in connection with the Abbreviated New Drug Applications (“ANDAs”) filed by Andrx seeking to market generic versions of. CONCERTA®, a drug developed and manufactured by Alza for distribution by McNeil. Joint Statement of Admitted Facts ¶¶ 10-11. Alza is the assignee of U.S. Patent Nos. 6,919,373 (the “’373 patent”) and 6,930,129 (the “'129 patent”), which pertain to extended release tablets containing methylphenidate (“MPH”) for use in treating Attention Deficit Hyperactivity Disorder (“ADHD”). Id. ¶ 7. Plaintiffs allege that by filing their ANDAs, Andrx infringes claims 1, 6 and 7 of the '373 patent. Plaintiffs also alleged infringement of claims 1 and 4-6 of the '129 patent, but dismissed these allegations just prior to trial. Andrx contests infringement of all these claims and asserts that they are invalid as obvious, for lack of enablement, and for failure to satisfy the written description requirement. Although Plaintiffs have dismissed their allegations pertaining to the '129 patent, Andrx urges the Court to nevertheless decide all issues related to this patent. The Court conducted a bench trial, and this Opinion constitutes the Court’s Findings of Fact and Conclusions of Law on the issues tried. BACKGROUND I. Procedural History On or before July 22, 2005, Andrx submitted to the FDA an amendment to ANDA No. 76-655 containing a certification under 21 U.S.C. § 355CÍ)(2)(A)(vii)(IV) (a “Paragraph IV certification”) and seeking approval to engage in the commercial manufacture, use, and sale of a generic version of Plaintiffs’ CONCERTA® product prior to the expiration of the '373 patent. Joint Statement of Admitted Facts ¶ 11; D.I. 1 ¶¶ 36-37. On August 16, 2005, Andrx submitted to the FDA an amendment to ANDA No. 76-722 containing a Paragraph IV certification and seeking approval to engage in the commercial manufacture, use, and sale of a generic version of Plaintiffs’ CONCERTA® product prior to the expiration of the '373 and '129 patents. Joint Statement of Admitted Facts ¶ 11; D.I. 1 ¶¶ 36-37; Defendants’ Proposed Findings of Fact And Conclusions of Law (“DFF”) ¶ 1212. On September 1, 2005, Plaintiffs sued Andrx, alleging that these ANDA filings constituted infringement of the '373 and '129 patents. See D.I. 1. In response to the Complaint, Andrx filed an Answer and Counterclaims denying infringement and asserting the defense of invalidity. D.I. 7. Andrx also counterclaimed for a declaratory judgment of non-infringement and invalidity of the '373 and '129 patents. Id. On the morning of the first day of Trial, Plaintiffs requested the dismissal with prejudice of their own infringement claims and Andrx’s declaratory judgment counterclaims on the '129 patent, representing on the record that it would not assert the '129 patent claims against Andrx in connection with products described in Andrx’s ANDAs. Tr. (Vol. 1), D.I. 148 at 3:6-9:17. The parties continue to dispute whether the Court has declaratory judgment jurisdiction over Defendants’ counterclaims pertaining to the '129 patent. II. Factual Background A. The Parties Alza is a corporation incorporated under the laws of the State of Delaware, with its principal place of business in Mountain View, California. Joint Statement of Admitted Facts ¶ 1. McNeil is a corporation incorporated under the laws of the State of New Jersey with a place of business in Fort Washington, Pennsylvania. Id. ¶ 2. Andrx is a corporation incorporated under the laws of the State of Delaware with its principal place of business in Weston, Florida. Id. ¶ 3. Andrx Corp. is a corporation incorporated under the laws of the State of Delaware with its principal place of business in Weston, Florida. Id. ¶ 4. B. Concerta® And The Patents At Issue Concerta® is the brand name for a once-daily medication for treating Attention Deficit Hyperactivity Disorder (“ADHD”). Concerta® is manufactured by Alza, while McNeil is the sole authorized distributor of Concerta®. Id. ¶ 10. The active ingredient in Concerta® is a compound called methylphenidate (“MPH”), which has been used in various forms to treat ADHD since the mid-1970s. See Tr. (Vol. 1), D.I. 148 at 24:7-17; PX 575 at 295. However, previously used MPH formulations generally required repeated dosing because the period of efficacy of each dose was relatively short. PX 575 at 295-96. Typical dosing regimes were twice-daily (referred to in the art as “BID” dosing) or three-times-daily (referred to in the art as “TID” dosing). Id. The need for repeated dosing was seen as a particularly significant drawback in the treatment of school-aged children because it necessitated the administration of an MPH dosage form in the middle of the school day. See Tr. (Vol. 1), D.I. 148 at 35:1-36:6. The Ritalin SR® product, introduced by Ciba-Geigy, was an attempt to provide an effective onee-daily dosage form of MPH. See id. at 27:9-19. Briefly, Ritalin SR® was a “sustained release” MPH dosage form that provided an MPH blood plasma concentration that was considered “constant” or “flat” because it stayed within a certain range over a period of several hours. See id. at 45:5^46:2. It was hoped that by providing a sustained “flat” MPH blood plasma concentration there would be no need for repeated dosing. However, Ritalin SR® ultimately proved to be unreliable and ineffective for the treatment of ADHD, and the prior art BID and TID MPH dosing regimens, though flawed, remained the “gold standard” in ADHD treatment. See Tr. (Vol. 3), D.I. 150 at 810:10-22; Tr. (Vol. 4), D.I. 151 at 1006:12-20,1021:12-1022:4. Thus, in 1993, Alza began further investigations into the development of an effective once-daily MPH-based treatment for ADHD. See Tr. (Vol. 1), D.I. 148 at 26:23-30:6. Briefly, the Alza researchers carried out “sipping studies” in which small amounts of MPH were administered to children in 30 minute intervals. By administering the drug in this controlled manner, the Alza researchers were able to simulate particular MPH plasma profiles. See id. at 50:2-51:11. As a result of these investigations, Alza scientists allegedly learned that an MPH blood plasma concentration that ascended over time provided greater efficacy than a concentration that remained constant over time. Id. at 68:9-69:10. Indeed, the efficacy of the ascending plasma profile approached the efficacy associated with conventional multidose BID and TID regimens. Id. at 73:7-23. In addition, Alza contends that the sipping studies established for the first time that MPH was subject to the phenomenon of acute tolerance, which refers to the propensity of a drug to have decreased efficacy over time even though the blood concentration of the drug remains static. Id. at 49:3-18, 76:4-6. By steadily increasing the level of MPH in the blood, an ascending plasma profile overcomes this phenomenon. Alza then sought patent protection for their alleged discovery, acquiring both the '373 and '129 patents, which share the same specification and same title, “Methods and Devices For Providing Prolonged Drug Therapy.” The '373 patent issued on July 19, 2005, to Alza, the assignee of named inventors, Andrew Lam, Padmaja Shivanand, Atul Ayer, Richard Weyers, Suneel Gupta, Diane Guinta, Carol Christopher, Samuel Saks, Lawrence Hamel, Jeri Wright, and Zahedeh Hatamkhany. DTX 1. The '129 patent shares the same inventors as the '373 patent, and issued roughly one month later, on August 16, 2005, to the same assignee as the '373 patent. DTX 2. The common specification explains that “[t]he invention broadly embraces oral sustained-release dosage forms that provide an ascending drug release rate over an extended time period .... ” As such, the asserted claims of the asserted patents are directed to methods for treating ADHD that include the administration of an MPH dosage form that provides either release of MPH at an ascending rate or an ascending MPH plasma drug concentration. Asserted claim 1 of the '373 patent is the only independent claim of the '373 patent and reads as follows: 1. A method for treating ADD or ADHD comprising administering a dosage form comprising methylphenidate that provides a release of methylphenidate at an ascending release rate over an extended period of time. Each dependent claim of the '373 patent depends from claim 1 and adds one additional limitation over claim 1; specifically, the requirement of a “substantially ascending methylphenidate plasma drug concentration” over a particular time frame. Alza has since amended its New Drug Application No. 21-121 to identify the '373 and '129 patents as patents “with respect to which a claim of patent infringement could reasonably by asserted if a person not licensed by the owner engaged in the manufacture, use, or sale” of Concerta®. Accordingly, the FDA listed these patents in its list of Approved Drug Products with Therapeutic Equivalence Evaluations (“the Orange Book”). Joint Statement of Admitted Facts ¶ 9. DISCUSSION I. Whether The Court Has Declaratory Judgment Jurisdiction Over Defendants’ Counterclaims On The '129 Patent The jurisdictional dispute currently before the Court involves the intricacies of the Hatch-Waxman statutory scheme and a factual scenario that parallels the situation considered by the Court in its recent decision in Dey, L.P. v. Sepracor, Inc., 595 F.Supp.2d 355 (D.Del.2009). Sepracor differs from the instant dispute in that there was no question as to which party was the first Paragraph IV ANDA filer. See infra. As a result, the Court’s decision in Sepracor does not resolve the jurisdictional question presented here. Nevertheless, the Court refers the reader to Sepracor for a summary of the relevant statutory background, an understanding of which is requisite to an understanding of the instant jurisdictional dispute. The chronology of the instant jurisdictional dispute is summarized as follows. Alza holds approved New Drug Application (“NDA”) No. 21-121 for methylphenidate hydrochloride, which is marketed under the tradename Concerta®. Joint Statement of Admitted Facts ¶ 8. In January 2003, Andrx submitted an ANDA to the FDA seeking permission to market a generic version of Concerta®. DFF ¶ 1207. At some point prior to July 2005, third party Impax Laboratories, Inc. (“Impax”) submitted an ANDA of its own. Id. at 1208. At this point, neither the '373 nor '129 patents had issued. However, on July 19, 2005, the '373 patent issued and, on the same day, Alza filed papers with the FDA to list the '373 patent in the Orange Book for Concerta®. Id. ¶ 1210; Joint Statement of Admitted Facts ¶ 10. Also on the same day, Impax submitted papers to the FDA for the purpose of amending its ANDA to include a Paragraph IV certification on the '373 patent. DFF ¶ 1210. It is unclear which set of documents the FDA received first. Although Andrx ultimately amended its ANDA to include a Paragraph IV certification on the '373 patent, there is no dispute that Impax is the first Paragraph IV filer with respect to the '373 patent. On August 16, 2005, the '129 patent issued. Id. ¶ 1212. As with the '373 patent, on the same day, Alza filed papers with the FDA to list the '129 patent in the Orange Book for Concerta®. Id. ¶ 1214. Likewise, on the same day, both Andrx and Impax filed papers with the FDA for the purpose of amending their ANDAs to include Paragraph IV certifications for the '129 patent. Id. ¶¶ 1212-13. Of these three sets of documents, it is unclear which set of documents the FDA received first. However, Defendants do not appear to suggest that the FDA did not receive them all on August 16, 2005. See DFF ¶¶ 1212-14. Furthermore, there does not appear to be a dispute that on August 16, 2005, both Andrx and Impax sent Alza letters notifying Alza of the Paragraph IV certifications. See id. ¶¶ 1212,1215. The parties further do not dispute that the pre-MMA version of the Hatch-Wax-man Act applies to the instant jurisdictional dispute. See DFF ¶ 1217; D.I. 173 at 3. In these circumstances, a separate 180-day exclusivity period exists for both the '373 and '129 patents. Impax, as the first Paragraph IV ANDA filer on the '373 patent, is entitled to 180-days of market exclusivity on the '373 patent. Given that the parties do not dispute that the Court has jurisdiction over claims pertaining to the '373 patent, this exclusivity may ultimately be triggered by the outcome of the instant litigation. See 21 U.S.C. § 355(j)(5)(B)(iv) (2000). However, if Impax is also considered to be the first filer on the '129 patent, then the FDA will nevertheless prohibit Andrx from taking its generic to market until Impax has also finished enjoying the exclusivity period for the '129 patent. This will not happen until 180 days after either (1) a Court decision on the '129 patent or (2) Impax begins marketing a generic version of Concerta®. Given that there is no indication that Impax will begin marketing its generic, Defendants contend that a decision by this Court on the '129 patent is necessary to remove Impax’s possible exclusivity on the '129 patent as a barrier to Andrx’s market entry. See DFF ¶ 1226-27. Pointing to the Federal Circuit’s recent decision in Carneo Pharm. Labs., Ltd. v. Forest Labs., Inc., 527 F.3d 1278 (Fed.Cir.2008), Defendants contend that this potential for delay is a cognizable injury creating a controversy sufficient to establish declaratory judgment jurisdiction over their counterclaims pertaining to the '129 patent. In the Court’s view, however, the harm to Defendants remains too speculative to establish declaratory judgment jurisdiction. The difficulty with Defendants’ position is that they simply do not know whether Impax or Andrx was the first party to submit a Paragraph IV certification for the '129 patent and hence gain entitlement to the 180-day exclusivity period for that patent. According to Defendants, a party is deemed to have “submitted” an ANDA with a Paragraph IV certification when both (1) its Paragraph IV certification papers have been received by the FDA and (2) it has sent notice letters to the NDA holder and patent owner. See id. ¶ 1219. With both Andrx and Impax having done both of these things on August 16, 2005, Defendants contend that the question of who is entitled to exclusivity on the '129 patent boils down to the exact times on August 16, 2005 when the FDA received each party’s certification papers. This is so, Defendants contend, because a party’s Paragraph IV certification may be invalid if the FDA receives it before receiving the NDA holder’s papers requesting that the corresponding patent be listed in the orange book, even if the FDA receives both documents on the same day. See DFF ¶ 1211, 1222. Thus, whether Impax holds exclusivity on the '129 patent, and hence has the potential to delay Defendants’ market entry, hinges on two unknowns: (1) the precise order in which the FDA received the relevant documentation on August 16, 2005 and (2) whether the FDA agrees with Defendants that this order could result in invalidation of one or more party’s ANDA. On these facts, the Court concludes that the potential for harm to Defendants remains too speculative to support declaratory judgment jurisdiction. Alternatively, Defendants’ contend that declaratory judgment jurisdiction exists because Alza has a pending patent application that may eventually issue as a patent that may include claims substantially identical to those in the '129 patent. Defendants contend that this patent may eventually pose a litigation threat. See DFF ¶¶ 1228-36. Defendants cite no eases suggesting that this set of circumstances gives rise to declaratory judgment jurisdiction. Accordingly, the Court concludes that this potential injury is also too speculative to support declaratory judgment jurisdiction over Defendants’ counterclaims on the '129 patent. The Court will thus dismiss Defendants’ declaratory judgment counterclaims concerning the '129 patent without prejudice. If, at some point, Defendants can confirm that only Impax holds exclusivity on the '129 patent, the Court will reconsider its dismissal of Defendants’ counterclaims. As set forth in the Order accompanying this Opinion, the Court shall permit Defendants to conduct additional limited discovery to gain clarity on this issue. II. Plaintiffs’ Motion To Strike Portions of Defendants’ Post-Trial Findings Of Fact (D.I. 188) By their Motion, Plaintiffs request that the Court strike paragraphs 1179 through 1198 of Defendants’ Proposed Findings Of Fact And Conclusions Of Law, which pertain to Defendants’ written description defense. Plaintiffs contend that Defendants waived a written description defense by failing to mention such a defense in their pretrial briefing. See D.I. 188 at 2. Plaintiffs further contend that Defendants failed to provide any evidence at trial on a written description defense, noting that Defendants’ seven-page section with 20 paragraphs on written description is composed almost entirely of legal argument and includes a mere four record citations. Id. at 4. Defendants respond that they included the written description defense in their post-trial briefing only in response to new arguments that Plaintiffs raised in their pre-trial briefing, in particular an alleged attempt by Plaintiffs to have the Court re-construe the claim term “dosage form.” See D.I. 189 at 5; infra Part IV.B.2. Because Defendants have the burden of proof on a written description defense, the Court concludes that Defendants were obligated to raise this defense in their pretrial briefing. In addition, on review of the record, the Court agrees with Plaintiffs that Defendants did not meaningfully introduce any evidence on written description at trial. Furthermore, to the extent Defendants contend that a written description defense flows from an allegedly over-broad construction of the term “dosage form,” the Court notes that Defendants had little trouble putting this theory to use in both their pre-trial brief and at trial with regard to their enablement defense. Accordingly, the Court will grant Plaintiffs’ Motion To Strike Portions of Defendants’ Post-Trial Findings Of Fact (D.I. 188). Defendants contend that the Court, having found that Defendants’ post-trial briefing on written description was inappropriate, must further find that Plaintiffs’ contingent proposed findings of fact an d conclusions of law on the '129 patent that appear in Plaintiffs’ post-trial briefing are also inappropriate. See D.I. 189 at 14-15. Specifically, Defendants contend that Plaintiffs, after electing to no longer assert the '129 patent, declined to discuss it in their pre-trial papers and should not be allowed to raise it in post-trial briefing. Defendants’ thus bring a contingent cross motion to strike Plaintiffs’ post-trial briefing on the '129 patent. See D.I. 189. The Court will deny this motion as moot in light of the Court’s conclusion that it does not have jurisdiction over Defendants’ counterclaims on the '129 patent. If it becomes necessary for the Court to consider Defendants’ counterclaims on the '129 patent, the Court will allow the parties to submit appropriate supplemental findings of fact and conclusions of law. III. Infringement Of Claims 1, 6, And 7 Of The '373 Patent A. Applicable Law A patent is infringed when a person “without authority makes, uses, offers to sell, or sells any patented invention, within the United States, or imports into the United States any patented invention during the term of the patent .... ” 35 U.S.C. § 271(a). Determining infringement requires a two step inquiry. Step one requires a court to construe the disputed terms of the patent at issue. Step two requires a court to compare the accused products with the properly construed claims of the patent. Step one is a question of law; step two is a question of fact. Markman v. Westview Instruments, Inc., 52 F.3d 967, 979-81 (Fed.Cir.1995) (en banc), aff'd, 517 U.S. 370, 116 S.Ct. 1384, 134 L.Ed.2d 577 (1996). Infringement may be proven under either of two theories: literal infringement or the doctrine of equivalents. Literal infringement occurs when each element of at least one claim of the patent is found in the alleged infringer’s product. Panduit Corp. v. Dennison Mfg. Co., 836 F.2d 1329, 1330 n. 1 (Fed.Cir.1987). The party asserting infringement has the burden of proof and must meet its burden by a preponderance of the evidence. Smith-Kline Diagnostics, Inc. v. Helena Lab. Corp., 859 F.2d 878, 889 (Fed.Cir.1988) (citations omitted). B. Discussion As an initial matter, the Court notes that all asserted claims of the '373 patent are method claims directed to methods for “treating ADD or ADHD.” In these circumstances, the Court concludes that Plaintiffs have no cause of action for direct infringement under 35 U.S.C. § 271(a). As the Federal Circuit explained, “pharmaceutical companies do not generally treat diseases; rather, they sell drugs to wholesalers or pharmacists, who in turn sell the drugs to patients possessing prescriptions from physicians. Pharmaceutical companies also occasionally give samples of drugs to doctors and hospitals. In none of these cases, however, does the company itself treat the disease.” Warner-Lambert Co. v. Apotex Corp., 316 F.3d 1348, 1363 (Fed.Cir.2003). Thus, Andrx, a pharmaceutical company that does not treat diseases, can at most be liable as a contributory infringer or an inducer of infringement. However, both these theories of indirect infringement require some underlying direct infringement, most likely by doctors who actually administer the accused products. See DSU Med. Corp. v. JMS Co., 471 F.3d 1293, 1303 (Fed.Cir.2006). The following analysis is thus carried out to resolve the issue of whether direct infringement could occur by such means. Claim 1 of the '373 patent, which is the only independent asserted claim from the '373 patent, requires “an ascending release rate over an extended period of time.” The Court construed this phrase to mean “a release of methylphenidate from the dosage form wherein the amount released in a periodic interval is increased over the amount released during the immediately preceding periodic interval starting at t=0 and continuing through at least the midpoint of the T90 and for at least three hours. The release rate is as determined by an appropriate in-vitro dissolution test. The ascending release rate does not include release of drug from any immediate-release drug coating that may be applied to the dosage form.” D.I. 130. The parties agree that whether the accused products satisfy this limitation is the key dispute with regard to infringement of the '373 patent. See DFF ¶¶ 515-18; Plaintiffs’ Proposed Post-Trial Findings Of Fact And Conclusions Of Law (“PFF”) ¶ 131. 1. Claim 1 Defendants contend that claim 1 is not infringed because the “ascending release rate” limitation requires infringing MPH dosage forms to, in an appropriate dissolution test, release methylphenidate from a source other than an immediate release (“IR”) coating at the very beginning of the dissolution test (i.e. at t=0). DFF ¶ 517. Put another way, Defendants contend that the “ascending release rate” limitation requires the release of some non-IR MPH during the first measurement interval of an appropriate dissolution test. Id. According to Defendants, although the accused tablets do exhibit immediate release of MPH from an IR-coating, they do not otherwise release MPH until what is typically the second measurement interval of an appropriate dissolution test. Id. ¶¶ 539-44. Hence, according to Defendants, the accused products do not infringe. Plaintiffs’ response is two-fold. First, Plaintiffs contend that Defendants are misinterpreting the Court’s claim construction. According to Defendants, “[i]t makes no difference how much, if any, MPH is released in the first interval so long as more is released in the next interval because the claim specifies only an ascending rate.” PFF ¶ 240. Second, Plaintiffs contend that even under Defendants’ interpretation of the Court’s construction, the accused products still infringe because in a substantial fraction of Defendants’ tablets some non-IR portion of MPH is released during the initial measurement interval of an appropriate dissolution test. Id. ¶ 253. Thus, to resolve the direct infringement issue, the Court must decide (1) whether the Court’s construction requires release of MPH during the initial interval of an appropriate dissolution test, and (2) if so, whether the accused products release MPH during that interval, a. Whether The Court’s Construction Requires Release of MPH During The Initial Interval of A Dissolution Test The Court’s construction does in fact require release of non-IR MPH during the initial interval of an appropriate dissolution test. The Court’s construction is clear that an “ascending release rate” requires, “starting at t=0,” the amount of non-IR MPH released per time interval to increase over the immediately preceding time interval. Calling for the “ascending release rate” to begin at “t=0,” the Court’s construction does not embrace the notion of some indeterminate time interval at the beginning of a dissolution test during which no non-IR drug release occurs. The patent is unequivocal on this point. In clarifying the meaning of “ascending release rate,” the patent states the following: It will be appreciated that the first periodic release rate measured, e.g., the periodic release rate at t=l hour (unless equal to 0), will always be greater than the release rate during the preceding period, e.g., the hour before the dosage form was administered, and, thus, the first periodic release rate always constitutes an occurrence of an ascending release rate. '373 patent at 10:10-16. Thus, to determine if the periodic release rate during the first interval constitutes an “ascending release rate,” the amount of drug released should be compared to the amount of drug released in the interval before the drug was even administered, which, by definition, is none. Accordingly, an “ascending release rate” during the first measurement interval requires a non-zero quantity of drug to be released during that interval. This passage further explains that because the amount of drug released during the initial measurement interval will be greater than the amount of drug released prior to administration, the “first periodic release rate always constitutes an occurrence of an ascending release rate.” The one exception to this rule is when the amount of drug released during the first measurement interval is “equal to 0,” in which case there is not an “ascending release rate” during the first measurement interval. Consistent with this guidance, every example in the patent describes a dosage form that releases a non-zero quantity of MPH during the first interval of a dissolution test and affirmatively describes this as an occurrence of an ascending release rate. See '373 patent at Tables 1-5. Plaintiffs position that “it makes no difference” how much MPH is released during the first interval of a dissolution test “so long as more is released in the next interval” is not only inconsistent with this intrinsic evidence but, in the Court’s view, rather difficult to apply. Particularly problematic is that Plaintiffs’ position appears to allow for the possibility of an indeterminate time interval following administration during which no non-IR MPH is released. Thus, as an example, Plaintiffs contend that an accused dosage form may still infringe if it does not release any non-IR MPH until the second hour of a dissolution study. According to Plaintiffs, because the amount of non-IR MPH released during the second hour would exceed the amount released during the first hour (i.e., none), there would still be an “ascending release rate.” However, if the testing interval is instead taken to be 30 minutes, then such a dosage form would not release any non-IR MPH during the first two intervals of the dissolution study. Under Plaintiffs’ understanding of the Court’s construction, there would then be no “ascending release rate” starting at “t=0” because the amount of MPH released did not increase on going from the first measurement interval to the second measurement interval. Thus, the determination of whether there was an “ascending release rate” starting at “t=0” would depend on the length of the testing interval, a result the Court finds unsatisfying. Indeed, the patent appears to embrace the possibility of using any desired measurement interval. See '373 patent at 8:58— 61 (describing “times following administration in appropriate time units, e.g., t=30 minutes or t=2 hours, etc.”); id. at 9:66— 10:9 (describing hourly measurement intervals as an “example”). In fact, during claim construction, Plaintiffs argued that the testing interval should not be limited to one specific, commonly-used length. D.I. 87 at 23 n. 14 (“Appropriate time units include 30-minute intervals (e.g., t=30 minutes, t=60 minutes; t=90 minutes, etc.”), 1-hour intervals and 2-hour intervals.); id. at 27 (“The fact that the specification explicitly refers to and envisions 30-minute and 2-hour intervals demonstrates that the claim term is not limited only to hourly intervals.”). Because the patent allows for different length testing intervals, the determination of whether there is an “ascending release rate” should not so strongly depend on the selected testing interval, as it would under Plaintiffs’ interpretation of the Court’s construction. Furthermore, the thrust of the '373 patent is to provide an MPH dosage form that overcomes the acute tolerance typically associated with MPH. The patent accomplishes this by providing a dosage form that releases an amount of MPH that increases over consecutive time intervals. To include a time period where the dosage form releases no MPH — and hence has no therapeutic effect whatsoever — in the evaluation of whether an MPH dosage form provides an “ascending release rate” would be to turn a blind eye to the very purpose and mechanism underlying the invention. Even worse, it would partially eviscerate the “ascending release rate” limitation, which, under the Court’s construction, requires at least three hours of ascending MPH release. Indeed, as Plaintiffs’ dissolution expert, Ms. Vivian Gray, testified, under the Plaintiffs’ interpretation of the Court’s construction, an initial time period where a dosage form releases no MPH constitutes a “free pass” towards meeting the three hour requirement. See Tr. (Vol. 2), D.I. 149 at 336:12-19. Thus, according to Dr. Gray, if a hypothetical MPH dosage form provided (1) a two hour period of no MPH release followed by (2) a two hour period of MPH release, the “ascending release rate” limitation would be satisfied, even though there was only one two hour interval of actual MPH release. Id. at 335:23-338:2. As reflected in the intrinsic evidence, the Court’s construction of “ascending release rate” simply does not countenance such extended periods of release dormancy as being a part of the “ascending release.” The testimony of Plaintiffs’ expert on ADHD pharmacology, Dr. Kennerly Patrick, provides additional confirmation that those of skill in the art would not understand this as being included in the Court’s claim construction. Specifically, after reviewing the Court’s claim construction, Dr. Patrick testified with respect to Fig. 8 of U.S. Patent No. 5,256,850 to Wong et al., which discloses an oral dosage form that releases no drug in the first two hours after administration, as follows: Q. Okay. And when we look at Figure 8, in your opinion, having read that claim construction, how long is it ascending or when does it start ascending?, A. I would say it started ascending at two hours and ascended to four, at least through four hours when you take the error bars into consideration. Q. Okay. And to your understanding, is that an ascending release rate from time equals zero? A. From time two hours to— Q. Right. A. —six hours? Q. Right. My question is that: An ascending release rate from time equals zero, not from time equals two. A. I — I would not characterize that as that. Q. And that — why? Because there’s no release in the first two hours? A. Yes. Tr. (Vol. 4), D.I. 151 at 1077:3-24; see also DTX 634 at Fig. 8 (depicting the release profile with little to no drug release during the first two hours). Thus, according to Dr. Patrick, time periods where a dosage form releases no drug do no constitute occurrences of ascending release. Having found that Defendants’ understanding of the Court’s construction is the proper one, the issue of direct infringement is reduced to whether the accused products exhibit release of some non-IR MPH during the first interval of an appropriate dissolution test, b. Whether The Accused Products Exhibit Release Of Non-IR MPH During The Initial Interval Of An Appropriate Dissolution Test i. Plaintiffs’ Dissolution Studies As necessary background for analyzing Plaintiffs’ infringement allegations, a brief summary of Plaintiffs’ dissolution testing of the proposed ANDA products is provided as follows. In general, in vitro dissolution tests involve the placement of a dosage form in a vessel containing a dissolution medium. The dosage form is agitated through rotation or stirring at a specific rate, and samples of the dissolution medium are withdrawn at periodic intervals for testing to determine the amount of drug present therein. See Tr. (Vol. 1), D.I. 148 at 220:8-222:21; PX 726. A publication entitled the U.S. Pharmacopoeia-National Formulary (“USP”) is the official compendium of standards for drugs marketed in the United States and sets forth a set of approved dissolution apparatuses. See 21 U.S.C. § 321(j); Tr. (Vol. 1), D.I. 148 at 209:23-211:1. Plaintiffs’ dissolution tests, utilized USP apparatus 1, which includes storage of the dosage form in a metal basket that is rotated at 100 RPM and a pH 7.5 phosphate buffer dissolution medium held at a temperature of 37° C. See Tr. (Vol. 1), D.I. 148 at 225:13-226:14, 244:6-245:4, 246:10-17; PX 229. Plaintiffs’ dissolution expert, Ms. Vivian Gray, directed dissolution tests on 12 samples of each of three different ANDA products, which contained 27, 36 or 54 mg of MPH. The percentage of MPH released was measured at hourly intervals. See Tr. (Vol. 1), D.I. 148 at 250:4-24. The ANDA products also included an 18 mg dosage form. PX207 at ANDRX 03926. However, during discovery, Defendants were unable to provide samples of these products because they had not yet successfully manufactured a commercial-scale, validated lot of the 18 mg product. See PX 233. Plaintiffs thus have no test results for these proposed products. On average, the 54, 36 and 27 mg dosage forms released 24.56%, 24.06%, and 23.44%, respectively, of their total MPH during the first interval of Plaintiffs’ dissolution studies. See id. at 271:3-272:7; PX 242; PX 244, PX 246. However, in accordance with the Court’s construction, the release of any IR MPH must be excluded before determining whether an accused product exhibits an “ascending release rate.” To do this, Plaintiffs relied on the fact that Defendants represented in their ANDAs that 25% of the MPH contained in their proposed products was contained in an immediate-release coating. See,' e.g., PX210 at ANDX206 (Andrx’s ANDA “Composition Statement”); Tr. (Vol. 1), D.I. 148 at 251:5-16; 2 53:4-254:13. Under this assumption, because none of the ANDA products released more than 25% of their MPH during the first testing interval, Plaintiffs’ dissolution tests demonstrate that, on average, no non-IR MPH is released during the first interval of an appropriate dissolution test. With regard to the 18 mg ANDA products, Plaintiffs contend that because they are “proportionally equivalent” to the 54 mg tablets they will exhibit equivalent dissolution rates. See Tr. (Vol. 1), D.I. 148 at 261:18-262:10 Notwithstanding these results demonstrating that, on average, no non-IR MPH is released during the initial interval of Plaintiffs’ dissolution studies, Plaintiffs contend that Andrx’s ANDA products still infringe. Briefly, Plaintiffs contend that their in vitro dissolution testing demonstrates that in a substantial number of tablets, the amount of MPH recovered during the first testing interval is too large to be attributable solely to the IR portion of the tablet. Hence, Plaintiffs contend that a reasonable conclusion is that some non-IR MPH is in fact released during the first interval. PFF ¶ 253. Plaintiffs further note that although the ANDA products are designed to have 25% of their total MPH in an IR coating, the actual amount of IR MPH can vary from 22.5% to 27.5% of the total MPH. See Tr. (Vol. 5), D.I. 152 at 1310:7-1311:3; DTX 1187 at ANDRX 36308. If one assumes that all of the tested samples are at the lower limit of allowable MPH in the IR layer (22.5%), Plaintiffs’ dissolution studies allegedly demonstrate that 31 of the 36 samples tested released some non-IR MPH during the first testing interval. See Tr. (Vol. 5), D.I. 152 at 1314:19-1315:1, 1312:18-1313:19, 1313:20-1314:17, 1314:18; PX 732; PX 733; PX 734. If one assumes that all samples are at the middle of the prescribed range (25%), then seven of the 36 samples tested allegedly released some non-IR MPH during the first testing interval. See Tr. (Vol. 5), D.I. 152 at 1311:17-22; PX 241; PX 243; PX 245. On average, these seven samples released an additional 1.3% of them total MPH during the first interval of the dissolution test. See PX 241; PX 243; PX 245. Finally, if one assumes that all samples are at the upper limit of the allowable range (27.5%), one of the 36 tested samples allegedly released non-IR MPH during the first measurement interval of Plaintiffs’ dissolution studies. See Tr. (Vol. 5), D.I. 152 at 1311:4-16. Noting that “an accused product that sometimes, but not always, embodies a claimed method nonetheless infringes ...,” Bell Communications Research v. Vitalink Communications Corp., 55 F.3d 615, 622-623 (Fed.Cir.1995), Plaintiffs contend that this evidence confirms infringement. Andrx responds that Plaintiffs’ approach of making assumptions regarding the fraction of total MPH contained in the IR-coating is simply wrong. DFF ¶ 550. The correct assumption, Andrx contends, is that “the amount of methylphenidate released in the first hour of the dissolution test is all attributable to the IR portion of methylphenidate,” an assumption Andrx terms the “first hour IR assumption.” Id. ¶ 551. With the Court’s construction of “ascending release rate” requiring the release of some non-IR MPH during the first measurement interval of an appropriate dissolution test, adoption of this assumption would amount to a finding of non-infringement. ii. Decision For the reasons set forth below, the Court concludes that substantial evidence supports the “first hour IR assumption,” and that Plaintiffs have not adequately rebutted this evidence so as to establish infringement by a preponderance of the evidence. In support of the “first hour” assumption, Andrx first points to the results of dissolution studies carried out on only the delayed release cores (“DRCs”) of the ANDA products (i.e., ANDA products that do not include an IR-MPH coating). These studies demonstrated that in the 27, 36, and 54 mg ANDA products, the DRCs released no MPH in the first hour of a dissolution test utilizing USP apparatus 1. See DTX 1141; DTX 1142; DTX 1143; Tr. Vol. 1, (D.I. 148) at 558:21-560:16. In fact, on reviewing the results of Andrx’s DRC tests, the Court concludes that an appreciable amount of MPH is not released from the DRC until the 90 minute point of the dissolution test, at which point the release rate increases rapidly and then remains relatively constant over roughly the next six hours. See DTX 1141; DTX 1442; DTX 1143. Plaintiffs contend first that Andrx’s DRC dissolution tests are unreliable methods of determining release rate from the DRC core. According to Plaintiffs’ expert, Dr. Martyn Davies, the additional manufacturing processes involved in applying the IR coating to a DRC, which include abrading and rubbing of the tablet cores, are likely to increase the rate at which the DRCs release MPH. See Tr. Vol. 5 (D.I. 152), at 1250:9-1251:21. The Court is unconvinced by this testimony. First, Dr. Davies’s testimony is unsupported by any experimental evidence or documentation. Second, Dr. Davies testified that it was “likely” that the manufacturing process would cause a change in the release characteristics of the DRCs and that he believed “that’s the possibility absolutely” that this would result in an increased rate of MPH release from the DRC. Id. (emphasis added). This language — and the lack of evidence supporting the testimony — suggests that this is merely a theory or hypothesis of Dr. Davies. Much more is required to establish infringement, and, in the Court’s view, Andrx’s DRC studies remain compelling evidence of non-infringement. Plaintiffs further respond to Andrx’s DRC studies with evidence of other Andrx dissolution tests that allegedly do, in fact, demonstrate that the ANDA DRCs release MPH during the firs interval of an appropriate dissolution test. This evidence, consisting of four documents, was introduced during Plaintiffs’ rebuttal case through the testimony of Dr. Davies. See PFF ¶ 268; Tr. (Vol. 5), D.I. 152 at 1252:3-1253:3, 1254:8-1255:11, 1307:7-1308:4; PX 197A at 63300; PX 557 at 46113-114; PX 563 at 66282. However, it is questionable whether the documents Dr. Davies pointed to even correspond to the testing of ANDA products. Indeed, the documents relied upon by Dr. Davies tend to demonstrate that -the studies correspond to products that do not actually fall within the ANDA’s specification because, at t=4 hours, the samples described in the studies all exhibited an MPH release that exceeded the limits set forth in the ANDAs. See PX 197A at ANDRX 63330 (though lacking a data point at t=4 hours, interpolation suggests that release exceeded the permissible threshold by roughly 5%); PX 557 at ANDRX 46113 (at t=4 hours release exceeded permissible threshold by 28%); PX 557 at ANDRX 46114 (at t=4 hours release exceeded permissible threshold by 14%); PX 563 at ANDRX 66282 (at t=4 hours release exceeded permissible threshold by 24%). Furthermore, one document Dr. Davies pointed to did not even include a sampling point until 1.5 hours, making it unclear whether any MPH was even released during the first hour of the dissolution test described in the document, as the Court’s construction requires. See PX 197A at ANDRX 63300. The three other documents Dr. Davies pointed to are mere excerpts taken from researcher laboratory notebooks that lack a clear connection to the ANDA products. See PX 557 at ANDRX 46081; PX 563 at ANDRX 66189. Accordingly, in the Court’s view, these documents do not establish by a preponderance of the evidence that the ANDA DRCs exhibit MPH release within the first interval of an appropriate dissolution test. As further support for the “first hour” assumption, Andrx points to dissolution studies its researchers carried out on the final ANDA products. These studies included sampling times not just at t=l hour, but also at t= 30 minutes. See PX 18 at ANDRX 00201-05; PX 25 at ANDRX 04042-43; DTX 388 at ANDRX 46502; DTX 1179. The data from these studies shows that during the first 30 minutes of the dissolution study, roughly 25% of the total MPH is released, while very little MPH, if any, is released during the second 30 minutes of the study. Indeed, with regard to Andrx’s dissolution tests on the 18 mg ANDA products, Plaintiffs’ dissolution expert, Vivian Gray, testified on cross-examination as follows: Q. Okay. But this gives us some information about there is something releasing pretty quickly in the .5 and pretty much nothing releasing in the second period, right, looks like there is a gap there? A. Yes. Tr. (Vol. 1), D.I. 148 at 339:3-8. Showing that the ANDA products release essentially no MPH for at least 30 minutes after an initial burst of MPH is released, these studies strongly suggest that any MPH release during the first hour of an appropriate dissolution test is, in fact, attributable to the IR component of the dosage form. As a final piece of evidence in support of the “first hour IR assumption,” Andrx points to “IR overcoat studies,” which were carried out by Alza’s own testing laboratories. These studies, which focused on the release of MPH from the IR overcoat, utilized USP apparatus 1 and included a sampling point every 15 minutes. See DTX 397A; DTX 1175. Briefly, the studies demonstrated that roughly 23% of the MPH is released within 15 minutes, but that it takes another 75 minutes for the release to exceed 24%, again strongly suggesting that MPH release during the first hour of an appropriate dissolution test is attributable to the IR component. Id,.; see also Tr. (Vol. 2), D.I. 149 at 562:21-563:14 (Defendants’ expert, Dr. Umesh Banakar, describes the “IR overcoat” studies). With regard to the slight increase in percentage MPH released from t=30 to t=75 minutes, Defendants’ expert, Dr. Umesh Banakar, testified that (1) the increase was within the measurement error of the dissolution tests, and (2) the increase was too small to reflect release from the delayed release core. See Tr. (Vol. 2), D.I. 149 at 563:15-565:3. In light of Andrx’s DRC and finished product studies discussed above, the Court finds this testimony credible. Plaintiffs’ dissolution expert, Vivian Gray, testified as follows with regard to the “IR overcoat” studies: Q. Okay. Does this look like to you as an dissolution expert that what you have got happening here is you have got an IR and basically your ER [sic] starts to begin releasing roughly around the ninety minute time frame? A. We can’t know. Q. You can’t tell? A. You know, because we don’t know exactly which is coming from the tablet core and which is coming from — but we you can assume when it starts getting above 25 percent that there is— Q. If we look at just the 25 percent, that also throws us past ninety minutes; correct? A. Yes Tr. (Vol. 1), D.I. 148 at 351:22-352:13. Thus, Ms. Gray testified that one could, at most, “assume” that release of MPH from the tablet core does not occur until after the t=90 minute mark, when the percentage of MPH release exceeded 25%. Otherwise, Ms. Gray testified that “[w]e can’t know” whether at earlier points MPH was in fact being released from the tablet core, casting doubt on Plaintiffs’ theory that, in some fraction of ANDA products, MPH is released during the first interval of an appropriate dissolution test. In sum, the Court concludes that Plaintiffs have not adequately rebutted the above evidence tending to establish that the ANDA products do not release any non-IR MPH during the first hour of an appropriate dissolution test, which the Court’s construction requires. Accordingly, the Court concludes that Plaintiffs have not established that the administration of Andrx’s proposed products to treat ADHD would constitute a direct infringement of claim 1 of the '373 patent. 2. Claims 6 And 7 Having concluded that Defendants’ ANDA products, if sold, would not infringe claim 1 of the '373 patent, the Court further concludes that Defendants’ ANDA products would also not infringe claims 6 and 7, which depend from claim 1. IV. INVALIDITY Defendants allege that claims 1, 6 and 7 of the '373 patent are invalid as (1) obvious and (2) not enabled. A. Obviousness 1. Applicable Law In pertinent part, 35 U.S.C. § 103 provides that a patent may not be obtained “if the differences between the subject matter sought to be patented and the prior art are such that the subject matter as a whole would have been obvious to a person having ordinary skill in the art.” 35 U.S.C. § 103. Obviousness is a question of law that is predicated upon several factual inquiries. RichardsonVicks v. Upjohn Co., 122 F.3d 1476, 1479 (Fed.Cir.1997). Specifically, the trier of fact must consider four issues: (1) the scope and content of the prior art; (2) the level of ordinary skill in the art; (3) the differences between the claimed subject matter and the prior art; and (4) secondary considerations of non-obviousness, such as commercial success, long felt but unsolved need, failure of others, and acquiescence of others in the industry that the patent is valid, and unexpected results. Graham v. John Deere Co., 383 U.S. 1, 17-18, 86 S.Ct. 684, 15 L.Ed.2d 545 (1966) (the “Graham factors”). The Supreme Court, in KSR Intern. Co. v. Teleflex Inc., 550 U.S. 398, 127 S.Ct. 1727, 167 L.Ed.2d 705 (2007), reaffirmed that the Graham factors “continue to define the inquiry that controls” an obviousness analysis. Because an issued patent is presumed valid, the party seeking to challenge the validity of a patent based on obviousness must demonstrate by clear and convincing evidence that the invention described in the patent would have been obvious to a person of ordinary skill in the art at the time the invention was made. Pfizer, Inc. v. Apotex, Inc., 480 F.3d 1348, 1359-60 (Fed.Cir.2007). Clear and convincing evidence is evidence that places in the fact finder “an abiding conviction that the truth of [the] factual contentions are ‘highly probable.’ ” Colorado v. New Mexico, 467 U.S. 310, 316, 104 S.Ct. 2433, 81 L.Ed.2d 247 (1984). 2. Discussion The Court will now consider in detail each of the four Graham factors. As set forth below, Defendants’ arguments are well taken, and some of the evidence Defendants present does indeed weigh in favor of a finding of obviousness. However, the Court ultimately concludes that Defendants have not met their burden of proving by clear and convincing evidence that the '373 patents is invalid as obvious. a. The Scope And Content Of The Prior Art Defendants rely on a number of pieces of prior art in support of their obviousness argument. Plaintiffs dispute the scope of the teachings of this art. The Court will summarize the parties’ position on each key piece of prior art in turn and then state its overall conclusion regarding the scope and content of this prior art. i. Angrist Defendants point out that the 1987 publication by Burton Angrist on central nervous system (“CNS”) stimulants states that “a type of tolerance to CNS stimulants that clearly does occur clinically is an acute tolerance after a single dose, which disappears quickly.” DTX 626 at 112-13. Defendants’ expert, Dr. Michael Mayersohn, testified that because MPH is a CNS stimulant, one of skill in the art would, upon reviewing the Angrist publication, understand that MPH would likely exhibit acute tolerance. Tr. (Vol. 3), D.I. 150 at 821:11-825:11. Dr. Mayersohn further testified that amphetamine was a close chemical analog of MPH and one of the first drugs used to treat ADHD. Id. Plaintiffs respond that the Angrist publication does not mention MPH and was focused on cocaine and d-amphetamine, and, in particular, the binging activity of drug abusers taking these substances. DFF ¶ 481. Plaintiffs’ expert, Dr. Kennerly Patrick, testified that, in these circumstances, those of skill in the art seeking to treat children with ADHD would not have looked to the Angrist publication for guidance. Tr. (Vol. 4), D.I. 151 at 1046:5-1047:18. Dr. Patrick further testified that one of skill in the art working on MPH would be unlikely to look to studies focused on cocaine and amphetamine because their physiological mechanism of action differs from that of MPH. Id. at 1048:15-1049:5. ii. Birmaher Defendants note that the 1989 publication by Birmaher et al. regarding plasma studies on Ritalin SR® reported a “flattened curve of MPH plasma concentrations after MPH-SR ingestion” and stated that this “raise[d] a question about whether MPH-SR may be more prone to tachyphylaxis” (i.e., acute tolerance). DTX 627 at 771. The Birmaher publication further states that the observed “flattened curve” was similar to what had been previously observed with amphetamines, where tachyphylaxis was a confirmed phenomenon. Id. Based on this, Defendants contend that the Birmaher publication, like the Angrist publication, confirms that MPH had been associated with acute tolerance prior to the filing of the '373 patent. In response, Plaintiffs’ expert, Dr. Patrick, testified that although tachyphylaxis was mentioned in the Birmaher publication, it was merely mentioned as one of many possible causes for the lack of efficacy of Ritalin SR® compared to Ritalin®. Tr. (Vol. 4), D.I. 151 at 1038:3-1040:13. Other possible causes mentioned in the Birmaher publication include problems with absorption of Ritalin-SR® in the gastrointestinal track, delayed Ritalin SR® absorption, pharmacokinetic differences between Ritalin SR® and Ritalin®, and different brain receptor responses to Ritalin SR® and Ritalin®. DTX 627 at 768. To the extent the authors of the Birmaher publication pointed to tachyphylaxis as a cause, they cited only to a personal communication from another researcher. See id. Dr. Patrick testified that such a citation was unusual and a “peculiar way to substantiate a position.” Tr. (Vol. 4), D.I. 151 at 1040:21-1041:10. Furthermore, Plaintiffs note that the Birmaher publication acknowledges that the study described therein was based on less than ideal controls and was not based on a comparison to standard twice-daily MPH dosing. DTX 627 at 771. In these circumstances, Plaintiffs contend that any conclusions stated in the Birmaher publication should be given little weight. PFF ¶ 447. iii. Perel Defendants point to an abstract published by Dr. J.M. Perel at the Ninety-Second Annual Meeting of the American Society for Clinical and Pharmacology and Therapeutics that states that MPH was associated with a phenomenon called “clockwise hysteresis.” DTX 153. Defendants pair this with a supplement to an FDA Citizen Petition submitted by Defendant McNeil that explains that acute tolerance is “seen graphically as a clockwise hysteresis in the plasma concentration-effect relationship.” PX 266 at Vol. 1 Pg. 8. Thus, according to Defendants, Perel’s prior observation of clockwise hysteresis was tantamount to an observation of acute tolerance. Plaintiffs expert, Dr. Patrick, however, testified that, like the Birmaher publication, the Perel abstract would not have been of interest to those working on ADHD treatment because of flaws in Perel’s study. In particular, Dr. Patrick testified that the Perel study involved MPH doses irrelevant to the treatment of pediatric ADHD patients and involved drawing blood from children using needles. The latter factor, Dr. Patrick explained, undermined the study because the effect of the subject observing blood being drawn would be difficult to “separate” from the underlying ADHD. Tr. (Vol. 5), D.I. 152 at 1040:21-1041:10. iv. Fung Defendants contend the 1984 article of Ho-Leung Fung on the use of nitrates to treat angina recognized that acute tolerance was associated with nitrates and proposed addressing that problem by providing an ascending release rate. Specifically, Fung stated that to overcome nitrate tolerance “an alternate input mode might be one that involves escalating rates of drug delivery so that increasing systemic nitrate concentrations may be acheived.” DTX 631 at 25. Defendants expert, Dr. Mayersohn, testified that the long-acting nitrates were particularly relevant because, like CNS stimulants, they have a “very high body clearance” and that one of skill in the art would be “encouraged” by the Fung article. Tr. (Vol. 3), D.I. 150 at 842:23-851:6. Plaintiffs respond that the Fung article explicitly stated the “escalating rate” dosing proposal was made in a “speculative fashion” and admitted that the “dosing approach [had] to be experimentally tested.” DTX 631 at 25. Furthermore, Plaintiffs’ expert, Dr. Patrick, testified that the novel dosing mode proposed in Fung provided a nitrate concentration far in excess of that provided with the conventional nitrate dosing mode and that, if this approach were taken with MPH, there would be intolerable side effects. See Tr. (Vol. 4), D.I. 151 at 1059:22-1060:6. Indeed, according to Dr. Patrick, providing an MPH concentration so far in excess of the conventional dose, as proposed in Fung, could pose a safety concern and even lead to hospitalization. Id. at 1060:18-1061:3. Dr. Patrick, further testified that in subsequent patents and publications Fung had, in fact, abandoned this approach in favor of a constant release rate of a related class of drugs. See Tr. (Vol. 4), D.I. 151 at 1064:14-1065:22; PX 420 at 2:3-7. Likewise, over a decade after making his “escalating rate” dosing proposal, Fung admitted in a publication that the efficacy of the “escalating rate” dosing approach compared to intermittent therapy had not been evaluated. See DTX 1221 at 1143. Dr. Patrick testified that this fact was consistent with his conclusion that those of skill in the art would not have viewed prior art pertaining to nitrates as being relevant to treating ADHD. See Tr. (Vol. 5), D.I. 152 at 1191:13-1192:8. v. Bayer U.S. Patent No. 4,956,181 issued to Bayer et al., like Fung, dealt with nitrate therapy. Notably, Bayer includes a passage specifically discussing Fung, which explained that Fung had previously disclosed “escalating rates of drug delivery.” See DTX 632 at 1:42-61. Bayer further disclosed a transdermal nitrate delivery system in which, following a “washout period,” the delivery rate is increased during a “ramp-up” time of about 8 to 21 hours. Id. at 3:10-50. Plaintiffs’ expert, Dr. Martyn Davies, testified that this system could have been used with MPH to provide an ascending release rate. Tr. (Vol. 5), D.I. 152 at 1245:12-18. In addition, Bayer explained that “pills, tablets, capsules, and caplets for oral administration” could be adapted for use “in accordance with the invention.” DTX 632 at 8:51-57. Dr. Patrick, testified that one of skill in the art trying to develop a once-a-day treatment for MPH would not, however, have found Bayer useful because (1) it dealt with a 24-hour time frame and (2) pertained to nitrates, which have a much higher margin of safety than MPH. See Tr. (Vol. 4), D.I. 151 at 1062:13-24. Dr. Patrick further explained that Bayer did not disclose an ascending release through the midpoint of the T90 of a dosage form. Id. at 1063:1-5. vi. Wong U.S. Patent No. 5,156,850 to Wong et al. specifically taught methods of manufacturing osmotic dosage forms that, after an initial period of no release, provided ascending release for at least three hours and through the midpoint of the T90. See, e.g., DTX 634 at 18:36-51, Figs. 10-11. Wong lists MPH as a drug that could be used in conjunction with the methods disclosed therein. Id. at 10:16-29. Furthermore, Defendants’ expert, Dr. Mayersohn, testified that one of the drugs Wong discusses at length, verapamil, has a solubility similar to MPH. One of skill in the art, Dr. Mayersohn testified, would thus expect MPH to be released from the Wong dosage forms similarly to verapamil. Tr. (Vol. 4), D.I. 151 at 888:15-21. However, Dr. Patrick testified that the drugs discussed in Wong have a different mechanism of action from MPH. Id. at 1067:24-1068:16. Dr. Patrick further questioned the relevance of Wong because certain release profiles set forth in Wong would lead to very little drug reaching the bloodstream during the hours shortly after administration and also include an extended period of steady release. Such a profile, Dr. Patrick explained, would be ineffective for ADHD treatment because it would provide inadequate therapy during the e