SUE L. ROBINSON, District Judge.
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®.
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
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.
Thereafter, on January 10, 2012 and February 21, 2012, Cephalon Inc. obtained issuance of the '92,832 and '158 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.1) 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.1) 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,
1. There are several different ways to deliver drugs to the human bloodstream.
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 aroundthe-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: paracellular 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,
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
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 (CO
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%.
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
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, croscarmelose sodium, crospovidone, 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:
(Emphasis added)
13. The '590 patent discloses fentanyl as the pharmaceutical agent. Its only independent claims reads:
(Emphasis added)
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,
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. ('158 patent, col. 1:61-2:24, 2:41-45)
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.
17. Despite the lower dose of fentanyl, the oral dosage forms taught by the Moe patents have a C
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 '158 patent:
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:
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.
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
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.
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)
26. The "providing a solid oral dosage form" limitation appears in claim 1 of the '604 patent.
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) suppl[ies] 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.
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.
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.
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
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."
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).
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,
(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)
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 CO
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.
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."
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
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,
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").
51. The results showed that the Ora-Vescent® tablets had significantly higher C
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
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 CEP-FEN00150997-98) 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")
54. Mylan concedes that the Ireland study compared formulations that had effervescent agents
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.
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 CEP-FEN00471812-13, 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 "noneffervescent" 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 CEP-FEN01146467) 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 CEP-FEN00471813) 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 ("P
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 noneffervescent tablets") — all of which were "unsuccessful." (PTX75.4; PTX188.3; D.I. 149 at 561.4-565:17) The noneffervescent 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 noneffervescent 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.
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. Wargo"), 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
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
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. Illum 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 "[I]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
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
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 totality of the evidence, it would be reasonable to infer that, more likely than not, the 4% SSG in the ANDA products is sufficient for tablet disintegration under the agreed-upon construction. Accordingly, Cephalon has carried its burden of showing that the amount of effervescent agent in the ANDA products is greater than required for disintegration.
72. Mylan does not dispute that its ANDA products meet the additional limitations recited in asserted dependent claims 2 and 7 of the '590 patent and claims 2, 3, 11, and 12 of the '604 patent.
73. Regarding indirect infringement, there is no genuine dispute of material fact that Mylan will encourage use through its product labeling and sale of its generic tablets and is aware that the label presents infringement problems. Therefore, it will induce infringement of the Khankari patents.
74. Because Cephalon has demonstrated that Mylan's ANDA products practice each and every requirement of the disputed limitations, Mylan infringes all asserted claims of the Khankari patents.
75. The court next turns to infringement of the '158 patent. Cephalon asserts both direct and indirect infringement of this patent. It does not assert the doctrine of equivalents. (See D.I. 153 at 30) Asserted claims 1, 15, 17, 19, and 21 of the '158 patent recite fentanyl dosage forms that contain, in part, an effervescent material and a pH-adjusting substance. The only dispute for infringement is whether the ANDA products meet the limitation "wherein said pH adjusting substance is not a component of said effervescent material."
76. There is no dispute that Mylan's ANDA products contain sodium carbonate as the pH-adjusting substance and that sodium carbonate is an effervescent material. (See D.I. 154 at 58) (citing D.I. 149 at 603:3-9, 609:24-611:23) Mylan's noninfringement defense hinges on its proposed claim construction of the limitation "wherein said pH adjusting substance is not a component of said effervescent material," which would require the pH-adjusting substance to not be an effervescent material.
77. The court has construed said limitation to mean "pH adjusting substance is in addition to the components of said effervescent agent." This construction allows the pH-adjusting substance to participate in an effervescent reaction. Mylan does not offer any noninfringement defense under the court's construction. In addition, Mylan does not dispute that the ANDA products satisfy the limitations of the dependent claims.
78. As with the Khankari patents, Mylan will encourage use through its product labeling and sale of its generic tablets and is aware that the label presents infringement problems. Therefore, it will induce infringement of all asserted claims of the '158 patent. AstraZeneca, 633 F.3d at 1056-60. The only authorized use for the ANDA products would infringe the '158 patent. As there is no substantial noninfringing use of Mylan's tablets, Mylan will also contribute to infringement of all asserted claims of the '158 patent. Eli Lilly, 435 Fed.Appx. at 926-27.
79. For the foregoing reasons, the court finds that Mylan indirectly infringes the Khankari patents and directly and indirectly infringes the '158 patent.
80. Mylan argues that claims 1, 3, 4, and 5 of the '92,832 patent and claims 1, 15, 17, 19, and 21 of the '158 patent are anticipated by the '604 patent. The '604 patent issued on March 13, 2001 from an application filed June 8, 1999. The parties do not dispute that the '604 patent is prior art vis a vis the Moe patents, which claim priority to, at the earliest, a provisional application filed on December 31, 2003. 35 U.S.C. § 102(b).
81. An anticipation inquiry involves two steps. First, the court must construe the claims of the patents in suit as a matter of law. See Key Pharm. v. Hereon Labs. Corp., 161 F.3d 709, 714 (Fed.Cir.1998). Second, the finder of fact must compare the construed claims against
82. The specification of the '604 patent discloses using an effervescent agent comprising a food acid and a bicarbonate, such as citric acid and sodium bicarbonate.
83. Independent claim 1 of the '604 patent, which is not limited to any specific medicament, teaches the use of "a pharmaceutically effective amount" of an orally administerable medicament. Example 1 of the '604 patent, the only example in which the medicament is fentanyl, describes a 1000 meg dose of fentanyl free base.
84. The written description of the '604 patent identifies mannitol in a list of five suitable fillers. (Id., col. 5:30-32) It also uses mannitol as a component of the formulation in example 2. (Id., col. 6:58, 7:6)
85. The '604 patent further discloses the use of non-effervescent disintegrants, including crospovidone and "potato starch and modified starches thereof." (Id., col. 4:40-47) Cephalon's expert, Dr. Ilium, drew attention to the fact that SSG is not mentioned by name in the '604 patent. (D.I. 151 at 1215:5-7) There is no dispute, however, that SSG is a modified potato starch. (See id. at 1196:18-22, 1214:22-24) Mylan's expert, Dr. Arthur Kibbe ("Dr. Kibbe"), opined that the '604 patent's disclosure of "potato starches and modified
86. Cephalon avers that the following limitations found in the asserted claims of the Moe patents are not disclosed by the '604 patent: (1) the amounts of fentanyl; and (2) the combination of the filler mannitol and the disintegrant SSG. (D.I. 155 at 4-11) In its post-trial briefing, Cephalon also asserts that the '604 patent does not disclose a dwell time less than 30 minutes, which is only a limitation of the asserted claims of the '92,832 patent. (Id. at 11-13) Cephalon does not dispute that the '604 patent discloses the other limitations recited in the asserted claims of the Moe patents. (See D.I. 152 at 33-35, 43-45) Because the court finds that the '604 patent does not disclose the claimed amounts of fentanyl, the Moe patents are not invalid for anticipation.
87. Claim 1 of the '92,832 patent requires that the claimed tablet contain specific dosages between about 100 and about 800 meg of fentanyl free base, and claim 1 of the '158 patent requires that the claimed dosage form contain about 200 to about 800 meg of fentanyl free base. Mylan's expert, Dr. Kibbe, contends that a person of ordinary skill in the art would understand that the "pharmaceutically effective amount" taught by the '604 patent includes fentanyl free base in the range of 100 to 800 meg. (D.I. 150 at 1005:15-24) However, Dr. Kibbe did not provide any support for his conclusive statement. The court finds as more credible and consistent with the 604 patent's disclosure the testimony from Cephalon's expert, Dr. Ilium, that the '604 patent only discloses fentanyl in doses greater than 800 meg to a person of ordinary skill in the art. (D.I. 151 at 1186:25-1187:7)
88. Mylan points to Dr. Kibbe's testimony that a person of ordinary skill would have looked to Actiq®, an FDA-approved product, and recognized that its range of fentanyl, 200-1600 meg, was pharmaceutically effective. (D.I. 150 at 1022:21-1023:4) Extrinsic evidence of anticipation "must make clear that the missing descriptive matter is necessarily present in the thing described in the reference." Cont'l Can Co. USA v. Monsanto Co., 948 F.2d 1264, 1268 (Fed.Cir.1991); see, e.g., Advanced Display Sys., 212 F.3d at 1282 ("Material not explicitly contained in the single, prior art document may still be considered for purposes of anticipation if that material is incorporated by reference into the document."). Actiq® is not mentioned in the '604 patent or incorporated therein. Mylan points to Key Pharmaceuticals, which noted that "it is quite sensible to look to the FDA to determine what amounts are considered pharmaceutically effective." Key Pharm., 161 F.3d at 717. However, Key Pharmaceuticals is inapplicable in the anticipation context. In Key
89. As the claimed fentanyl ranges are not found in the four corners of the '604 patent, the Moe patents are not anticipated. See Advanced Display Sys., 212 F.3d at 1282 (holding that a patent claim is anticipated only if every element of a claimed invention can be found in "the four corners of a single, prior art document"). To the extent Mylan relies on the Actiq® brochure for the disclosure of the fentanyl ranges, its argument relates to obviousness, not anticipation, because the Actiq® brochure is a separate reference.
90. Mylan next argues that the asserted claims of the Moe patents are obvious in view of the '604 patent in combination with the Actiq® brochure and the Handbook. Cephalon contends that "[c]ombining certain ranges of fentanyl with effervescence, mannitol, and SSG are the novel aspects of the Moe patent inventions" and does not dispute the other limitations of the Moe patents for purposes of obviousness. (D.I. 155 at 32)
91. "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 at the time the invention was made to a person having ordinary skill in the art." 35 U.S.C. § 103(a). Obviousness is a question of law, which depends on several underlying factual inquiries.
KSR Int'l Co. v. Teleflex Inc., 550 U.S. 398, 406, 127 S.Ct. 1727, 167 L.Ed.2d 705 (2007) (internal quotation marks omitted) (quoting Graham v. John Deere Co., 383 U.S. 1, 17-18, 86 S.Ct. 684, 15 L.Ed.2d 545 (1966)).
92. "[A] patent composed of several elements is not proved obvious merely by demonstrating that each of its elements was, independently, known in the prior art." KSR, 550 U.S. at 418, 127 S.Ct. 1727. Likewise, a defendant asserting obviousness in view of a combination of references has the burden to show that a person of ordinary skill in the relevant field had a reason to combine the elements in the manner claimed. Id. at 418-19, 127 S.Ct. 1727. The Supreme Court has emphasized the need for courts to value "common sense" over "rigid preventative rules" in determining whether a motivation to combine existed. Id. at 419-20, 127 S.Ct. 1727. "[A]ny need or problem known in the field of endeavor at the time of invention and addressed by the patent can provide a reason for combining the elements in the manner claimed." Id. at 420, 127 S.Ct. 1727. In addition to showing that a
PowerOasis, Inc. v. T-Mobile USA, Inc., 522 F.3d 1299, 1304 (Fed.Cir.2008) (quoting Am. Hoist & Derrick Co. v. Sowa & Sons, 725 F.2d 1350, 1359 (Fed.Cir.1984)).
93. As discussed supra, Actiq® is a commercial fentanyl product, available in dosages between 200 and 1600 meg. (PTX472 at 7-8; DTX586 at 1; D.I. 147 at 100:22-101:9) The parties do not dispute that the Actiq® package insert ("the Actiq® brochure") disclosing these dosages is a prior art reference. Mylan's expert, Dr. Kibbe, avers that a person of ordinary skill in the art would have been motivated to look at the Actiq® brochure and combine it with the teachings of the '604 patent. (D.I. 150 at 1023:21-1024:4)
94. The Handbook — which describes the physical and chemical characteristics, uses, and methods of manufacture for individual compounds — bears a copyright date of 2000 for the third edition and is a prior art reference. (Id. at 997:7-17; DTX722; DTX723; DTX737) It disclosed mannitol and its characteristics, as well as the disintegrants approved for use in pharmaceutical products at the time. (DTX722 at 327; DTX737 at 651; D.I. 150 at 997:7-17) Of the disintegrants, Mylan's expert, Dr. Kibbe, asserted that the Handbook only disclosed three different superdisintegrants that were known in the art at the time of the alleged invention: sodium croscarmelose, crospovidone, and SSG. (D.I. 150 at 1015:6-11, 1024:10-1026:3) Cephalon's expert, Dr. Ilium, agreed that the Handbook identified only those superdisintegrants, and possibly a fourth — tragacanth.
95. Mylan's expert, Dr. Kibbe, testified that a person of ordinary skill in the art would have been motivated by the '604 patent's disclosure of pharmaceutically effective amounts of fentanyl to look to known, FDA-approved amounts of fentanyl.
96. As noted supra, the '604 patent explicitly discloses mannitol as a filler and, although the '604 patent does not disclose SSG by name, there is no dispute that its disclosure of "potato starches and modified starches thereof" as a disintegrant includes the superdisintegrant SSG.
97. Cephalon does not specifically argue that the combination of the disclosures of the '604 patent with the dosage range from the Actiq® brochure and the use of SSG from the Handbook does not result in all of the claimed limitations.
98. Mylan's expert, Dr. Kibbe, cited stability problems with formulations containing lactose and crospovidone as a motivation to substitute those components with mannitol and SSG, respectively. For support, he averred that it was known at the time of the claimed invention that crospovidone contains "contaminant peroxides," whereas SSG does not. (D.I. 150 at 1027:10-12) He then referred to the stability issues that Cima encountered when trying to develop a commercial version of Fentora®, which led to the inventions claimed in the Moe patents. (See id. at 1028:21-1029:20) He relied on a Cima memorandum and the data contained therein to opine that "[c]rospovidone appears to play a role in the oxidative degradation pathway of fentanyl. This has been shown with stability and forced degradation data." (Id. at 1027:25-1029:20) Accordingly, Dr. Kibbe opined that, "if a person of ordinary skill in the art encountered oxidation issues, he would have substituted crospovidone with SSG." (Id. at 1027:9-19, 1028:2-5; D.I. 151 at 1099:8-21) (emphasis added) Cephalon contends that this is an inappropriate reliance on hindsight. (D.I. 155 at 17-18)
99. "The inventor's own path itself never leads to a conclusion of obviousness; that is hindsight. What matters is the path that the person of ordinary skill in the art would have followed, as evidenced by the pertinent prior art." Otsuka Pharm. Co. v. Sandoz, Inc., 678 F.3d 1280, 1296 (Fed.Cir.2012) (citing 35 U.S.C. § 103(a)). Dr. Kibbe never testified that a person of ordinary skill in the art,
100. As long as the person of ordinary skill in the art would have been motivated to combine references by the prior art taken as a whole, however, it is not necessary that the references be combined for the same reasons contemplated by the inventor or to address the specific problem solved by the invention. In re Kahn, 441 F.3d 977, 988 (Fed.Cir.2006) (citing In re Beattie, 974 F.2d 1309, 1312 (Fed.Cir. 1992)); see also KSR, 550 U.S. at 420, 127 S.Ct. 1727 ("[A]ny need or problem known in the field of endeavor at the time of invention and addressed by the patent can provide a reason for combining the elements in the manner claimed."). In this regard, Dr. Kibbe opined that mannitol has been "commonly used in every single chewable tablet that has been on the market for the last 50 to 60 years" and was known to provide a sweet, cooling, and comfortable feeling in the mouth, or a "good mouth feel." (D.I. 150 at 1016:12-22, 1031:8-11) Dr. Moe agreed, testifying that, at the time he was formulating the Fentora® formulation, mannitol was known to have a cooling effect. (D.I. 148 at 321:9-18) In addition, lactose, though inexpensive, is incompatible with several compounds because it participates in the Maillard reaction, which causes mottling, or browning, of tablets. (D.I. 150 at 1031:24-1032:18) Mannitol, on the other hand, does not participate in the Maillard
101. Even if a person of ordinary skill would have been motivated to substitute lactose with mannitol, however, the court does not find that Mylan has submitted sufficient evidence of motivation to use SSG, alone or in combination, with mannitol. "To render a claim obvious, prior art cannot be `vague' and must collectively, although not explicitly, guide an artisan of ordinary skill
102. Because Mylan has not provided sufficient evidence of motivation to use SSG, alone or in combination with mannitol, Mylan has not met its burden of showing obviousness.
103. Cephalon points to unexpected results, commercial success, praise, failure of others, copying, and long-felt need as objective evidence of nonobviousness. (D.I. 155 at 24-37)
104. With respect to objective indicia of nonobviousness based on unexpected results, the Moe patents teach that the claimed invention surprisingly permitted the use of a lower dosage of fentanyl while maintaining pK characteristics comparable with prior art fentanyl dosage forms. ('158 patent, abstract, col. 2:41-61, 4:43-50) The specification teaches 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) It then names mannitol and SSG as the preferred filler and disintegrant, respectively. (Id., col. 4:43-50) The broadest asserted claims of the Moe patents recite mannitol in "an amount between about 10% and about 80%" and SSG in "an amount of about 0.25% to 20%."
105. The Moe patents reported the unexpected benefits of higher maximum plasma concentration (C
106. The court finds that the unexpected results are sufficiently supported by Cephalon's testing. Dr. Jerling analyzed two studies on formulations based on the Khankari patents ("the Khankari formulations") (the 099-09 and 099-10 studies) and two studies on formulations based on the Moe patents ("the Moe formulations") (the 099-11 and 099-18 studies). (D.I. 151 at 1133:23-1134:17; PTX546A; PTX317; PTX261; PTX367A) The four studies collected the same bioavailability data, and the 99-10 and 99-11 studies tested the Khankari and Moe formulations, respectively, against 1600 meg Actiq® as a control. (PTX317; PTX261; D.I. 151 at 1132:22-1133:13, 1134:20-1135:2, 1136:15-1140:10) Dr. Jerling opined that, because the 1600 meg Actiq® data in the 99-10 and 99-11 studies were similar, the 1600 meg Actiq® served as an "active control" that allowed him to compare pK data from those two studies. (D.I. 151 at 1139:15-1140:10, 1146:15-23, 1148:8-22; PTX357.4) He concluded, from comparing the 99-10 and 99-11 studies, that the Moe formulations resulted in significantly higher C
107. Mylan's expert, Dr. Kibbe, took issue with Dr. Jerlin's analysis because the Moe and Khankari formulations were not compared in a "head-to-head" study. (D.I. 151 at 1225:20-1227:7, 1239:12-24) Even if a "head-to-head" study would have been more robust (see D.I. 151 at 1159:10-16), the court is satisfied with the reliability of Dr. Jerling's analysis because the similarity of the 1600 Actiq® control data across the 99-10 and 99-11 studies served as a common baseline for comparison. The court also finds that it was valid for Dr. Jerling to focus on comparing the data from the 99-10 and 99-11 studies, rather than all four studies, because the 99-09 and 99-18 studies did not share the same active control. (See PTX456A; D.I. 151 at 1138:14-1140:21, 1183:22-1184:5) The court is also persuaded by Dr. Jerling's testimony that the 5% significance level
108. In addition to challenging the robustness of the evidence, Mylan asserts that the scope of the unexpected results is disproportionate to the Moe patents' claims. (D.I. 152 at 54-56) For unexpected results to support nonobviousness, the unexpected results must be reasonably commensurate with the scope of the claims. Genetics Inst, LLC v. Novartis Vaccines & Diagnostics, Inc., 655 F.3d 1291, 1308-09 (Fed.Cir.2011). "[A]bsolute identity of scope" is not required; rather, unexpected results are rejected "where the evidence [i]s plainly disproportionate to the scope of the claim." Id. Cephalon does not dispute that the unexpected benefits of using mannitol and SSG were based on only one study which tested a formulation containing 3% SSG and 47-49% mannitol. (See D.I. 155 at 30) Cephalon avers that the unexpected results that were observed support the conclusion that unexpected
109. There is no evidence of record to the contrary. Mylan's argument that the unexpected results may not occur for higher or lower amounts of mannitol and SSG is based solely on attorney argument. (See D.I. 152 at 25-26) The court finds that the unexpected results at bar are not so disproportionate to the scope of the claim as to reject unexpected results. See, e.g., In re Peterson, 315 F.3d 1325, 1331 (Fed. Cir.2003) (finding a few data points did not evidence unexpected results for the entire claimed range of about 1-3% rhenium, where evidence suggested that 3% rhenium possessed inferior properties); In re Greenfield, 571 F.2d 1185, 1189 (C.C.P.A. 1978) (affirming the obviousness of a genus containing "several hundred compounds," where unexpected results were demonstrated for only one compound); cf. In re Glatt Air Techniques, Inc., 630 F.3d 1026, 1030 (Fed.Cir.2011) (stating that objective evidence of commercial success relating "only to a single embodiment" should be considered even if claim covers "multiple embodiments"). On the facts of record, the court finds that unexpected results weigh in favor of nonobviousness.
110. Cephalon also claims that the success of Fentora® supports a finding of nonobviousness. (D.I. 155 at 33-36) For evidence of commercial success, Mr. Jeffrey G. Snell ("Mr. Snell"), an economic evaluation consultant for Cephalon, cited Cephalon's sales and profits, as well as the fact that three other transmucosal immediate-release fentanyl products that entered the market between January 2011 and January 2012 have each failed to gain more than 6% market share. (D.I. 151 at 1107:4-9, 1109:14-16, 1113:18-22; see also id. at 1270:7-10)
111. "When a patentee offers objective evidence of nonobviousness, there must be a sufficient relationship between that evidence and the patented invention." In re Paulsen, 30 F.3d 1475, 1482 (Fed.Cir.1994). "A prima facie case of nexus is made when the patentee shows both that there is commercial success, and that the product that is commercially successful is the invention disclosed and claimed in the patent." Crocs, Inc. v. Int'l Trade Comm'n, 598 F.3d 1294, 1310-11 (Fed.Cir.2010). Commercial success must be "due to the merits of the claimed invention beyond what was readily available in the prior art." J.T. Eaton & Co. v. Atl. Paste & Glue Co., 106 F.3d 1563, 1571 (Fed.Cir.1997); see also Dippin' Dots, Inc. v. Mosey, 476 F.3d 1337, 1345 (Fed.Cir. 2007). There is no relevant commercial success when market entry of others is precluded due to the patentee's ownership of earlier patents covering the product. Merck & Co. v. Teva Pharm. USA, Inc., 395 F.3d 1364, 1377 (Fed.Cir.2005).
112. Mylan asserts that the Khankari patents, not the Moe patents, are responsible for any of Fentora®'s commercial success because the listing of the Khankari patents in the Orange Book blocked market entry even before the Moe patents issued. (D.I. 152 at 60) On his cross-examination, Mr. Snell testified that he did not distinguish commercial success attributable to the Moe patents and that the Khankari patents allowed Fentora® to enter the market. (D.I. 147 at 113:5-16; D.I. 151 at 1117:9-20) There is no dispute that the Orange Book listed the Khankari patents for Fentora® before the Moe patents were issued. Therefore, Fentora®'s success is at least partially attributable to the monopoly that Cephalon had on the market before the issuance of the Moe
113. Cephalon avers that nonobviousness is further supported by praise in the field for Fentora®. (D.I. 155 at 35-36) Mylan's expert, Dr. Johnston Loeser ("Dr. Loeser"), co-authored a book in 2010 entitled "Cancer Pain: Assessment, Diagnosis and Management." (D.I. 151 at 1289:23-1290:7, 1292:4-5) Chapter 19 of the book, entitled "Opioid Analgesics," describes Fentora® as a drug that employs a "novel" drug delivery platform using effervescence to enhance fentanyl absorption through the buccal mucosa and notes that a single dose of Fentora® provides "clinically significant improvement to pain intensity." (Id. at 1298:7-1300:13; DTX502 at 205) For the same reasons that Cephalon has not established a sufficient nexus for commercial success, the court finds that the purported praise in Dr. Loeser's book is not sufficiently related to the novel aspects of the Moe patents. See Transocean Offshore Deepwater Drilling, Inc. v. Maersk Drilling USA, 699 F.3d 1340, 1351 (Fed.Cir.2012) (considering whether industry praise was sufficiently related to features made possible by the patented technology). Praise in the field also does not weigh toward a finding of nonobviousness.
114. Cephalon argues that Mylan's failure to develop a noneffervescent formulation that was bioequivalent to Fentora® is an indication of nonobviousness. (D.I. 155 at 32) (citing Ortho-McNeil Pharm., Inc. v. Mylan Labs., Inc., 348 F.Supp.2d 713, 759 (N.D.W.Va.2004). Cephalon's argument, however, is misplaced. "The purpose of evidence of failure of others is to show `indirectly the presence of a significant defect in the prior art, while serving as a simulated laboratory test of the obviousness of the solution to a skilled artisan.'" In re Cyclobenzaprine Hydrochloride Extended-Release Capsule Patent Litigation, 676 F.3d 1063, 1082 (Fed.Cir.2012). Here, Mylan's experimentation with noneffervescent formulations does not show that it struggled to solve a prior art defect that was addressed by the Moe patents. Rather, it struggled to make a formulation that was bioequivalent to Fentora®. Mylan's testing, which was geared at avoiding a patent, is distinguishable from evidence that others had attempted and failed to develop a solution to the drawback identified by the Moe patents (the use of high amounts of fentanyl). As a result, there is no evidence of the failure of others relevant to obviousness.
115. Cephalon also contends that Mylan's copying of Fentora® should be considered an objective indicia of nonobviousness. "[J]ust as with the commercial success analysis, a nexus between the copying and the novel aspects of the claimed invention must exist for evidence of copying to be given significant weight in an obviousness analysis." Wm. Wrigley Jr. Co. v. Cadbury Adams USA LLC, 683 F.3d 1356, 1364 (Fed.Cir.2012). The Federal Circuit, however, has held that it "do[es] not find compelling ... evidence of copying in the ANDA context where a showing of bioequivalency is required for FDA approval." Purdue Pharma Products LP v. Par Pharm., Inc., 377 Fed. Appx. 978, 983 (Fed.Cir.2010); see also Bayer, 713 F.3d at 1377 ("[C]opying in the ANDA context is not probative of nonobviousness because a showing of bioequivalence is required for FDA approval."). Given the FDA's stringent requirement for showing bioequivalence, it is not surprising that such a showing would require copying of the brand name drug.
116. Finally, Cephalon points to the long-felt need in the area of breakthrough pain management for opioid-tolerant patients. (D.I. 155 at 36-37) (citing D.I. 147 at 68:3-10) Specifically, it avers that treatment options for breakthrough pain were not absorbed fast enough by the body. (Id. at 36) (citing D.I. 147 at 76:12-77:4) Actiq® allegedly had clinical limitations due to its lozenge-on-a-stick dosage form, requirement for active manipulation by the patient (which many ill patients have trouble doing), social stigma from use, attractiveness to children, risk of diversion, and dental caries or teeth decay. (D.I. 147 at 78:20-79:2, 81:3-8, 82:14-86:1) Cephalon asserts that Fentora® provides a more rapid onset of delivery, eliminates the lozenge-on-a-stick dosage form, and produces greater fentanyl bioavailability. (D.I. 155 at 37) (citing D.I. 147 at 87:19-88:7, 92:8-25; PTX247.8-0.9)
117. Cephalon's argument fails to take into account the prior art '604 patent. As Cephalon's expert, Dr. Craig Blinderman ("Dr. Blinderman"), admitted, the long-felt needs that Cephalon points to — rapid onset of delivery, elimination of the lozenge-on-a-stick dosage form, and enhanced fentanyl absorption — were satisfied by the invention of the '604 patent. (D.I. 147 at 113:5-114:24) Cephalon presented no evidence that the Moe patents' differences over the '604 patent — the lower amount of fentanyl (which still provided comparable pK characteristics) and the use of mannitol and SSG (as the filler and disintegrant) — solved the alleged long-felt needs.
118. Mylan has not provided sufficient evidence that a person of ordinary skill in the art, at the time of invention, would have been motivated to use the disintegrant SSG, alone or in combination with mannitol. The unexpected pK results from combining SSG and mannitol also support this finding of nonobviousness. Therefore, Mylan has not met its burden of proof that the Moe patents are invalid for being obvious.
119. The court concludes that Mylan has not shown, by clear and convincing evidence, that the Moe patents are either anticipated or obvious in light of the prior art references. Accordingly, the court finds that the Moe patents are valid.
120. For the foregoing reasons, the court finds that Mylan infringes the asserted claims of the '604, '590, and '158 patents and that the '92,832 and '158 patents are valid. An appropriate order shall issue.
At Wilmington this 22nd day of July, 2013, consistent with the opinion issued this same date;
IT IS ORDERED that:
2. The asserted claims of the '92,832 and '158 patents are valid.
3. The infringement claims related to the '62,832 and '833 patents are dismissed.
Civ. No. 09-318, 2012 WL 928189, at *11 (D.Del. Mar. 16, 2012). Accordingly, the court finds that a disposition including dismissal of the '62,832 and '833 patents with prejudice is appropriate.
