Cephalon Inc. v. Mylan Pharmaceuticals Inc. (962 F. Supp. 2d 688, 2013)

United States District Court for the District of Delaware 2013-07-22

Citations

Full opinion text

OPINION

SUE L. ROBINSON, District Judge.

I. INTRODUCTION

This Hatch-Waxman action arises out of the filing of an Abbreviated New Drug Application (“ANDA”) by defendants Mylan Pharmaceuticals Inc. and Mylan Inc. (collectively, “Mylan”) seeking to market generic fentanyl buccal tablets. Plaintiff Cephalon Inc. is the holder of approved New Drug Application (“NDA”) No. 21-947 for Fentora® brand fentanyl buccal tablets, used to treat breakthrough pain in cancer patients. (D.I. 138, ex. 1 at ¶ 35) It is also the assignee of U.S. Patent Nos. 6,200,604 (“the ’604 patent”), 6,974,590 (“the ’590 patent”), 8,092,832 (“the ’92,832 patent”), and 8,119,158 (“the ’158 patent”) (collectively, “the patents-in-suit”), which are directed to oral effervescent pharmaceutical dosage forms. {Id., ex. 1 at ¶¶ 2, 17, 30, 34) The patents-in-suit are among six patents listed in the Food and Drug Administration’s (“FDA’s”) publication titled “Approved Drug Products with Therapeutic Equivalence Evaluations” (known as the “Orange Book”) for Fentora®. {Id., ex. 1 at ¶ 36) Plaintiff CIMA Labs, Inc. (“Cima”) is a wholly owned subsidiary of Cephalon Inc. {Id., ex. 1 at ¶ 3) It was previously the assignee of the ’604 and ’590 patent. {Id., ex. 1 at ¶¶ 13,18)

In January 2011, pursuant to 21 U.S.C. § 355(j)(2)(B), Mylan notified Cephalon Inc. and Cima (hereinafter, collectively “Cephalon”) that it had submitted ANDA No. 202577 for a 300 meg generic version of fentanyl citrate buccal tablets with a paragraph TV certification stating that the ’604 and ’590 patents are not infringed and are invalid. (Id, ex. 1 at ¶ 38) Cephalon responded by filing this suit for infringement of the ’604 and ’590 patents. (D.I. 1)

On September 29, 2011, Cephalon received a second paragraph IV letter from Mylan regarding an amendment to Mylan’s ANDA, which sought FDA approval for additional dosages of Mylan’s generic version of fentanyl citrate buccal tablets. (D.I. 138, ex. 1 at ¶ 41) This notice again alleged that the ’604 and ’590 patents are not infringed and are invalid; it further alleged that U.S. Patent Nos. 7,862,832 (“the 62,832 patent”) and 7,862,833 (“the ’833 patent”) are not infringed and are invalid. (Id) On November 9, 2011, Cephalon filed a second suit (Civ. No. lililí) Alleging infringement of those four patents. (Id, ex. 1 at ¶ 42)

Thereafter, on January 10, 2012 and February 21, 2012, Cephalon Inc. obtained issuance of the ’92,832 and T58 patents, respectively. Cephalon filed suits (Civ. Nos. 12-73 and 12-247) alleging infringement of the ’92,832 and ’158 patents. (Id, ex. 1 at ¶¶43, 45) On October 4, 2012, Cephalon received a third paragraph IV letter from Mylan, which alleged that the ’92,832 and ’158 patents are not infringed and are invalid. (Id, ex. 1 at ¶¶ 44, 46) The parties subsequently agreed to consolidate the four actions into the instant action.

The court held a Markman hearing on February 8, 2013. Prior to trial, the parties informed the court that Cephalon would not assert infringement of the ’62,-832 and ’833 patents and that Mylan would not challenge the validity of those two patents. (D.I. 144) In addition, Mylan dropped its invalidity counterclaims for the ’604 and ’590 patents and did not contest infringement of the ’92,832 patent. (Id; D.I. 154 at 1 n.l) Therefore, the issues presented at trial were as follows: infringement of claims 1-3, 11, and 12 of the ’604 patent; infringement of claims 1, 2, and 7 of the ’590 patent; validity of claims 1 and 3-5 of the ’92,832 patent; and infringement and validity of claims 1, 15, 17, 19, and 21 of the ’158 patent. (See D.I. 154 at 1 n.l) The court held a bench trial on these issues between March 11 and 15, 2013, and the parties have since completed post-trial briefing. The 30-month stay of FDA final approval on Mylan’s ANDA having expired on July 13, 2013, the court entered an order enjoining Mylan from launching its generic product until July 22, 2013 or the issuance of the court’s decision, whichever was earlier. (D.I. 164) The court has jurisdiction over this matter pursuant to 28 U.S.C. §§ 1331, 1338(a), 2201, and 2202. Having considered the documentary evidence and testimony, the court makes the following findings of fact and conclusions of law pursuant to Federal Rule of Civil Procedure 52(a).

II. FINDINGS OF FACT AND CONCLUSIONS OF LAW

A. The Technology at Issue 1. Drug delivery across the oral mucosa

1. There are several different ways to deliver drugs to the human bloodstream. In traditional oral administration, the dosage form is swallowed and the drug is absorbed across the gastrointestinal mucosa of the stomach or intestines. (D.I. 147 at 150:17-25, 153:11-14, 158:1-4) By contrast, in oral transmucosal administration, the drug is absorbed across the mucosa of the mouth and directly into the blood stream. (Id. at 79:6-11,154:9-19)

2. The inventions of the patents-in-suit relate to oral transmucosal drug delivery. The oral mucosa are the mucous membranes lining the mouth, and include the buccal, sublingual, and gingival mucosa. (Id. at 77:14-21, 154:4-8; D.I. 149 at 724:2-16) The buccal mucosa is along the inside of the cheek; the sublingual mucosa is under the tongue; and the gingival mucosa is between the upper lip and gum. (D.I. 147 at 77:14-21, 154:4-8; D.I. 149 at 724:2-16)

3. Oral transmucosal drug delivery results in faster onset of action than traditional oral drug delivery and avoids the “first pass effect,” or degradation of the drug by the liver. (D.I. 147 at 79:6-12, 157:8-158:24; D.I. 149 at 723:10-22; D.I. 150 at 915:23-916:15) As a result, the same therapeutic effect can be achieved with a lower dose of drug administered by oral transmucosal delivery than by traditional oral delivery. Rapid absorption of the drug into the bloodstream is also advantageous to the treatment of conditions requiring fast relief, such as breakthrough cancer pain — occasional flares of severe and intense pain that cancer patients experience. (D.I. 147 at 69:2-7, 71:25-72:1) Such pain is termed breakthrough pain because it “breaks through” the around-the-clock medication used to treat persistent, or background, pain caused by cancerous tumors or side effects of cancer therapy. (Id. at 68:12-70:12, 71:8-72:1) Breakthrough pain is debilitating and lasts for about one hour, but can last anywhere from a half-hour to two or more hours. (Id. at 69:5-21, 76:3-11; D.I. 151 at 1141:13-1143:9)

4. Drugs may be absorbed across the oral mucosa through two pathways: para-cellular or transcellular absorption. (D.I. 147 at 154:9-155:20) In paracellular absorption, the drug travels in between cells, through gateways called tight junctions, to reach the bloodstream. (Id. at 154:12-14, 155:1-20, 157:1-7, 161:24-162:2; D.I. 149 at 725:14-20) In transcellular absorption, the drug travels from cell to cell, through cell membranes, until reaching the bloodstream. (D.I. 147 at 154:14-15, 155:14-20; D.I. 149 at 725:21-24)

5. Fentanyl, a potent narcotic analgesic, is a lipophilic drug, meaning that it is soluble in lipids (e.g., fats and oils). (D.I. 147 at 155:25-156:3) Lipophilic drugs like fentanyl reach the bloodstream primarily by the transcellular pathway. (Id. at 155:21-24, 156:4-10) In order for a drug to be absorbed, it must dissolve into solution first. (Id. at 162:14-21) Acidic (low) pH levels favor dissolution of weakly basic drugs, including fentanyl. (Id. at 162:18-21, 164:21-165:1; DTX411 at 150-51) When dissolved, fentanyl becomes ionized. (D.I. 147 at 164:23-165:1; DTX411 at 150-51)

6. For transcellular absorption, however, fentanyl needs to be in its unionized form. (D.I. 147 at 162:22-24, 165:2-5) The unionized form of fentanyl is favored at a more basic (higher) pH. (Id. at 162:23-24, 165:6-8) Herein lies the drug formulator’s quandary; while low pH conditions promote dissolution of fentanyl, the opposite (high) pH conditions promote absorption. (Id. at 162:3-163:6, 164:16-165:6) Therefore, the “holy grial” for formulators is to provide a drug for oral mucosal delivery that has both improved solubility and absorption. (Id. at 162:2-3)

2. The Khankari patents

7. The ’604 and ’590 patents (hereinafter, collectively the “Khankari patents”) claim inventions that achieve this result by using an effervescent agent to enhance absorption of a medicament across oral mucosa. The Khankari patents list the same five inventors: Drs. Sathasivan Indiran Pather (“Dr. Pather”), Rajentra K. Khankari (“Dr. Khankari”), Jonathan D. Eichman (“Dr. Eichman”), Joseph R. Robinson (“Dr. Robinson”), and John Hontz (“Dr. Hontz”). The ’604 patent was filed on June 8, 1999 and issued on March 13, 2001. The ’590 patent was filed on February 20, 2002 as a progeny of the ’604 patent and issued on December 13, 2005. Both patents claim priority, at the earliest, to a provisional application filed March 27, 1998 and share a common disclosure.

8. Dr. Khankari testified that the inventions achieve enhanced absorption of the medicament by a “dynamic change” in pH. (Id. at 163:7-164:10, 191:18-192:8) The dynamic change in pH occurs due to the incorporation of effervescent agents that react to form carbon dioxide (C02) in the oral cavity. (Id. at 163:7-13, 164:8-10) First, the effervescent reaction forms a weak acid (carbonic acid) in saliva, which depresses the pH of the saliva. (Id. at 163:12-19, 164:11-17, 194:3-6) The carbonic acid then dissociates into water and C02, which leaves the solution as a gas, causing the pH to slowly rise. (Id. at 163:20-164:1, 164:18-20, 166:22-167:2) This dynamic change in pH achieves a balance between dissolution and absorption. The inventors believed that effervescence increases the rate and extent of absorption of a medicament by “one or all of the following mechanisms: (1) reducing the mucosal layer thickness and/or viscosity; (2) tight junction alteration; (3) inducing a change in the cell membrane structure; and (4) increasing the hydrophobic environment within the cellular membrane.” (’590 patent, col. 2:23-31)

9. The Khankari patents teach that the inventions “should include an amount of an effervescent agent effective to aid in penetration of the drug across the oral mucosa.” (Id., col. 2:32-34) The detailed description teaches that the preferred amount of effervescent agent is between 5% and 95% and, more preferably, between 30% and 95%. (Id., col. 2:34-38) While most often a soluble acid source (including food acids) and a carbonate source will be used, which reaction produces C02 gas, reactants which evolve other gases and are safe for human consumption may also be used. (Id., col. 2:48-3:3)

10. The Khankari patents also disclose the use of suitable pH-adjusting substances (or “pH adjustors”), which permit a sufficient concentration of the drug that is known or suspected to be absorbed via the transcellular pathway to be present in the unionized (and more absorbable) form. (Id., col. 3:18-20, 3:31-37) “Suitable pH-adjusting substance[s] for use in the present invention include any weak acid or weak base in amounts additional to that required for the effervescence or, preferably, any buffer system that is not harmful to the oral mucosa.” (Id., col. 3:47-51) Suitable disintegrants include, but are not limited to, “any of the acids or bases previously mentioned as effervescent compounds, disodium hydrogen phosphate, sodium dihydrogen phosphate and the equivalent potassium salt.” (Id., col. 3:51-55)

11. Other ingredients, including non-effervescent disintegration agents (“disintegrants”) and excipient fillers (“fillers”), may also be incorporated into the dosage form of the invention for a variety of purposes. “Disintegrants may comprise up to about 20[%]” of the composition and, preferably, between 2% and 10% of the composition. (Id., col. 4:41-51) The specification lists non-limiting examples of disintegrants, including “microcrystalline, cellulose, eroscarmelose sodium, erospovidone, starches, corn starch, potato starch and modified starches thereof, sweeteners, clays, such as bentonite, alginates, gums such as agar, guar, locust bean, karaya, pecitin and tragacanth.” (Id., col. 4:44-49) Fillers may be used “to facilitate tableting” of a solid, oral tablet dosage form and “desirably will also assist in the rapid dissolution of the dosage form in the mouth.” (Id., col. 5:28-32) “Non-limiting examples of suitable fillers include: mannitol, dextrose, lactose, sucrose, and calcium carbonate.” (Id., col. 5:30-32)

12. The ’604 patent has one independent claim, which reads:

1. A method of administering at least one systemically distributable pharmaceutical agent across the oral mucosa comprising:

a)providing a solid oral dosage form including a pharmaceutically effective amount of an orally administerable medicament; and at least one effervescent agent in an amount sufficient to increase absorption of said orally administerable medicament across the oral mucosa; wherein said orally administer-able medicament is not substantially encompassed by or dispersed in a material that prevents absorption of said medicament across the oral mucosa;

b) placing said solid oral dosage form in the mouth of a patient so that saliva in said patient’s mouth activates said at least one effervescent agent in said tablet; and

c) holding said solid oral dosage form and the dissolving contents of said solid oral dosage form in the mouth of a patient whereby said at least one effervescent agent promotes absorption of said orally administerable medicament across the oral mucosa.

(Emphasis added)

13. The ’590 patent discloses fentanyl as the pharmaceutical agent. Its only independent claims reads:

1. A method of administration of fentanyl to a mammal across the oral mucosa thereof, said method comprising: providing a solid oral dosage form comprising fentanyl or a pharmaceutically acceptable salt thereof and at least one saliva activated effervescent agent in an amount sufficient to increase absorption of said fentanyl or pharmaceutically acceptable salt thereof across said oral mucosa, at least one pH adjusting substance, and wherein said amount of said at least one effervescent agent is between about 5% by weight and about 80% by weight; and buccally, sublingually or gingivally administrating said solid oral dosage form to said mammal.

(Emphasis added)

3. The Moe patents

14. The ’92,832 and ’158 patents (hereinafter, collectively the “Moe patents”) are directed to orally disintegrable dosage forms of fentanyl, as well as methods and uses thereof, which reduce the dose of fentanyl compared to prior art doses of fentanyl. Both of the Moe patents were filed on November 29, 2010 and claim priority, at the earliest, to a provisional application filed on December 31, 2003. They share a common disclosure and list the same three inventors: Drs. Derek Moe (“Dr. Moe”), Vikas Agarwal (“Dr. Agarwal”), and Walib Habib (“Dr. Habib”). The ’92,832 patent issued on January 10, 2012, and the T58 patent issued on February 21, 2012.

15. According to the specification of the Moe patents, reducing the dose of fentanyl “while still achieving beneficial management of breakthrough pain in cancer patients” is desirable for several reasons. (T58 patent, col. 1:61-2:24, 2:41-45) In particular, using less of the potent opiate may reduce the cost of patient care and reduce the risk of side effects, such as drug dependence or serious or fatal respiratory depression. (Id., col. 2:61-3:24)

16. The orally disintegrate dosage forms taught by the Moe patents contain “at least about 45% less fentanyl” compared to prior art fentanyl dosage forms, such as “noneffervescent lollipop formulations.” (Id, col. 2:56-58) Those “lollipop” fentanyl formulations are available in the form of an oral lozenge or compressed tablet on a stick and are sold under the trade name Actiq®. (Id, col. 1:24-47; see also DTX586; D.I. 147 at 73:4-10) The Moe patents incorporate the Actiq® label by reference. (’158 patent, col. 1:46-47)

17. Despite the lower dose of fentanyl, the oral dosage forms taught by the Moe patents have a Cmw or “the highest observed concentration in the blood of a patient after administration,” that is “comparable to other dosage forms containing much more, e.g., about twice as much drug.” (Id, col. 2:58-61, 3:63-64) “ ‘Comparable’ in this context means that the Cmsx of a dosage form of the ... invention is at least about 75% to about 125% of that of A[ctiq®] having about twice as much fentanyl.” (Id, col. 2:63-64)

18. The oral dosage form of the Moe patents excludes lollipop formulations like Actiq® and are preferably effervescent tablets. (Id, col. 3:18-22) The dosage form may be delivered through the oral transmucosa (like the inventions of the Khankari patents). (Id, col. 3:3:30-41) The Moe patents disclose that “the use of effervescence and/or a pH adjusting substance, and most preferably both, can provide significant advantages particularly in terms of the amount of fentanyl that is required for dosing.” (Id, col. 8:65-9:1; see also id, col. 4:29-32)

19. The dosage form may also include a disintegrant and filler. (Id, col. 3:23-27) The specification teaches that “[i]t has ... been found that certain disintegrants and fillers in combination with at least one effervescent couple and at least one pH adjusting substance can provide even better, and very unexpected, results.” (Id, col. 9:1-5) The preferred disintegrant is SSG, and the preferred filler is mannitol. (Id, col. 4:43-50)

20. Claim 1 is the only independent claim among the asserted claims of the T58 patent:

1. A dosage form comprising: from about 200 micrograms to about 800 micrograms of fentanyl, a salt form of fentanyl, or combinations thereof, calculated as fentanyl free base; an effervescent material in an amount of about 15% to no more than about 60% by weight of the dosage form; a pH adjusting substance in an amount of about 0.5 to about 25% by weight of the dosage form, wherein said pH adjusting substance is not a component of said effervescent material;

mannitol in an amount of between about 10 and about 80% by weight of the dosage form;

a starch glycolate in an amount of about 0.25 to about 20% by weight of the dosage form;

wherein said dosage form is suitable for delivery of said fentanyl across the oral mucosa of a patient by buccal, gingival or sublingual administration.

21. The ’92,832 patent claims a tablet as the dosage form and particular dosages of about 100 meg, 200 meg, 300 meg, 400 meg, 600 meg, and 800 meg of fentanyl free base. Furthermore, it includes a limitation of “a dwell time that is less than about 30 minutes.” Claim 1 of the ’92,832 patent reads:

1. A tablet comprising:

an amount of fentanyl free base or an equivalent amount of salt thereof selected from the group consisting of about 100 micrograms, about 200 micrograms, about 300 micrograms, about 400 micrograms, about 600 micrograms, and about 800 micrograms, calculated as fentanyl free base,

an effervescent agent comprising a food acid and a bicarbonate in an amount of about 15 to about 60% by weight of said tablet;

a pH adjusting substance comprising a carbonate in an amount of about 0.5 to about 25% by weight of said tablet, wherein said pH adjusting substance is different from the food acid and the bicarbonate in the effervescent agent; a starch glycolate in an amount of about 0.25 to about 20% by weight of said tablet;

mannitol in an amount of about 10 to about 80% by weight of said tablet; said tablet being suitable for delivery of said fentanyl across the oral mucosa of a patient by buccal administration and having a dwell time that is less than about 30 minutes.

4. Mylan’s ANDA products

22. Mylan’s proposed generic fentanyl citrate buccal tablets (hereinafter, the “ANDA products”) contain dosage strengths of 100 meg, 200, meg, 300 meg, 400 meg, 600 meg, and 800 meg of fentanyl free base. (PTX188.1) There is no dispute that Mylan’s ANDA products contain the same ingredients as Fentora®, namely mannitol (between 46-47%); sodium bicarbonate (21.0%); citric acid (anhydrous) (15.0%), sodium carbonate (10.0%), sodium starch glycolate (“SSG”) (4.0%), magnesium stearate (1.0%), and fentanyl citrate. (Id.; PTX264.18) The amount of fentanyl citrate, the active ingredient, varies between 0.16% and 0.63% depending on the dosage strength of the tablet. (PTX188.1) The ANDA products also contain silicon dioxide (2.0%), which is not found in Fentora®. (Id. at .1, .3; PTX264.18)

B. Claim Construction

1. Standard

23. Claim construction is a matter of law. Phillips v. AWH Corp., 415 F.3d 1303, 1330 (Fed.Cir.2005) (en banc). Claim construction focuses on intrinsic evidence — the claims, specification, and prosecution history — because intrinsic evidence is “the most significant source of the legally operative meaning of disputed claim language.” Vitronics Corp. v. Conceptronic, Inc., 90 F.3d 1576, 1582 (Fed.Cir.1996); Markman v. Westview Instruments, Inc., 52 F.3d 967, 979 (Fed.Cir.1995) (en banc), aff'd, 517 U.S. 370, 116 S.Ct. 1384, 134 L.Ed.2d 577 (1996). Claims must be interpreted from the perspective of one of ordinary skill in the relevant art at the time of the invention. Phillips, 415 F.3d at 1313.

24. Claim construction starts with the claims, id. at 1312, and remains centered on the words of the claims throughout. Interactive Gift Express, Inc. v. Compuserve, Inc., 256 F.3d 1323, 1331 (Fed.Cir.2001). In the absence of an express intent to impart different meaning to claim terms, the terms are presumed to have their ordinary meaning. Id. Claims, however, must be read in view of the specification and prosecution history. Indeed, the specification is often “the single best guide to the meaning of a disputed term.” Phillips, 415 F.3d at 1315.

2. Issues at bar

25.The parties agree that the court should apply at bar the same claim construction for the Khankari patents as found in Cephalon, Inc. v. Watson Pharm., Inc., 769 F.Supp.2d 729 (D.Del.2011), rev’d on other grounds, 707 F.3d 1330 (Fed.Cir. 2013), except for two disputed claim terms: “providing a solid oral dosage form” from the ’604 patent and “pH adjusting substance is not a component of said effervescent material” from the ’158 patent. The constructions of the other disputed terms have either been mooted because the ’62,-832 and ’833 patents are no longer at issue or, in the case of the “dwell time” limitation, are no longer being disputed. (See D.I. 122 at 8 n.4; D.I. 126)

3. “Providing a solid oral dosage form”

26. The “providing a solid oral dosage form” limitation appears in claim 1 of the ’604 patent. Cephalon avers that no construction is necessary because the plain and ordinary meaning is apparent. (D.I. 117) Mylan proposes the construction “supplying a solid oral dosage form to a patient,” which would exclude a patient supplying the dosage form to herself. (Id.)

27. Both parties purport to adhere to the ordinary meaning of “providing.” (D.I. 122 at 9; D.I. 126 at 7) Cephalon asserts that “providing” means “supplying” or “making available” and that “a patient can provide a dosage form for herself just like she can provide food or shelter for herself.” (D.I. 122 at 9; D.I. 132 at 3) Mylan asserts that “[i]n ordinary English usage, one does not ‘provide’ things to oneself’ but that “one party (the supplier) supplies] the needs of another.” (D.I. 126 at 7)

28. The dictionary definition of “providing” is “[t]o furnish; supply” or “[t]o make available, afford.” Am. Heritage Dictionary (4th ed. 2009). Nothing in the claims, specification, or prosecution history narrows the meaning of “providing” to specify who must do the providing. A medical doctor or nurse may “furnish” or “supply” a dosage form by administering it to a patient, but the patient may also provide a dosage form to herself. For instance, a patient may make the drug available for use by removing it from a package. See Meyers Intellectual Props. Ltd. v. Bodum, 690 F.3d 1354, 1369 (Fed.Cir.2012) (construing a “providing” step broadly such that any single party could perform it because “nothing in the claim language or the patent specification limited] the ‘providing’ step to a specific party”).

29. Mylan argues that if “providing” were construed to include a patient supplying the drug to herself, the limitation would be superfluous for covering all the necessary steps within the “providing” step. (D.I. 126 at 6) The court disagrees. “Providing” a specified dosage form is not the same as “placing” or “holding” said dosage form in the mouth so as to activate and promote absorption of the medicament, respectively. The “providing” step, even given its broad ordinary meaning, does not supplant the other claimed steps.

30. Mylan also contends that requiring a non-patient party to perform the “providing” step is consistent with how a person of ordinary skill in the art would understand the limitation, given that the medicament is fentanyl, a narcotic subject to strict regulatory oversight, and that healthcare providers and patients of fentanyl products must enroll in a Risk Evaluation Mitigation Strategy Access program. (Id. at 7) (citing D.I. 128, ex. 3 at ¶ 39, ex. 4 at ¶ 21) There are two problems with Mylan’s reliance on this extrinsic evidence. First, the ’604 patent claims are not limited to fentanyl or any specific drug. Second, the routes or requirements for a patient to obtain fentanyl are of no moment. Even if a patient must obtain a prescription, enroll in a risk mitigation program, or take a medication under close supervision, neither the intrinsic nor the extrinsic evidence indicates that a patient, or any single party, cannot still perform the claimed “providing” step.

31. Therefore, the court agrees with Cephalon that the “providing a solid oral dosage form” step is not limited to any particular party. As the ordinary meaning suffices, construction of the limitation is not necessary.

4. “pH adjusting substance is not a component of said effervescent material”

32. The parties also dispute the limitation “pH adjusting substance is not a component of said effervescent material.” This term appears in independent claims 1 and 5 of the ’158 patent. Cephalon proposes that no construction is necessary or, to the extent the court finds that the term requires construction, “pH adjusting substance is in addition to the components of said effervescent agent.” (D.I. 117) Mylan’s proposed construction — “the pH adjusting substance is not one of the components used to generate effervescence”— adds the limitation that the pH-adjusting substance cannot participate at all in any effervescent reaction. (Id.; D.I. 126 at 12)

33. The specification of the ’158 patent teaches that the use of an effervescent substance with a pH-adjusting substance can offer advantages: “[Ejffervescence and/or a pH adjusting substance, and most preferably both, can provide significant advantages particularly in terms of the amount of fentanyl that is required for dosing.” (’158 patent, col. 8:65-9:1; see also id., col. 4:29-32) The specification further provides that, if a pH-adjusting substance is used, “[m]ost preferably, the pH adjusting substance is something other than one of the components, compounds or molecules used to generate effervescence” (id., col. 4:32-35); and “[t]he selection of another pH adjusting substance such as, for example, anhydrous sodium carbonate which operates separate and apart from the effervescent agents would be preferred.” (Id., 26:64-67) Even if it is highly-preferred that the pH-adjusting substance does not also generate effervescence, such a preference is an embodiment that is not properly read into the limitation. See Phillips, 415 F.3d at 1323 (“[Although the specification often describes very specific embodiments of the invention, we have repeatedly warned against confining the claims to those embodiments.”). The specification does not require that the pH-adjusting substance be entirely noneffervescent, i.e., that it not participate at all in any effervescent reaction.

34. In fact, the specification of the ’158 patent identifies sodium carbonate, potassium carbonate, magnesium carbonate “and the like” as possible effervescent agents, while also noting that each may be “more preferably used as a pH adjusting substance.” (’158 patent, col. 26:26-29) In other words, an agent which generates effervescence may also be suitable — perhaps even more preferable — as a pH-adjusting substance. Mylan’s proposed construction would read out this embodiment by requiring that the pH-adjusting substance not generate effervescence. The specification clearly does not contemplate such a narrowing limitation.

35. Therefore, while the effervescent agent and pH-adjusting substance must be separate and distinct, there is no further requirement that the pH-adjusting substance cannot be used to generate effervescence. The court adopts Cephalon’s proposed construction: “pH adjusting substance is not a component of said effervescent material” means “pH adjusting substance is in addition to the components of said effervescent agent.”

C. Infringement

1. Standard

36. A patent is infringed when a person “without authority makes, uses or sells any patented invention, within the United States ... during the term of the patent.” 35 U.S.C. § 271(a). A two-step analysis is employed in making an infringement determination. See Markman, 52 F.3d at 976. First, the court must construe the asserted claims to ascertain their meaning and scope. See id. Construction of the claims is a question of law subject to de novo review. See Cybor Corp. v. FAS Techs., 138 F.3d 1448, 1454 (Fed.Cir.1998). The trier of fact must then compare the properly construed claims with the accused infringing product. See Markman, 52 F.3d at 976. This second step is a question of fact. See Bai v. L & L Wings, Inc., 160 F.3d 1350, 1353 (Fed.Cir.1998).

37. “Direct infringement requires a party to perform each and every step or element of a claimed method or product.” BMC Res., Inc. v. Paymentech, LP., 498 F.3d 1373, 1378 (Fed.Cir.2007), overruled on other grounds by 692 F.3d 1301 (Fed.Cir.2012). “If any claim limitation is absent from the accused device, there is no literal infringement as a matter of law.” Bayer AG v. Elan Pharm. Research Corp., 212 F.3d 1241, 1247 (Fed.Cir. 2000). If an accused product does not infringe an independent claim, it also does not infringe any claim depending thereon. See Wahpeton Canvas Co. v. Frontier, Inc., 870 F.2d 1546, 1553 (Fed.Cir.1989). However, “[o]ne may infringe an independent claim and not infringe a claim dependent on that claim.” Monsanto Co. v. Syngenta Seeds, Inc., 503 F.3d 1352, 1359 (Fed.Cir.2007) (quoting Wahpeton Canvas, 870 F.2d at 1552) (internal quotations omitted). The patent owner has the burden of proving infringement and must meet its burden by a preponderance of the evidence. See SmithKline Diagnostics, Inc. v. Helena Labs. Corp., 859 F.2d 878, 889 (Fed.Cir.1988) (citations omitted).

38. To establish indirect infringement, a patent owner has available two theories: active inducement of infringement and contributory infringement. See 35 U.S.C. § 271(b) & (c). To establish active inducement of infringement, a patent owner must show that an accused infringer “knew or should have known [its] actions would induce actual infringements.” DSU Med. Corp. v. JMS Co., 471 F.3d 1293, 1306 (Fed.Cir.2006). To establish contributory infringement, a patent owner must show that an accused infringer sells “a component of a patented [invention] ... knowing the same to be especially made or especially adapted for use in an infringement of such patent, and not a staple article or commodity of commerce suitable for substantial noninfringing use.” Golden Blount, Inc. v. Robert H. Peterson Co., 365 F.3d 1054, 1061 (Fed.Crr.2004) (quoting 35 U.S.C. § 271(c)). Liability under either theory, however, depends on the patent owner having first shown direct infringement. Joy Techs., Inc. v. Flakt, Inc., 6 F.3d 770, 774 (Fed. Cir.1993).

2. The Khankari patents

39. Cephalon asserts indirect infringement of the Khankari patents; it does not assert direct infringement. Also, Cephalon only asserts literal infringement of the Khankari patents; it does not assert any arguments under the doctrine of equivalents. (See D.I. 153 at 30) The only limitation of the asserted claims of the Khankari patents that Mylan argues is not met by the ANDA products is “at least one [salival activated] effervescent agent in an amount sufficient to increase absorption.” As such, the court will only address this limitation for infringement of the Khankari patents.

40. The parties agree that the court’s construction from Watson, 769 F.Supp.2d at 743, applies to this limitation:

At least one compound that evolves gas by means of an effervescent reaction is present in an amount sufficient to increase the rate and/or extent of absorption of an orally administerable medicament across the oral mucosa. This amount is greater than that required for disintegration and does not include the pH-adjusting substance separately claimed.

(See D.I. 117) Cephalon argues that the citric acid and sodium bicarbonate components of Mylan’s ANDA products satisfy the court’s construction. Namely, these components allegedly: (1) are effervescent agents; (2) do not include the pH-adjusting substance in Mylan’s ANDA products; (3) are present in an amount sufficient to enhance the rate and/or extent of absorption of fentanyl across the oral mucosa; and (4) are present in an amount greater than required for tablet disintegration. (D.I. 153 at 4-5)

a. At least one effervescent agent

41. Cephalon avers that the sodium bicarbonate and citric acid in Mylan’s ANDA products are effervescent agents under the agreed-upon construction because they evolve carbon dioxide gas by means of an effervescent reaction. (Id. at 34) Cephalon’s expert, Dr. Bernard Olsen (“Dr. Olsen”), offered mass loss testing to demonstrate the volume of C02 that evolves when the ANDA products are exposed to water or saliva and visual observation testing, including videos, to show that the ANDA products evolve C02 gas when exposed to water and artificial saliva. (D.I. 148 at 359:5-360:15, 361:4-12, 362:3-365:8, 366:5-371:19, 372:18-376:19; PTX371; PTX373; PTX375; PTX376; PTX377; PTX378; PTX379; PTX380) Another Cephalon expert, Dr. Elizabeth Ilium (“Dr. Ilium”), agreed with Dr. Olsen’s testing methods and also opined that citric acid and sodium bicarbonate in the ANDA products evolve C02 gas by means of an effervescent reaction. (D.I. 149 at 552:20-553:11, 687:13-15)

42. Mylan does not dispute that the sodium bicarbonate and citric acid in its ANDA products evolve gas by means of an effervescent reaction. (D.I. 154 at 23-57; see also D.I. 150 at 908:4-14) Therefore, the ANDA products meet this requirement of the agreed-upon construction.

b. Amount of effervescent agent that does not include the pH-adjusting substance separately claimed

43. Cephalon also submits that the ANDA products meet the agreed-upon construction’s requirement that the amount of effervescent agent that is present to enhance absorption “does not include the pH-adjusting substance separately claimed.” (D.I. 153 at 47) Cephalon avers that the effervescent agents are citric acid and sodium bicarbonate and that the pH-adjusting substance separately claimed is sodium carbonate. (Id.) Cephalon’s expert, Dr. Ilium, opined that sodium carbonate is a well-known basic pH-adjusting substance and is included in Mylan’s ANDA products for that function. (D.I. 149 at 578:6-579:13, 608:11-609:9) He also opined that the ANDA tablets contain sodium bicarbonate and citric acid in amounts that will cause the sodium bicarbonate to fully react to produce effervescence. (Id. at 609:19-23)

44. The only factual issue that Mylan disputes is whether some portion of the sodium carbonate will also effervesce; it does not otherwise contest this requirement. (See D.I. 154 at 23-57) Whether some sodium carbonate will effervesce, however, is not relevant to the Khankari patents. It is not a requirement of the agreed-upon construction that the pH-adjusting substance cannot effervesce. The sodium bicarbonate and citric acid in the ANDA products are the effervescent agents and meet the requirement that the amount of effervescent agent that is present to enhance absorption does “not include the pH-adjusting substance separately claimed.”

c. Effervescent agent sufficient to increase the rate and/or extent of absorption

45. Mylan focuses its non-infringement position for the Khankari patents on the remaining two requirements of the agreed-upon construction. It argues that the effervescent agents in the ANDA products do nothing more than their prior, art function of disintegration and that the pH-adjusting substance, not effervescence, is responsible for any enhanced absorption. In essence, Mylan asserts that the Khankari patents do not teach anything new about effervescence because the only beneficial effect of effervescence is its prior art use to speed up tablet disintegration. (Id. at 23-39)

46. The agreed-upon construction requires that the amount of effervescent agent be sufficient to increase the rate and/or extent of absorption. As a threshold matter, the parties disagree on what Cephalon must show regarding the relationship between effervescence and absorption in the ANDA products. Cephalon contends that the agreed-upon construction only requires the effervescent formulation to increase absorption compared to a non-effervescent formulation (D.I. 153 at 32), whereas Mylan asserts that any increase in absorption attributable to effervescence must be separate and distinct from any absorption attributable to the pH adjustor. (D.I. 154 at 3, 8) Put another way, Cephalon avers that the effervescence must enhance absorption, whether by itself or synergistically with another component, while Mylan avers that the effervescence, alone, must enhance absorption.

47. Contrary to Mylan’s assertion, the agreed-upon construction does not require effervescence to improve absorption independently from pH adjustors. Rather, it only requires that the effervescent agent be present in “an amount sufficient to increase the rate and/or extent of absorption” and that said amount “not include the pH-adjusting substance separately claimed.” The agreed-upon construction does require that the effervescent agent function to enhance absorption separately and independently from the pH-adjusting substance. It does not preclude the pH-adjusting substance and the effervescent agent from acting synergistically to increase absorption.

48. Mylan also attempts to discredit the various theories, including the dynamic pH effect, that would explain why effervescence would increase absorption. However, the agreed-upon construction does not require proof of the mechanism or mechanisms by which effervescence increases absorption. It is irrelevant, for purposes of infringement, why effervescence increases absorption.

49. To prove that the citric acid and sodium bicarbonate in the ANDA products enhance the rate or extent of fentanyl absorption across the oral mucosa, Cephalon’s expert, Dr. Ilium, relied primarily on data and results from the following: (1) an in vivo study in dogs conducted by Anesta at Cima’s direction (“the dog study”); (2) a clinical study in Ireland conducted by Cima (“the Ireland study”); (3) an in vitro human study conducted by Absorption Systems at Cima’s direction (“the Absorption Systems study”); and (4) development efforts by Mylan.

50. During the development of Fentora®, Cima enlisted Anesta to conduct the dog study on prototype fentanyl formulations named the OraVescent® technology. (PTX320.6) OraVescent® technology incorporated components for both effervescence and pH adjustment. (D.I. 147 at 179:23-180:8) The dog study tested four different tablets: short disintegrating and long disintegrating tablets with effervescence and pH adjustment (“the OraVescent® tablets”), and short disintegrating and long disintegrating tablets lacking both effervescence and pH adjustment (“the nonenhanced tablets”). (D.I. 149 at 587:24-588:12; D.I. 150 at 879:15-880:25, 950:14-23; PTX320.6, .9) Two fentanyl solutions were also tested, one with a pH of 7, and one with a target pH of 8.5 but that reached a pH of 8.05. (D.I. 149 at 588:13-589:4; D.I. 150 at 950:14-951:2; PTX320.il; DTX397 at CEPFEN00395029; DTX204; DDX215) “The objective of [the dog] study was to evaluate the hypothesis that effervescence, independent of pH, enhances the permeability of fentanyl through the buccal mucosa.” (PTX320.6; D.I. 149 at 587:8-10)

51. The results showed that the OraVescent® tablets had significantly higher Cmsx values and shorter Tmax values than the nonenhanced tablets and fentanyl solutions. (D.I. 149 at 587:5-591:6, 591:19-593:10, 705:4-22; D.I. 150 at 956:1-958:8; PTX320.20) The parties’ experts agreed that the Cmax value reflects the rate and extent of absorption and that the Tmax value is related to the rate of absorption. (D.I. 149 at 593:3-5, 705:10-12; D.I. 150 at 954:14-955:7)

52. Anesta’s scientists concluded that the dog study’s design and results “d[id] not support the hypothesis that effervescence enhances fentanyl absorption, as pH was not constant during the administration of the fentanyl tablets.” (D.I. 153 at 11; PTX320.2, .20) This conclusion is consistent with Mylan’s contention that the dog study does not show that effervescence alone, isolated from pH adjustment, increases absorption. Cima, however, concluded from the dog study that pH was not constant during the experiment because of effervescence, that is, “effervescence is the mechanism whereby pH is continually changing.” (D.I. 149 at 707:16-708:7; DTX320.32-.34) As Mylan’s expert, Dr. Norman Weiner (“Dr. Weiner”), testified, Anesta and Cima’s different conclusions were akin to “two ships passing in the night.” (D.I. 150 at 962:10-14) They did not necessarily conflict but, rather, focused on answering different hypotheses. While Anesta was focused on isolating the effect of effervescence, which it could not do from the results, Cima concluded from the enhanced absorption data that effervescence, through pH adjustment, at least partially contributed to absorption. (DTX320.32-.34) Because the agreed-upon construction at issue does not require a showing that effervescence, alone, increases absorption, the results of the dog study support Cima’s argument that citric acid and sodium bicarbonate, as effervescent agents, at least contribute to an enhancement in absorption.

53.Thereafter, Cima conducted the Ireland study to evaluate the OraVescent® tablets in humans. (D.I. 147 at 180:11-18) The Ireland study compared the OraVescent® tablets with Actiq® (the commercially available lollipop formulation) and a “nonenhanced” buccal tablet, both of which lacked effervescence and pH-adjusting components. (D.I. 147 at 181:13-25; PTX266A.3-.4; DTX541 at CEPFEN00150997-98) All three formulations contained the same amount of fentanyl. (D.I. 149 at 554:15-20) It was reported that the OraVescent® tablets had better pharmacokinetic (“pK”) parameters than both Actiq® and the nonenhanced buccal tablet formulations. (PTX266A.4-6) Specifically, fentanyl absorption was faster and more complete with the OraVescent® tablets and also reached a higher peak level in the blood. (D.I. 147 at 182:1-183:21; D.I. 149 at 554:1-555:24, 616:17-25, 688:18-689:11; PTX266A.5-6) Mylan’s expert, Dr. Weiner, did not dispute these findings. (D.I. 150 at 940:7-941:3)

54. Mylan concedes that the Ireland study compared formulations that had effervescent agents and pH-adjusting substances to formulations that had neither effervescent agents nor pH-adjusting substances. Like the dog study, the Ireland study showed that formulations containing both effervescent agents and pH-adjusting substances enhanced absorption compared to formulations without any effervescence or pH-altering mechanisms. Because the formulations tested in the Ireland study contained the same effervescent agents (citric acid and sodium bicarbonate) and pH-adjusting substance (sodium carbonate) as the ANDA products, the Ireland study is additional evidence that the ANDA products contain effervescent agents in an amount sufficient to increase the rate and/or extent of absorption.

55. Furthermore, Cephalon points to the Absorption Systems study, an in vitro study on human buccal cells that allegedly confirms that effervescence improves absorption as compared to pH modification alone. (D.I. 153 at 42) The Absorption Systems study is the only study cited by Cephalon that attempted to isolate the effect of effervescence, alone, on absorption. As discussed swpra, however, the court need not determine whether Cephalon has shown that effervescence enhances absorption separate and distinct from pH adjustors.

56. In the Absorption Systems study, the rate of fentanyl permeating across a cultured buccal cell membrane (from a donor chamber to a receiver chamber) was measured for six different fentanyl tablets: an “effervescent” tablet; a “half effervescent” tablet; a “no sodium carbonate” tablet; a “citric acid only” tablet; a “sodium carbonate only” tablet; and a “noneffervescent” tablet. (D.I. 149 at 666:23-667:11, 709:24-710:6; DTX56 at CEPFEN00471812-13, CEP-FEN00471819) The “effervescent” tablet contained effervescent agents (citric acid and sodium bicarbonate) and a pH-adjusting substance (sodium carbonate), and the “half effervescent” tablet contained those same ingredients in half the concentrations. (D.I. 149 at 667:7-19) The “no sodium carbonate” formulation contained effervescent agents (citric acid and sodium bicarbonate) but not the pH-adjusting substance sodium carbonate, whereas the “citric acid only” and “sodium carbonate only” tablets each contained an effervescent agent with no pH adjustor. (Id. .at 667:20-667:23, 668:14-668:24, 669:6-11) Finally, the “noneffervescent” tablet did not contain any citric acid, sodium bicarbonate, or sodium carbonate; it had no components for generating effervescence or controlling pH. (Id. at 668:25-669:5)

57. The “effervescent” and “half effervescent” tablets both had significantly greater permeability values than the “no sodium carbonate” (pH-adjusting substance only) tablet and the “nonefferveseent” tablet (no effervescent agents or pH-adjusting substances). (Id. at 713:18-714:21; D.I. 150 at 964:13-966:16; DTX56 at CEP-FEN00471819; DTX57 at CEPFEN01146467) Cephalon’s expert, Dr. Ilium, opined that the Absorption Systems study thus demonstrated that the synergy of using both effervescence and a separate pH adjustor enhances absorption. (D.I. 149 at 713:18-714:21)

58.The tablets in the Absorption Systems study were allowed to dissolve for four minutes, followed by application of a donor solution for approximately one minute “to provide appropriate dispersion of the dissolved content.” (DTX56 at CEPFEN00471813) As a result, “time [zero],” when the first measurements were taken, actually corresponded to approximately five minutes after the tablets were exposed to the mucosa. (Id.; D.I. 149 at 710:9-711:3; D.I. 150 at 970:3-11) The parties’ experts disagree as to whether the Absorption Systems study accounted for the amount of drug that passed through the membrane during the first five minutes of the experiment, an important omission because the dynamic pH effect of the effervescence would allegedly occur within those first few minutes. (Compare D.I. 148 at 374:5-375:19; D.I. 149 at 690:15-24, 709:24-710:18, 711:1-713:17; DTX57 at CEP-FEN01146466 (fig. 6) with D.I. 150 at 965:4-11, 966:11-23, 967:5-20) Regardless of whether the Absorption Systems study accounted for absorption during the first five minutes, the parties’ experts agreed that the average apparent permeability (“Papp”) of the “effervescent” and “half effervescent” tablets was greater than the average Papp of the “no sodium carbonate” tablet. (D.I. 149 at 713:18-714:21; D.I. 150 at 964:13-966:16) The only two tablets that showed absorption greater than zero at the time zero measurement (five minutes after exposure to the buccal tissue) were the “effervescent” and the “no sodium carbonate” tablets — the tablets that contained the full concentration of effervescent agents and provided rapid disintegration. (DTX56 at CEPFEN00471826-29; D.I. 150 at 972:13-973:2) These results support the notion that a combination of effervescence and a pH-adjusting substance, identical to that of the ANDA products, improves absorption compared to tablets lacking effervescence and a pH-adjusting substance.

59.Finally, Cephalon points to Mylan’s development path to argue that the amount of effervescence in the ANDA products increases the rate and extent of fentanyl absorption. (D.I. 153 at 37-39) Mylan initially tried three different noneffervescent formulations — the 1000306, 1000367, and 1000368 tablets (collectively, “Mylan’s nonefferveseent tablets”) — all of which were “unsuccessful.” (PTX75.4; PTX188.3; D.I. 149 at 561:4-565:17) The nonefferveseent formulations all had pH-adjusting mechanisms but lacked effervescence. (PTX115.3; D.I. 149 at 562:18-563:8) In a presentation reviewing fentanyl tablet development, Mylan noted that the pH profiles of these formulations did not directly correlate to observed pK and that the “pH modifier effect [was] unclear.” (DTX680 at MYLAN518098) After finding that the nonefferveseent formulations were not bioequivalent to Fentora®, Mylan proceeded to test three formulations that were effervescent — the 1000489, 1000490, and 1000544 tablets (collectively, “Mylan’s effervescent tablets”). (PTX75.3-4; D.I. 148 at 423:16-424:3; D.I. 149 at 565:18-23) These formulations contained sodium bicarbonate, citric acid, and sodium carbonate. (PTX75.3-4; D.I. 148 at 423:16-424:3) Dr. Ilium opined that, when Mylan turned to the effervescent formulations, there was “an enormous change” in the pK profiles of the effervescent formulations compared to the nonefferveseent formulations. (D.I. 149 at 567:10-568:3; PTX75.4) The effervescent formulations showed higher pK profiles and absorption than the nonefferveseent formulations. (D.I. 149 at 580:20-582:1, 583:11-584:3; PTX75.4)

60. Cephalon asserts that Mylan itself concluded during the formulation process that “effervescence has [a] larger effect on PK than other pH modifiers; pH modification alone and effervescence are not equivalent.” (PTX75.4; D.I. 149 at 569:24-570:12) Another Mylan presentation states both “Fentora[®] and [Mylan’s] [b]uccal formulation use effervescent couple [sic] to take advantage of’ the dynamic pH effect. (PTX115.8; D.I. 149 at 558:1-559:22) Mylan avers that Ms. Tammy Bartley (“Ms. Bartley”), a senior principal scientist at Mylan, and Dr. David Wargo (“Dr. War-go”), Mylan’s Vice President of Product Development, testified at trial that these statements were mere quotations or regurgitations of principles that Mylan did not independently evaluate or test. (D.I. 154 at 15-16) (citing D.I. 148 at 389:16-390:18, 457:2-7, 507:12-24) Even if Mylan did not explicitly test the dynamic pH theory, it did test and conclude, at a minimum, that the combination of effervescent agents and a pH-adjusting substance improved absorption (regardless of why such improvement came about).

61. Cephalon has presented substantial evidence that effervescence, at least in combination with a pH-adjusting substance, increases the rate and/or extent of absorption. Mylan’s argument that Cephalon has failed to demonstrate that the ANDA products’ effervescence, acting alone, would increase absorption is of no avail under the agreed-upon construction. Cephalon did not need to demonstrate how much of the improved absorption in the ANDA products is due to the effervescent agents as compared to the pH-adjusting substance. Accordingly, the court finds that Cephalon has carried its burden of proving, by a preponderance of the evidence, that the amount of effervescent agent in the ANDA products is sufficient to increase the rate and/or extent of absorption.

d. Amount of effervescent agent that is greater than that required for disintegration

62. With respect to the remaining requirement of the agreed-upon construction, Cephalon asserts that the effervescent agents are also present in an amount greater than that required to disintegrate Mylan’s ANDA products. Specifically, Cephalon claims that no amount of effervescent agent is required for disintegration because a separate component, the superdisintegrant SSG, is sufficient for tablet disintegration. (D.I. 153 at 39-41, 44-47)

63. There is no dispute that the ANDA products contain 4% SSG as a separate ingredient. There is also no dispute that SSG is a known superdisintegrant. According to the Handbook of Pharmaceutical Excipients (“the Handbook”), “[t]he usual concentration [of SSG] employed in a formulation is between 2-8%, with the optimum concentration about 4% although in many cases 2% is sufficient.” (DTX723 at 501) The fact that SSG is a superdisintegrant is consistent with Mylan’s ANDA, which identified SSG as the only component that functions as a “disintegrant” in its ANDA products. (PTX188.1, .3)

64. Cephalon argues that the ANDA products use even more SSG (4%) than Fentora® (3%) and that the Ireland study showed that 3% crospovidone, which is also a superdisintegrant, was sufficient to disintegrate tablets without effervescent assistance. (D.I. 153 at 45) (citing PTX264.18; D.I. 149 at 577:13-25; PTX226A.3; D.I. 150 at 940:17-941:3) The Ireland study reported that 3% crospovidone tablets with effervescence and a pH adjustor and 3% crospovidone tablets with neither effervescence nor a pH adjustor “had similar disintegration times (10 minutes) as tested by a specially developed method for buccal tablets.” (PTX266A.3; D.I. 150 at 940:17-941:3) Although the ANDA products contain SSG (not crospovidone) as the superdisintegrant, the conclusion of the Ireland study is circumstantial evidence from which one can reasonably conclude that the ANDA products contain an amount of effervescent agent greater than that required for disintegration.

65. At trial, Cephalon’s expert, Dr. Ilium, opined that the amount of SSG in the ANDA products is more than sufficient to disintegrate the ANDA products without the aid of any effervescent agent. (PTX264.18; D.I. 149 at 571:9-572:13, 577:13-25, 578:1-5) Dr. Ilium relied, in part, on Mylan’s in vivo testing (“the in vivo testing”) that compared the disintegration of Fentora® to that of Mylan’s noneffervescent formulations, which contained 5% SSG but did not have absorption that was bioequivalent to Fentora®. She opined that “the reason for not having [ ] significant absorption from these [noneffervescent] formulations was not due to the tablets not disintegrating,” i.e., the 5% SSG did not cause any disintegration issues. (D.I. 149 at 572:22-573:2)

66. The results of the in vivo testing showed that the 1000306 tablet had a mean disintegration time of 27.5 minutes, compared to 24.2 minutes for Fentora®. (DTX27 at MYLAN487574; DTX680 at MYLAN518160; PTX102.14; PTX115.74) Mylan concluded from the in vivo testing that the disintegration of the 1000306 tablet and Fentora® was “similar when administered to the buccal membrane,” even though “[l]ittle or no buccal absorption [was] observed.” (PTX102.15, .18) The 1000367 and 1000368 tablets had mean disintegration times of 30.1 and 30.2 minutes, respectively, after which the subject was instructed to swallow the tablet, compared to a mean disintegration time of 25.5 minutes for Fentora®. (D.I. 150 at 849:16-850:8; PTX115.74; DTX680 at MYLAN518160) None of the 1000367 and 1000368 tablets disintegrated completely within the 30-minute administration time. (D.I. 150 at 851:8-9) Because the testing stopped at 30 minutes, it was not possible to determine how long it would take for tablets that had remnants left at 30 minutes to disintegrate completely. (Id. at 850:9-12) Dr. Ilium testified that the mean disintegration time disguised the fact that five out of seven Fentora® tablets also failed to disintegrate completely within 30 minutes. (D.I. 149 at 576:12-20) She concludes from this observation that there was “hardly any difference” in disintegration among the 1000367 tablets, the 1000368 tablets, and Fentora®. (Id. at 576:12-20)

67. Mylan, on the other hand, argues that the 1000367 and 1000368 tablets “failed to achieve adequate disintegration within the requisite administration time.” (D.I. 154 at 39) Its expert, Dr. Weiner, emphasized that two of the Fentora® tablets in the in vivo testing were able to disintegrate completely within 30 minutes and that the mean disintegration time for Fentora® was shorter, from which he concluded that Fentora® had a higher disintegration rate. (D.I. 150 at 849:4-15, 850:17-851:12, 855:1-9; see also D.I. 148 at 481:7-12)

68. Mylan further submits evidence from an in vitro “screen test” (“the screen test”) that also studied disintegration of Mylan’s noneffervescent tablets compared to Fentora®. (D.I. 154 at 39) Unlike traditional oral drugs for delivery through the gastrointestinal mucosa, there is no standardized disintegration test for tablets directed at delivering drugs through the oral mucosa. (D.I. 150 at 852:5-853:4) Dr. Wargo devised and conducted the screen test, in which he partially exposed tablets to water (up to about 20% of the tablets’ height) in a petri dish and observed disintegration overtime. (D.I. 148 at 479:15-481:6, 496:15-18; DTX32 at MYLAN026040) At trial, he pointed to time-lapse pictures to show that, while Fentora® started disintegrating immediately and had completely disintegrated within about 1 minute, the cores of the 1000367 and 1000368 tablets remained after 20 minutes. (Id. at 479:15-480:20; DTX32 at MYLAN026040) He testified that he attributed the faster disintegration of Fentora® to its effervescent characteristics. (Id. at 481:21-482:1)

69. As a threshold matter, the parties’ experts disagreed on whether the screen test was an appropriate method to demonstrate disintegration. While Mylan’s expert, Dr. Weiner, opined that the screen test was appropriate and reliable (D.I. 150 at 854:7-11), Cephalon’s expert, Dr. Ilium, opined that the screen test did not have very much relation to what would actually happen in a patient’s mouth. (D.I. 149 at 576:21-577:12) The court agrees with Dr. Ilium that the screen test does not reliably mimic in vivo disintegration. In a patient’s mouth, a tablet would be moist on all surfaces, rather than just on one side and up to 20% of its height. (D.I. 148 at 497:11-14) As such, the court gives the screen test little weight.

70. Even were the court to assume that the screen test appropriately modeled tablet disintegration, it only documented disintegration for 20 minutes. (Id. at 497:16-23) Similarly, the in vivo testing only documented disintegration for 30 minutes. The agreed-upon construction does not require disintegration within a prescribed amount of time or at a certain rate. Therefore, the court does not find testing that placed an artificial temporal limitation on disintegration to be particularly helpful. To the extent the in vivo testing did document the complete disintegration of the 1000306 tablets, however, that data is probative of disintegration of a tablet containing 5% SSG.

71.Cephalon has submitted circumstantial evidence that 4% SSG is sufficient for tablet disintegration by pointing to its identification as a disintegrant in FDA materials; the teaching in the literature; the Ireland study; and the fact that the 1000306 tablets disintegrated completely and comparably to Fentora® (which contains less SSG) during the in vivo testing. Mylan’s evidence, at most, suggests that effervescence helps to speed up disintegration. As noted before, this is permissible under the agreed-upon construction. Weighing the to