Briefs in Support of Motion to Dismiss for invalidity unpatentable subject matter under 35 U.S.C...

IN THE UNITED STATES DISTRICT COURT FOR THE DISTRICT OF DELAWARE

ENDO PHARMACEUTICALS INC. and MALLINCKRODT LLC,

Plaintiffs,

v.

ACTAVIS INC. and ACTAVIS SOUTH ATLANTIC LLC,

Defendants.

) ) ) ) ) ) ) ) ) ) )

C.A. No. 14-1381-RGA

OPENING BRIEF IN SUPPORT OF

DEFENDANTS’ MOTION TO DISMISS COUNTS I, III AND IV OF PLAINTIFFS’ COMPLAINT PURSUANT TO FED. R. CIV. P. 12(b)(6)

YOUNG CONWAY STARGATT & TAYLOR LLP Adam W. Poff (No. 3990) Robert M. Vrana (No. 5666) Rodney Square 1000 North King Street Wilmington, DE 19801 (302) 571-6600 [email protected] [email protected] OF COUNSEL:

HOLLAND & KNIGHT LLP Charles Weiss 31 West 52nd Street New York, NY 10019 (212) 513-3551 [email protected]

Attorneys for Defendants Actavis Inc. and

Dated: January 20, 2015 Actavis South Atlantic LLC

Case 1:14-cv-01381-RGA Document 12 Filed 01/20/15 of 18 PageID #: 123

i

TABLE OF CONTENTS

INTRODUCTION .......................................................................................................................... 1

NATURE AND STAGE OF THE PROCEEDINGS ..................................................................... 2

SUMMARY OF THE ARGUMENT ............................................................................................. 3

STATEMENT OF FACTS ............................................................................................................. 4

ARGUMENT .................................................................................................................................. 6

I. The Complaint does not plead sufficient facts to show intent to induce infringement of the ‘737 patent ........................................................................................... 6

A. Endo has not pled sufficient facts to show that Actavis’s future sales of the pending ANDA product will induce infringement of the ‘737 patent .......................... 7

B. Endo has not pled sufficient facts to show that Actavis induces infringement of the ‘737 patent by selling its already-approved extended-relief oxymorphone tablets ..................................................................................................... 8

II. The ‘737 patent is invalid for claiming unpatentable subject matter under 35 U.S.C. § 101 ........................................................................................................................ 9

CONCLUSION ............................................................................................................................. 12


ii

TABLE OF AUTHORITIES

Cases

Abbott Labs. v. TorPharm, Inc., 300 F.3d 1367 (Fed. Cir. 2002)........................................................................................... 7

Artemi Ltd. v. Safe-Strap Co., Inc., 947 F. Supp. 2d 473 (D.N.J. 2013) ..................................................................................... 9

Ashcroft v. Iqbal, 556 U.S. 662 (2009) ............................................................................................................ 6

AstraZeneca Pharms. LP v. Apotex Corp., 669 F.3d 1370 (Fed. Cir. 2012)....................................................................................... 6, 7

Bayer Schering Pharma AG v. Lupin, Ltd., 676 F.3d 1316 (Fed. Cir. 2012)........................................................................................... 8

Bell Atlantic Corp. v. Twombly, 550 U.S. 544 (2007) ........................................................................................................ 6, 9

DSU Medical Corp. v. JMS Co., Ltd., 471 F.3d 1293 (Fed. Cir. 2006)........................................................................................... 9

Genetic Techs., Ltd. v. Bristol-Myers Squibb Co., __ F. Supp. 3d __, 2014 WL 5507637 (D. Del. Oct. 30, 2014) ........................................ 10

Genetic Techs., Ltd. v. Lab. Corp. of Am. Holdings, Civ. No. 12-1736-LPS-CJB, 2014 WL 4379587 (D. Del. Sept. 3, 2014) ........................ 10

Global-Tech Appliances, Inc. v. SEB S.A., 131 S. Ct. 2060 (2011) ........................................................................................................ 8

In re Bill of Lading Transmission & Processing Sys. Patent Litig., 681 F.3d 1323 (Fed. Cir. 2012)........................................................................................... 9

In re Burlington Coat Factory Securities Litig., 114 F.3d 1410 (3d Cir. 1997).............................................................................................. 6

Mallinckrodt, Inc. v. E-Z-Em Inc., 670 F. Supp. 2d 349 (D. Del. 2009) .................................................................................... 9

Mayo Collaborative Servs. v. Prometheus Labs., Inc., 132 S. Ct. 1289 (2012) ........................................................................................ 1, 9, 10, 11

Morrow v. Balaski, 719 F.3d 160 (3d Cir. 2013)................................................................................................ 6


iii

Ricoh Co. v. Quanta Computer Inc., 550 F.3d 1325 (Fed. Cir. 2008)........................................................................................... 7

Warner-Lambert Co. v. Apotex Corp., 316 F.3d 1348 (Fed. Cir. 2003)....................................................................................... 6, 7

Xpoint Techs., Inc. v. Microsoft Corp., 730 F. Supp. 2d 349 (D. Del. 2010) .................................................................................... 9

Statutes

35 U.S.C. § 101 ............................................................................................................................... 3

35 U.S.C. § 271(a) .......................................................................................................................... 2

35 U.S.C. § 271(b) .......................................................................................................................... 6

35 U.S.C. § 271(c) ...................................................................................................................... 6, 8

35 U.S.C. § 271(e)(2) ...................................................................................................................... 2


1

INTRODUCTION

The complaint of plaintiffs (collectively, “Endo”) alleges that defendants (collectively,

“Actavis”) have infringed U.S. Patents 8,808,737 (“the ‘737 patent”) and 8,871,779 (“the ‘779

patent”) by (i) selling an FDA-approved extended-release formulation of oxymorphone, and (ii)

submitting an Abbreviated New Drug Application (“ANDA”) seeking FDA approval for a

different formulation of the same drug. Because this is a motion to dismiss under Fed. R. Civ. P.

12(b)(6), the lengthy history of litigation between Endo and Actavis on these products is for now

largely irrelevant, and in the interest of brevity Actavis will dispense with it in this brief.1 With

respect to the current part of that saga, Endo has related cases pending against Actavis in the (i)

Southern District of New York for infringement of other patents allegedly infringed by the same

product and ANDA (Civil Action Nos. 12-08985 and 13-00436), and (ii) District of New Jersey

for false advertising of the commercial product (Civil Action No. 12-07591, on remand from

Endo Pharms. Inc. v. Actavis Inc., No. 13-4096, 2014 WL 6844812 (3d Cir. Dec. 5, 2014)).

Actavis now moves to dismiss Endo’s claims for infringement of the ‘737 patent (Counts

I, III, and IV), because (1) the Complaint fails to state a claim for indirect infringement (and

cannot state a claim for direct infringement) and (2) all claims of the ‘737 patent are invalid for

claiming a law of nature that is unpatentable under 35 U.S.C. § 101, namely, the relationship

between bioavailability of oxymorphone and impaired kidney function. See Mayo Collaborative

Servs. v. Prometheus Labs., Inc., 132 S. Ct. 1289 (2012).

1 Defendants follow the Complaint’s lead of referring to both defendants collectively as “Actavis,” because for present purposes it is not necessary to distinguish between them.


2

NATURE AND STAGE OF THE PROCEEDINGS

In November 2014, Endo filed its Complaint for patent infringement (D.I. 1). It accuses

one already-marketed product of infringement under 35 U.S.C. § 271(a), and accuses a pending

ANDA of infringement under 35 U.S.C. § 271(e)(2).

As noted above, both the commercial product and the as-yet-unapproved product that is

the subject of the ANDA are extended-release formulations of oxymorphone.2 Oxymorphone is

a opioid analgesic, and its use in extended-release form is for people who need strong, around-

the-clock pain relief over lengthy periods of time.

In lieu of filing an Answer, Actavis is moving under Fed. R. Civ. P. 12(b)(6) to dismiss

Endo’s claims for infringement of the ‘737 patent (Counts I, III, and IV of the Complaint).

2 The details of the products are not important for this motion, but the commercial product is generic to the original formulation of Endo’s branded product Opana ER, and the pending ANDA seeks approval of a product generic to the current formulation of Opana ER.


3

SUMMARY OF THE ARGUMENT

1. Because all claims of the ‘737 patent are directed to methods of treatment, Actavis can be

liable only for indirect infringement. To state a claim, Endo must plead not just that the products

at issue are capable of use by doctors (or patients) in an infringing manner, but that Actavis’s

instructions for use affirmatively direct their use in an infringing manner. As to the still-

unapproved product described in Actavis’s pending ANDA, the inquiry is limited to the product

label, which does not direct use of the product in the manner claimed by the ‘737 patent. Endo

has not pled, and cannot plead, that the label directs users (doctors or patients) to infringe.

As to the already-approved commercial product, the legal standard of induced

infringement is same but the permissible inquiry is not automatically limited to the label.

Specifically, although it is highly unusual for manufacturers of generic products to detail their

use to physicians (in the way that manufacturers of branded products detail those products), it is

at least theoretically possible that: (i) if such promotion occurred, and (ii) if that promotion

directed physicians to use the product in a way not described on the label, the generic

manufacturer could be found to induce infringement even if the label itself did not give

directions for that use. But even if such activities are possible in theory, they are implausible in

practice. And most importantly, they are not alleged by Endo in the Complaint.

2. All claims of Endo’s ‘737 patent are invalid because they are directed to unpatentable

subject matter under 35 U.S.C. § 101, viz., a law of nature. Specifically, the claims recite the

natural law that the bioavailability of oxymorphone is increased in people with impaired kidney

function, and are not transformed into a patent-eligible “process” by reciting that doctors should

“in dependence on” the measurement of kidney function give a “lower dosage” of drug.


4

STATEMENT OF FACTS

Claim 1 of the ‘737 patent is exemplary, and is reproduced below:

1. A method of treating pain in a renally impaired patient, comprising the steps of:

a. providing a solid oral controlled release dosage form, comprising:

i. about 5 mg to about 80 mg of oxymorphone or a pharmaceutically acceptable salt thereof as the sole active ingredient; and ii. a controlled release matrix;

b. measuring a creatinine clearance rate of the patient and determining it to be (a) less than about 30 ml/min, (b) about 30 mL/min to about 50 mL/min, (c) about 51 mL/min to about 80 mL/min, or (d) above about 80 mL/min; and c. orally administering to said patient, in dependence on which creatinine clearance rate is found, a lower dosage of the dosage form to provide pain relief; wherein after said administration to said patient, the average AUC of oxymorphone over a 12-hour period is less than about 21 ng·hr/mL.

‘737 patent (D.I. 1, Ex. A) at 48:7-26. Dependent claims 2 and 3 specify that the AUC in the

terminal “wherein” clause is less than about 20 and 19 ng·hr/mL, respectively.

Independent claim 4 is identical to claim 1, except the final clause reads “wherein after

said administration to said patient, the Cmax of oxymorphone is less than about 1.4 ng/mL.”

Dependent claims 5 and 6 limit the Cmax to about 1.3 and 1.2 ng/mL, respectively.

Neither of the accused Actavis products (nor Endo’s branded product Opana ER) are

specially designed or labelled for treatment of pain in people with impaired kidney function.

The only discussion in the labels (of all these products) on this point is (i) information about

increased bioavailability of oxymorphone in people with renal impairment, and (ii) general


5

advice to start with a low dose in people with a creatinine clearance of less than 50 mL/min and

to “titrate slowly” while monitoring side effects.

2.6 Patients with Renal Impairment

In patients with creatinine clearance rates less than 50 mL/min, start OPANA ER in the opioid-naïve patient with the 5 mg dose. For patients on prior opioid therapy, start OPANA ER at 50% lower than the starting dose for a patient with normal renal function on prior opioids and titrate slowly. Monitor patients closely for signs of respiratory or central nervous system depression.

* * *

8.7 Renal Impairment

Patients with moderate to severe renal impairment were shown to have an increase in oxymorphone bioavailability ranging from 57-65%. Start opioid naïve patients with the 5 mg dose of OPANA ER and titrate slowly while closely monitoring for respiratory and central nervous system depression. For patients on prior opioid therapy, start at 50% of the dose for a patient with normal renal function on prior opioids and titrate slowly.

* * *

Renal impairment Data from a pharmacokinetic study involving 24 patients with renal dysfunction show an increase of 26%, 57%, and 65% in oxymorphone bioavailability in mild (creatinine clearance 51-80 mL/min; n=8), moderate (creatinine clearance 30-50 mL/min; n=8), and severe (creatinine clearance <30 mL/min; n=8) patients, respectively, compared to healthy controls.

Exhibit 1 at ¶¶ 2.6, 8.7, 12.3 (label of Opana ER, parenthetical references omitted); see also

Exhibits 2 and 3 (labels for Actavis commercial product and pending ANDA product,

respectively).3

3 Exhibits are to the Declaration of Adam Poff in Support of Defendants’ Motion to Dismiss.


6

ARGUMENT

“To survive a motion to dismiss, a complaint must contain sufficient factual matter,

accepted as true, to ‘state a claim to relief that is plausible on its face.’” Ashcroft v. Iqbal, 556

U.S. 662, 678 (2009). The complaint “requires more than labels and conclusion, and a formulaic

recitation of the elements of a cause of action will not do.” Bell Atlantic Corp. v. Twombly, 550

U.S. 544, 555 (2007). Unsupported conclusions, unwarranted inferences, and legal conclusions

phrased as factual allegations also are not accepted as true for the purposes of a Rule 12(b)(6)

motion. See Morrow v. Balaski, 719 F.3d 160, 165 (3d Cir. 2013) (“[W]e are not compelled to

accept unsupported conclusions and unwarranted inferences, or a legal conclusion couched as a

factual allegation.”).

In ruling on motions to dismiss, courts may examine documents “integral to or explicitly

relied upon in the complaint.” In re Burlington Coat Factory Securities Litig., 114 F.3d 1410,

1426 (3d Cir. 1997). In ANDA cases, the applicants’ submissions to the FDA are in this

category. See AstraZeneca Pharms. LP v. Apotex Corp., 669 F.3d 1370, 1378 n.5 (Fed. Cir.

2012).

I. The Complaint does not plead sufficient facts to show intent to induce infringement of the ‘737 patent

Because the ‘737 patent is directed to methods of treatment, the Complaint does not

suggest that Actavis has practiced or will practice the claimed method. See Warner-Lambert Co.

v. Apotex Corp., 316 F.3d 1348, 1363 (Fed. Cir. 2003) (no direct infringement by drug

manufacturer where patent is to method of treatment). Thus, Endo’s claim must be based on

induced infringement under 35 U.S.C. § 271(b) or contributory infringement under 35 U.S.C. §

271(c). See id. When as here the accused product has substantial noninfringing uses, intent to

induce infringement requires not simply “knowledge that it may be put to infringing uses,” but


7

“statements or actions directed to promoting infringement.” Ricoh Co. v. Quanta Computer Inc.,

550 F.3d 1325, 1341 (Fed. Cir. 2008).

A. Endo has not pled sufficient facts to show that Actavis’s future sales of the pending ANDA product will induce infringement of the ‘737 patent

For method-of-treatment claims like those in the ‘737 patent, an applicant’s submission

of an ANDA can be found to induce infringement only if it seeks approval to market the drug for

the patented use. See AstraZeneca, 669 F.3d at 1379; Warner-Lambert, 316 F.3d at 1354-55.

“Because drug manufacturers are bound by strict statutory provisions to sell only those products

that comport with the ANDA’s description of the drug, an ANDA specification defining a

proposed generic drug in a manner that directly addresses the issue of infringement will control

the infringement inquiry. Abbott Labs. v. TorPharm, Inc., 300 F.3d 1367, 1373 (Fed. Cir. 2002).

Here, the proposed label in the ANDA (Exhibit 3) does not direct physicians (or anyone

else) to practice any claim of the ‘737 patent. Claim 1, which is representative, requires in part

(i) measuring a person’s creatinine clearance, (ii) determining if it is less than about 30 ml/min,

about 30 to about 50 mL/min, about to about 80 mL/min, or above about 80 mL/min, and (iii)

orally administering to the patient “in dependence on which creatinine clearance rate is found,” a

lower dosage of drug to provide pain relief. Nothing on the label directs doctors to perform any

of these steps, and inducement would require that it direct the physician to perform all of them.

First, the label does not direct doctors to measure the creatinine clearance at all. Second,

even if the creatinine clearance is measured, the label does not direct the doctor to “determine” if

it falls within one of the four specified ranges. Third, it does not direct administration of a lower

dose “in dependence on” which of the four ranges contains the measured creatinine clearance

rate. Fourth, it does not direct giving a lower dose correlating to the four ranges “to provide

pain relief,” but instead speaks only to monitoring side effects. Cf. Bayer Schering Pharma AG


8

v. Lupin, Ltd., 676 F.3d 1316, 1322-24 (Fed. Cir. 2012) (statements in label providing

information on pharmacokinetics of a drug are not directions to infringe).

Endo’s claim for contributory infringement similarly fails. There is no factual allegation

that the product is “especially made or especially adapted for use in an infringement,” and it is

also plain on the face of the label that the product is “suitable for substantial noninfringing use.

35 U.S.C. § 271(c). See also Global-Tech Appliances, Inc. v. SEB S.A., 131 S. Ct. 2060, 2068

(2011) (contributory infringement under section 271(c) requires knowledge that the product will

be used to infringe).

Accordingly, the Complaint fails to state a claim that commercial manufacture and sale of

the proposed ANDA product with the label information submitted to the FDA for approval

would infringe. Counts III and IV must be dismissed.

B. Endo has not pled sufficient facts to show that Actavis induces infringement of the ‘737 patent by selling its already-approved extended-relief oxymorphone tablets

The label for Actavis’s currently sold extended-release oxymorphone tablets (Exhibit 3)

contains the same language regarding impaired kidney function as does the label for the

proposed ANDA product. For the same reasons, Endo does not and cannot plead a claim for

infringement based on the label itself.

Nor has Endo pled facts outside the label that would demonstrate indirect infringement.

As noted above, it is at least theoretically possible in the case of a marketed product that the

manufacturer could induce infringement by promoting (off-label) infringing uses. The question

of whether allegations to that effect are sufficiently plausible is not at issue, because Endo has

pled no facts to that effect. The only fact pled by Endo regarding the existing product is that

Actavis sells it (Complaint ¶¶ 29-33).


9

But to survive a motion to dismiss, the Complaint “must contain facts plausibly showing

that [defendants] specifically intended their customers to infringe [the ‘737 patent] and knew that

the customer’s acts constituted infringement.” In re Bill of Lading Transmission & Processing

Sys. Patent Litig., 681 F.3d 1323, 1339 (Fed. Cir. 2012). Induced infringement requires

“purposeful, culpable expression and conduct.” DSU Medical Corp. v. JMS Co., Ltd., 471 F.3d

1293, 1306 (Fed. Cir. 2006). A complaint that merely recites the elements for indirect

infringement is insufficient to state a claim. See Xpoint Techs., Inc. v. Microsoft Corp., 730 F.

Supp. 2d 349, 357 (D. Del. 2010); Mallinckrodt, Inc. v. E-Z-Em Inc., 670 F. Supp. 2d 349, 354

(D. Del. 2009); Artemi Ltd. v. Safe-Strap Co., Inc., 947 F. Supp. 2d 473, 480 (D.N.J. 2013).

Here, the only statement in the Complaint regarding induced infringement of the ‘737

patent is a legal conclusion that Actavis’s sale of the accused product induces infringement:

37. Actavis’s commercial manufacture, offer for sale, or sale of its Generic Oxymorphone ER Tablets infringe the ‘737 Patent under 35 U.S.C. § 271(a)-(c), including without limitation that it induces physicians and patients to infringe the ‘737 Patent by performing all of the recited steps of one or more of claims 1 – 6 of the ‘737 Patent.

Complaint ¶ 37. Unlike well-pled and plausible facts, which generally must be taken as true on a

motion to dismiss, legal conclusions such as this have no weight and do not carry Endo’s burden

to state a claim for indirect infringement. Twombly, 550 U.S. at 555. Thus, Count I must be

dismissed.

II. The ‘737 patent is invalid for claiming unpatentable subject matter under 35 U.S.C. § 101

In Mayo, the Supreme Court held invalid a method of treatment claim highly analogous

to the claims of the ‘737 patent for claiming unpatentable subject matter because the method of

treatment claimed did nothing more than state a natural law governing the effects of a certain

drug on the human body and add routine and conventional treatment steps by a physician.


10

Following Mayo, the District of Delaware has repeatedly dismissed similar claims as invalid at

the pleading stage for claiming similar unpatentable subject matter. See, e.g., Genetic Techs.,

Ltd. v. Bristol-Myers Squibb Co., __ F. Supp. 3d __, 2014 WL 5507637, *6-*12 (D. Del. Oct. 30,

2014) (method of analyzing and amplifying natural variations in non-coding DNA held invalid

on motion to dismiss); Genetic Techs., Ltd. v. Lab. Corp. of Am. Holdings, Civ. No. 12-1736-

LPS-CJB, 2014 WL 4379587, *10-*14 (D. Del. Sept. 3, 2014) (method of analyzing DNA to

predict athletic performance held invalid on motion to dismiss).

The claim language held invalid in Mayo is provided in the table below comparing that

language to exemplary Claim 1 of the ‘737 patent:

Claim 1 of the patent held invalid in Mayo 132 S. Ct. at 1295

Claim 1 of the ‘737 patent

1. A method of optimizing therapeutic efficacy for treatment of an immune-mediated gastrointestinal disorder, comprising:


(a) administering a drug providing 6-thioguanine to a subject having said immune-mediated gastrointestinal disorder; and

a. providing a solid oral controlled release dosage form, comprising: i. about 5 mg to about 80 mg of oxymorphone or a pharmaceutically acceptable salt thereof as the sole active ingredient; and ii. a controlled release matrix;

(b) determining the level of 6-thioguanine in said subject having said immune-mediated gastrointestinal disorder,

b. measuring a creatinine clearance rate of the patient and determining it to be (a) less than about 30 ml/min, (b) about 30 mL/min to about 50 mL/min, (c) about 51 mL/min to about 80 mL/min, or (d) above about 80 mL/min; and

c. orally administering to said patient, in dependence on which creatinine clearance rate is found, a lower dosage of the dosage form to provide pain relief;

wherein the level of 6-thioguaninine less than about 230 pmol per 8x108 red blood cells indicates a need to increase the amount of said drug subsequently administered to said subject

wherein after said administration to said patient, the average AUC of oxymorphone over a 12-hour period is less than about 21


11

and

wherein the level of 6-thioguaninine greater than about 400 pmol per 8x108 red blood cells indicates a need to decrease the amount of said drug subsequently administered to said subject.

ng·hr/mL.

In analyzing the claim in Mayo, the Supreme Court observed that the patent sets forth a

law of nature, “namely, relationships between concentrations of certain metabolites in the blood

and the likelihood that a dosage of a thiopurine drug will prove ineffective or cause harm.” 132

S. Ct. at 1296. Such relationships are natural laws because they are a consequence of the ways in

which drugs are metabolized, which are entirely natural processes. Id. at 1297. To become

patent eligible, the claims would have to add enough to the law of nature to qualify as a patent-

eligible process that applies natural laws. Id.

The Supreme Court held that the additional steps in Mayo did not add enough to confer

patentability. It held that the “administering” step did nothing more than limit the relevant

audience to “doctors who treat patients with certain diseases with thiopurine drugs,” and that

merely limiting a natural law to a particular technological environment did not render the claim

patent-eligible. Id. at 1297. The “wherein” clauses simply told the doctor what the relevant

natural laws were, at most suggesting that doctors take the laws into account when treating

patients. Id. And the “determining” step tells the doctor to determine the level of the relevant

metabolites in the blood. Id. Because the patents stated that such methods were well-known in

the art, the “determining” step was conventional “pre-solution activity” that did not apply the law

of nature in a way to create a patent-eligible process. Id. at 1298.

The ‘737 patent has many of the same flaws. As in Mayo, the ‘737 patent states a natural

law: the bioavailability of oxymorphone is increased in patients with renal impairment. Indeed,

it describes the invention using that exact language. D.I. 1, Ex. A at Abstract.


12

The claims’ other steps are a “providing” step, a “measuring/determining” step, and an

“administering” step. The “providing” and “administering” steps, like the “administering” step

in Mayo, simply defines the audience, and the patent states that (i) extended-release

oxymorphone was already on the market (D.I. 1, Ex. A at 3:40-49), and that oxymorphone is

“widely used in the treatment of acute and chronic pain.” Id. at 1:19-22.

The “measuring/determining” step tells the doctor to measure the patient’s creatinine

level to determine the severity of renal impairment, but the specification necessarily describes

this as a known method. D.I. 1, Ex. A at 28:4-11, 28:61-29:15. Like the “determining” step in

Mayo, this is just routine pre-solution activity using well-known methods to gather the

information needed to apply the natural law.

None of these infirmities illustrated with respect to exemplary Claim 1 is eliminated by

elements of the remaining claims, and thus they fall together with Claim 1 for the same reason.

CONCLUSION

For the foregoing reasons, Actavis respectfully urges the Court to grant its motion and

dismiss Counts I, III, and IV of the Complaint.

Of Counsel: HOLLAND & KNIGHT LLP Charles Weiss 31 West 52nd Street New York, NY 10019 (212) 513-3551 [email protected] Dated: January 20, 2015

YOUNG CONAWAY STARGATT & TAYLOR, LLP /s/ Adam W. Poff Adam W. Poff (No. 3990) Robert M. Vrana (No. 5666) Rodney Square 1000 North King Street Wilmington, DE 19801 (302) 571-6600 [email protected] [email protected] Attorneys for Defendants Actavis Inc. and Actavis South Atlantic LLC


01:16529567.1

CERTIFICATE OF SERVICE

I, Adam W. Poff, hereby certify that on January 20, 2015, I caused to be electronically

filed a true and correct copy of the foregoing document with the Clerk of the Court using

CM/ECF, which will send notification that such filing is available for viewing and downloading

to the following counsel of record:

Jack B. Blumenfeld, Esquire Julia Heaney, Esquire Morris Nichols Arsht & Tunnell LLP 1201 North Market Street P.O. Box 1347 Wilmington, DE 19899-1347 [email protected] [email protected] Attorneys for Plaintiffs

I further certify that on January 20, 2015, I caused a copy of the foregoing document

to be served by e-mail on the above-listed counsel and on the following:

Jonathan D.J. Loeb, Esquire Dechert LLP 2440 W. El Camino Real Suite 700 Mountain View, CA 94040 [email protected] Martin J. Black, Esquire Dechert LLP Circa Centre 2929 Arch Street Philadelphia, PA 19104 [email protected] Robert D. Rhoad, Esquire Dechert LLP 902 Carnegie Center Suite 500 Princeton, NJ 08540 [email protected]


2 01:16529567.1

Dated: January 20, 2015 YOUNG CONAWAY STARGATT & TAYLOR, LLP

/s/ Adam W. Poff Adam W. Poff (No. 3990) Robert M. Vrana (No. (5666) Rodney Square 1000 N. King Street Wilmington, Delaware 19801 [email protected] Attorneys for Defendants



ENDO PHARMACEUTICALS INC. and MALLINCKRODT LLC,

Plaintiffs,

v.

ACTAVIS INC. and ACTAVIS SOUTH ATLANTIC LLC,

Defendants.

) ) ) ) ) ) ) ) ) ) )

C.A. No. 14-1381-RGA

REPLY BRIEF IN FURTHER SUPPORT OF DEFENDANTS’ MOTION TO DISMISS COUNTS I, III AND IV

OF PLAINTIFFS’ COMPLAINT PURSUANT TO FED. R. CIV. P. 12(b)(6)




Dated: March 23, 2015 Actavis South Atlantic LLC

Case 1:14-cv-01381-RGA Document 20 Filed 03/23/15 Page 1 of 15 PageID #: 330

i

TABLE OF CONTENTS

INTRODUCTION .......................................................................................................................... 1

ARGUMENT .................................................................................................................................. 2

I. ENDO CANNOT SUSTAIN A CLAIM FOR INFRINGEMENT ON THE PLEADINGS ...................................................................................................................... 2

A. The acts that Actavis has taken, as pled by Endo, cannot constitute inducement to infringe the ’737 patent ......................................................................... 2

B. Mere notice of Endo’s claims is insufficient to survive this motion to dismiss ........... 4

II. THE ’737 PATENT IS INVALID FOR CLAIMING AN UNPATENTABLE LAW OF NATURE ............................................................................................................ 5

A. Endo’s argument for induced infringement precisely illustrates why the ’737 patent is directed to unpatentable subject matter .......................................................... 5

B. Straightforward application of the Mayo/Alice two-part test shows the ’737 patent to claim unpatentable subject matter .................................................................. 7

CONCLUSION ............................................................................................................................. 10


ii


Cases

Abbott Labs. v. TorPharm, Inc., 300 F.3d 1367 (Fed. Cir. 2002)........................................................................................... 3

Alice Corp. Pty, Ltd. v. CLS Bank Int’l, 134 S. Ct. 2347 (2014) ........................................................................................................ 7

AstraZeneca LP v. Apotex, Inc., 633 F.3d 1042 (Fed. Cir. 2010)........................................................................................... 4

AstraZeneca Pharms. LP v. Apotex Corp., 669 F.3d 1370 (Fed. Cir. 2012)....................................................................................... 3, 5

Classen Immunotherapies, Inc. v. Biogen IDEC, 659 F.3d 1057 (Fed. Cir. 2011)........................................................................................... 8

Classen Immunotherapies, Inc. v. Biogen IDEC, No. WDQ-04-2607, 2012 WL 3264941 (D. Md. Aug. 9, 2012) ........................................ 9

Gottschalk v. Benson, 409 U.S. 63 (1972) .............................................................................................................. 7

In re Bill of Lading Transmission & Processing Sys. Patent Litig., 681 F.3d 1323 (Fed. Cir. 2012)........................................................................................... 5

Lucent Techs., Inc. v. Gateway, Inc., 580 F.3d 1301 (Fed. Cir. 2009)........................................................................................... 2

Mayo Collaborative Servs. v. Prometheus Labs., Inc., 132 S. Ct. 1289 (2012) ............................................................................................... passim

Mirror World, LLC v. Apple Inc., 692 F.3d 1351 (Fed. Cir. 2012)........................................................................................... 3

MONEC Holding AG v. Motorola Mobility, Inc., 897 F. Supp. 2d 225 (D. Del. 2012) .................................................................................... 5

Simon v. FIA Card Servs., N.A., 732 F.3d 259 (3d Cir. 2013)................................................................................................ 5

Warner-Lambert Co. v. Apotex Corp., 316 F.3d 1348 (Fed. Cir. 2003)....................................................................................... 2, 3

Statutes

35 U.S.C. § 101 ............................................................................................................................... 7


1

INTRODUCTION

Endo cannot state a claim for induced infringement of U.S. Patent No. 8,808,737 (“the

’737 Patent”) against Actavis because it cannot point to specific language in Actavis’s product

label directing physicians to infringe the claims. The ’737 patent’s claims require physicians to

measure a patient’s creatinine clearance level (an indication of kidney function), determine

which of four specified ranges it falls into, and administer a lower dose of oxymorphone to the

patient “in dependence on” the measured level such that the concentration of oxymorphone in the

patient’s blood remains under a particular number. The language of Actavis’s product labels,

which do nothing more than instruct physicians to “reduce the dose” of oxymorphone in renally

impaired patients and inform them of a clinical study, cannot induce infringement of each

limitation of these claims.

Endo’s claims related to the ’737 patent should also be dismissed because the ’737

patent’s addition of a step to administer oxymorphone for pain relief, a step described in the

patent’s own specification as having been known in the art for decades, is trivial post-solution

activity that does not render claims patentable. A patent “could not simply recite a law of nature

and then add the instruction ‘apply the law.’” Mayo Collaborative Servs. v. Prometheus Labs.,

Inc., 132 S. Ct. 1289, 1297 (2012). Not only does the ’737 patent do nothing more than that, but

Endo argues that Actavis induces infringement by doing nothing more than telling doctors the

law of nature; Endo cannot even argue that Actavis has instructed doctors to apply it. This is not

to say that no method of treatment patent is patentable, simply that a claim to a law of nature—

here, as Endo freely admits, a discovered relationship between bioavailabity of oxymorphone

and level of renal impairment (D.I. 18 (Opp. Br.) at 14)—cannot be made patentable by adding

an “administering” step that is common knowledge within the relevant art and confirmed to be

common knowledge within the asserted patent itself.


2

ARGUMENT

I. ENDO CANNOT SUSTAIN A CLAIM FOR INFRINGEMENT ON THE PLEADINGS

A. The acts that Actavis has taken, as pled by Endo, cannot constitute inducement to infringe the ’737 patent

Endo cannot show that the label for either of Actavis’s products instructs physicians to

practice every limitation of a claim of the ’737 patent. The ’737 patent’s claims require a

physician to perform a series of specific steps:

(1) providing a solid oral controlled release dosage of oxymorphone from about 5 mg to about 80 mg in a controlled release matrix;

(2) measuring a creatinine clearance rate of a patient;

(3) determining that rate to be within one of four ranges (which correspond to a patient’s level of renal impairment);

(4) administering a lower dosage of oxymorphone “in dependence on which creatinine clearance rate is found,” such that

(5) after administration, either the average area-under-curve or maximum concentration of oxymorphone is less than a specified number (which varies between the six patent claims).

D.I. 12 (Opening Br.) at 4; D.I. 1, Ex. A at 48:7-26. In its opposition brief, Endo fails to identify

language in Actavis’s labels instructing a physician to follow these steps; it only points generally

to language instructing a physician to “reduce the dose” in “patients with renal impairment.” D.I.

18 at 9-10.

In order to show inducement, Endo would have to show that Actavis’s product labels

instruct physicians to perform every limitation of a patented claim. See Warner-Lambert Co. v.

Apotex Corp., 316 F.3d 1348, 1363 (Fed. Cir. 2003) (“Inducement requires proof that the

accused infringer knowingly aided and abetted another’s direct infringement of the patent.”);

Lucent Techs., Inc. v. Gateway, Inc., 580 F.3d 1301, 1317 (Fed. Cir. 2009) (“To infringe a


3

method claim, a person must have practiced all steps of the claimed method.”). Its failure to

identify such language is dispositive.

In particular, an ANDA applicant cannot be liable for induced infringement of a method

of treatment patent where the product label does not direct a physician to perform each step of

the patented method. AstraZeneca Pharms. LP v. Apotex Corp., 669 F.3d 1370, 1379 (Fed. Cir.

2012) (“AstraZeneca II”); Warner-Lambert, 316 F.3d at 1354-55. Endo’s suggestion that these

cases only apply to ANDAs for a “different indication” from the patented method, D.I. 18 at 11-

12, is incorrect. The question, per the Court in AstraZeneca II, is whether a “use” listed in the

ANDA or on the proposed label is claimed in a patent. 669 F.3d at 1378. The use claimed by

the ’737 patent is not merely the administration of oxymorphone for pain relief; the patent freely

admits that oxymorphone was “widely used in the treatment of acute and chronic pain” in the

prior art. D.I. 1, Ex. A at 1:19-22.

Moreover, even if Endo could somehow find suggestion to perform each step of a claim

somewhere in Actavis’s label, the possibility that a physician could cobble together separate

instructions in a label to infringe a method claim is insufficient to show inducement. In Mirror

World, LLC v. Apple Inc., 692 F.3d 1351, 1360 (Fed. Cir. 2012), the court affirmed judgment as

a matter of law of no induced infringement where the only evidence of inducement came from

the defendant’s user manuals containing instructions in separate places, not connected to each

other, to perform the steps claimed by the patent. “When manuals only teach ‘customers each

step of the claimed method in isolation,’ but not ‘all the steps of the claimed method together,’

the manuals alone cannot support infringement.” Id. Here, Endo relies on Actavis’s labels alone

to show inducement—it is forced to rely on the label alone for the ANDA product, Abbott Labs.

v. TorPharm, Inc., 300 F.3d 1367, 1373 (Fed. Cir. 2002), and has pled no other factual


4

allegations to show inducement for the already-approved extended-release oxymorphone tablets.

D.I. 12 (Opening Br.) at 8-9. The possibility that a physician could theoretically combine

instructions scattered throughout the label—e.g., advice to “reduce the dose” in patients with

renal impairment, direction from another section to “initiate the dosing regimen for each patient

individually,” direction from another section to start at a dose of 50% and titrate slowly, and

information in section 12.3 about a study comparing bioavailability of oxymorphone to

creatinine clearance rates (D.I. 18 at 9-10)—does not show inducement as a matter of law.

Endo’s reliance on AstraZeneca LP v. Apotex, Inc., 633 F.3d 1042 (Fed. Cir. 2010)

(“AstraZeneca I”), fails because the patent in that case, unlike the patent here, was broad enough

to encompass the language in the product label. The representative claim of the patent in that

suit was simply: “A method of treating a patient suffering from a respiratory disease, the method

comprising administering to the patient a nebulized dose of a budesonide composition in a

continuing regimen at a frequency of not more than once per day.” Id. at 1048. The court found

that the label’s instruction to “titrate down” from a twice-daily dose would induce infringement

because the only way a physician could reduce the dosage was to administer the drug once-daily

and therefore infringe. Id. at 1057. No such inferred instruction to perform the steps of the ’737

patent can be found in Actavis’s product label, as merely reducing a dose slowly cannot instruct

a physician to perform the precise measuring, determining, and administering a lower dose

dependent on level of renal impairment required by the ’737 patent.

B. Mere notice of Endo’s claims is insufficient to survive this motion to dismiss

The fact that Endo’s Complaint “identifies the specific infringing acts, the entity that

actively induces infringement (Actavis), and the people it is inducing to infringe” (D.I. 18 at 9)

does not immunize the Complaint from a Rule 12(b)(6) motion to dismiss. A Rule 12(b)(6)

motion to dismiss may be granted “if, accepting the well-pleaded allegations in the complaint as


5

true and viewing them in the light most favorable to the plaintiff, a court concludes that those

allegations ‘could not raise a claim of entitlement to relief.’” Simon v. FIA Card Servs., N.A.,

732 F.3d 259 (3d Cir. 2013); MONEC Holding AG v. Motorola Mobility, Inc., 897 F. Supp. 2d

225, 234-35 (D. Del. 2012) (dismissal of induced infringement claim for failure to allege facts

necessary to show intent). Endo’s Complaint as to the ’737 Patent fails not because it failed to

provide enough factual detail, but because the details Endo provided, taken as true, are

insufficient to plausibly demonstrate that Actavis will induce infringement through selling its

ANDA product or has induced infringement through selling its already-sold extended-release

oxymorphone tablets. A claim for indirect patent infringement can be dismissed on a Rule

12(b)(6) motion if the facts pled by the complaint are inadequate to state a claim for indirect

infringement, as they do here. See In re Bill of Lading Transmission & Processing Sys. Patent

Litig., 681 F.3d 1323, 1338-39 (Fed. Cir. 2012) (affirming dismissal of contributory infringement

because complaint identified substantial non-infringing uses); AstraZeneca II, 669 F.3d at 1379

(affirming dismissal of induced infringement in ANDA case because ANDA was submitted only

for noninfringing use).

II. THE ’737 PATENT IS INVALID FOR CLAIMING AN UNPATENTABLE LAW OF NATURE

A. Endo’s argument for induced infringement precisely illustrates why the ’737 patent is directed to unpatentable subject matter

The Court in Mayo explained that a patent that states a law of nature does not become

patentable simply by adding a limitation instructing to apply that law of nature:

A patent [] could not simply recite a law of nature and then add the instruction “apply the law.” Einstein, we assume, could not have patented his famous law by claiming a process consisting of simply telling linear accelerator operators to refer to the law to determine how much energy an amount of mass has produced (or vice versa). Nor could Archimedes have secured a patent for his famous principle of flotation by claiming a process consisting of simply


6

telling boat builders to refer to that principle in order to determine whether an object will float.

132 S. Ct. at 1297.

Endo is forced to argue, however, that Actavis induced infringement by telling doctors

about a law of nature and advising them to “apply the law.” Endo attempts to preclude Actavis

from informing doctors about a useful law of nature—exactly the type of activity the courts

intended to allow through the judicially-created rule that laws of nature, natural phenomena, and

abstract ideas are not patentable. The Court in Mayo explained that even a claim tied to a narrow

law of nature, such as the relationship between measured drug levels and treatment protocol,

preempts use and further research into that basic law of nature:

The laws of nature at issue here are narrow laws that may have limited applications, but the patent claims that embody them nonetheless implicate this concern [that it will inhibit future innovation]. They tell a treating doctor to measure metabolite levels and to consider the resulting measurements in light of the statistical relationships they describe. In doing so, they tie up the doctor’s subsequent treatment decision whether that treatment does, or does not, change in light of the inference he has drawn using the correlations. And they threaten to inhibit the development of more refined treatment recommendations . . . that combine [the patentee’s] correlations with later discovered features of metabolites, human physiology or individual patient characteristics.

132 S. Ct. at 1302. Endo, to show induced infringement, is forced to argue that Actavis may not

tell doctors about a discovered law of nature, and that doctors may not make treatment decisions

based on that law of nature. Oxymorphone is an old drug, and doctors have treated and will

continue to treat patients for pain relief by giving them oxymorphone. Endo’s induced

infringement claim does exactly what the Court cautioned against in Mayo: it ties up doctors’

treatment decisions by forbidding Actavis from informing of them of the results of a clinical

study, and it inhibits the development of any other treatment recommendation that might be


7

developed as a result of that study. As a result, Endo’s patent cannot possibly be directed to

patent-eligible subject matter.

B. Straightforward application of the Mayo/Alice two-part test shows the ’737 patent to claim unpatentable subject matter

Endo’s argument suggests that all method of treatment claims meet the requirements of

35 U.S.C. § 101, because any administering step is an “application” of a law of nature. D.I. 18 at

14. This is not the law under Mayo, 132 S. Ct. 1289, and Alice Corp. Pty, Ltd. v. CLS Bank Int’l,

134 S. Ct. 2347 (2014).

Alice Corp., quoting Mayo, sets forth a two step framework for determining whether a

claim is patent-eligible. 134 S. Ct. at 2355. The first step is to determine whether the claims at

issue are directed to a patent-ineligible concept, i.e., a law of nature, natural phenomenon, or

abstract idea. Id. The second step, if the claim is directed to a patent-ineligible concept, is to

“search for an ‘inventive concept’—i.e., an element or combination of elements that is ‘sufficient

to ensure that the patent in practice amounts to significantly more than a patent upon the

[ineligible concept] itself.’” Id.

Endo effectively concedes the first step of the analysis. Endo writes, “it is true that the

claimed inventions relate to the unexpected discovery that the bioavailability of oxymorphone is

increased in patients with renal impairment.” D.I. 18 at 14. But “Phenomena of nature, though

just discovered . . . are not patentable, as they are the basic tools of scientific and technological

work.” Gottschalk v. Benson, 409 U.S. 63, 67 (1972). Endo’s suggestion that the first step of

analysis should consider the patent to be “a method of treating pain in renally impaired patients

by decreasing the dosage of oxymorphone” (D.I. 18 at 19) is contradicted by Supreme Court

precedent and by Endo’s own statements in its brief and in its patent, and by Supreme Court

precedent. As noted above, Endo conceded that the inventions relate to the discovery of the


8

relationship between bioavailability of oxymorphone and level of renal impairment, not to the

development of a novel method of treatment. D.I. 18 at 14. The patent itself explains that

oxymorphone was already widely used for pain relief (D.I. 1, Ex. A at 1:19-23), so the

administration of oxymorphone is not the invention. Rather, the purported discovery of the

relationship between bioavailability of oxymorphone and level of renal impairment—described

in extensive detail in the patent (D.I. 1, Ex. A at 27:59-46:46), and summarized under the

heading “CONCLUSION,” (D.I. 1, Ex. A at 46:50-57)—is the concept that is the subject of the

patent. That relationship, “a consequence of the ways in which [oxymorphone is] metabolized

by the body,” is an unpatentable law of nature. Mayo, 132 S. Ct. at 1296-97.1

The second step of the Mayo/Alice test is to determine whether the claims “add enough to

their statements of the correlations to allow the processes they describe to qualify as patent-

eligible processes that apply natural laws.” Mayo, 132 S. Ct. at 1297 (emphasis in original).

Endo’s reference to the Classen series of cases in contrast to Mayo supports, rather than defeats,

Actavis’s argument for invalidity. Classen Immunotherapies, Inc. v. Biogen IDEC, 659 F.3d

1057 (Fed. Cir. 2011) (“Classen I”), heavily cited by Endo, is not governing law to the extent it

conflicts with the later Supreme Court decision in Mayo. When the District of Maryland, on

remand from the Federal Circuit’s vacation of its dismissal in Classen I, reexamined the section

101 issues in light of Mayo, it distinguished Mayo on the ground that the administering steps in

Mayo, unlike the administering steps in Classen, were stated by the patent itself to be well-

understood, routine activity:

1 It is this distinction—that the ’737 patent does nothing more than tell doctors to use a natural law to adjust their use of a common drug for its well-known purpose—that avoids Endo’s slippery slope argument that Actavis’s position would lead to invalidation of all method-of-treatment patents. (D.I. 18 at 19).


9

In [Mayo], the patent acknowledged that “scientists routinely measured metabolites as part of their investigations into the relationships between metabolite levels and efficacy and toxicity of thiopurine compounds.” The Supreme Court was thus able to conclude that the steps involved “well-understood, routine, conventional activity previously engaged in by scientists who work in the field.” There is no information in the record here that allows the Court, on a motion to dismiss for failure to state a claim, to conclude that the Classen patent claims involve “well-understood, routine, [or] conventional activity.”

Classen Immunotherapies, Inc. v. Biogen IDEC, No. WDQ-04-2607, 2012 WL 3264941 at *4

(D. Md. Aug. 9, 2012) (“Classen II”). Like in Mayo and unlike in Classen II, the ’737 patent

here acknowledged that the administration of oxymorphone for pain relief is “well-understood,

routine, conventional activity.” D.I. 1, Ex. A at 1:19-23. Endo’s supposedly new “treatment

regimen for renally-impaired patients” (D.I. 18 at 20) does nothing more than administer

oxymorphone for pain in a conventional way, and instruct doctors to use a natural law to adjust

the dosage. Accordingly, the administering step cannot save the ’737 patent. Endo does not

argue that any other step of the ’737 patent converts the patent-ineligible discovery of low

bioavailability of oxymorphone in renally impaired patients into a patent-eligible application.

D.I. 18 at 16.

Endo’s attempt to distinguish Mayo fails, and Mayo still corresponds directly to the claim

limitations of the ’737 patent. Endo incorrectly argues that the Mayo claim is different from the

’737 patent claim because the Mayo claim administers a drug in order to measure the resulting

metabolite, but the ’737 patent claim administers a drug “to provide safe and effective pain

relief.” D.I. 18 at 16-20. The Mayo claim in fact specified that the drug is used “for treatment of

an immune-mediated gastrointestinal disorder.” 132 S. Ct. at 1232. The Mayo claim is simply to

administer the drug to a patient, measure the level of metabolite, and adjust the dosage

accordingly to optimize treatment effectiveness. Id. The only conceptual difference between


10

this and the ’737 patent claim is that the ’737 patent claim suggests that the doctor should adjust

the dosage based on measurement of a different quantity than the concentration of the

administered drug (while specifying that the concentration of the administered drug should

remain below a certain level).

CONCLUSION

For the foregoing reasons and those in Actavis’s opening brief, Actavis respectfully urges

the Court to grant its motion and dismiss Counts I, III, and IV of the Complaint.

Of Counsel: HOLLAND & KNIGHT LLP Charles Weiss 31 West 52nd Street New York, NY 10019 (212) 513-3551 [email protected] Dated: March 23, 2015

YOUNG CONAWAY STARGATT & TAYLOR, LLP /s/ Robert M. Vrana Adam W. Poff (No. 3990) Robert M. Vrana (No. 5666) Rodney Square 1000 North King Street Wilmington, DE 19801 (302) 571-6600 [email protected] [email protected] Attorneys for Defendants Actavis Inc. and Actavis South Atlantic LLC

01:16841669.1


01:16841743.1


I, Robert M. Vrana, hereby certify that on March 23, 2015, I caused to be electronically




Jack B. Blumenfeld, Esquire Julia Heaney, Esquire Morris Nichols Arsht & Tunnell LLP 1201 North Market Street P.O. Box 1347 Wilmington, DE 19899-1347 [email protected] [email protected] Attorneys for Plaintiffs

I further certify that on March 23, 2015, I caused a copy of the foregoing document


Jonathan D.J. Loeb, Esquire Dechert LLP 2440 W. El Camino Real Suite 700 Mountain View, CA 94040 [email protected] Martin J. Black, Esquire Dechert LLP Circa Centre 2929 Arch Street Philadelphia, PA 19104 [email protected]


2 01:16841743.1

Robert D. Rhoad, Esquire Brian Goldberg, Esquire Dechert LLP 902 Carnegie Center, Suite 500 Princeton, NJ 08540 [email protected] [email protected] Blake B. Greene, Esquire Dechert LLP 300 W. 6th Street, Suite 2010 Austin, TX 78701 [email protected] Attorneys for Plaintiff Endo Pharmaceuticals Inc. Jeffrey J. Toney, Esquire Marcus A. Barber, Esquire Kasowitz, Benson, Torres & Friedman LLP 333 Twin Dolphin Drive, Suite 200 Redwood Shores, CA 94065 [email protected] [email protected] Rodney R. Miller, Esquire Paul G. Williams, Esquire Kasowitz, Benson, Torres & Friedman LLP 1349 W. Peachtree Street, N.W., Suite 1500 Atlanta, GA 30309 [email protected] [email protected] Attorneys for Plaintiff Mallinckrodt LLC

Dated: March 23, 2015 YOUNG CONAWAY STARGATT & TAYLOR, LLP

/s/ Robert M. Vrana Adam W. Poff (No. 3990) Robert M. Vrana (No. (5666) Rodney Square 1000 N. King Street Wilmington, Delaware 19801 [email protected] Attorneys for Defendants



) ENDO PHARMACEUTICALS INC. and ) MALLINCKRODT LLC, ) ) Plaintiffs, ) ) v. ) C.A. No. 14-1381-RGA ) ACTAVIS INC. and ACTAVIS SOUTH ) ATLANTIC LLC, ) ) Defendants. ) )

ACTAVIS’S RESPONSE TO ENDO’S OBJECTIONS TO THE REPORT AND RECOMMENDATION

REGARDING DISMISSAL UNDER 35 U.S.C. § 101




Dated: October 30, 2015 Actavis South Atlantic LLC


i

TABLE OF CONTENTS

Page

INTRODUCTION .......................................................................................................................... 1

FACTUAL BACKGROUND ......................................................................................................... 1

ARGUMENT .................................................................................................................................. 2

I. The R&R correctly concluded that the ’737 patent’s claims were invalid as claiming an unpatentable law of nature .............................................................................. 2

A. The ’737 patent’s claims are directed to the law of nature that bioavailability of oxymorphone is increased in patients with renal impairment .............................................................................................................. 3

B. The R&R correctly concluded that nothing in the ’737 patent’s claims transforms them into patent-eligible subject matter ................................................ 4

C. The R&R correctly found that the ’737 patent claims would preempt future inventions and discoveries in the field ......................................................... 6

D. The R&R’s reasoning would not lead to invalidation of all method-of-treatment patents ..................................................................................................... 8

II. If the Court finds that the R&R is in error, the Court should remand Actavis’s motion to dismiss to the Magistrate Judge for further consideration of the alternate ground of no induced infringement ..................................................................................... 8

CONCLUSION ............................................................................................................................... 9


ii


Page(s) CASES

Alice Corp. Pty. Ltd. v. CLS Bank Intern., 134 S. Ct. 2347 (2014) ...................................................................................................1, 2, 5, 6

Classen Immunotherapies, Inc. v. Biogen IDEC, 659 F.3d 1057 (Fed. Cir. 2011)..................................................................................................5

Classen Immunotherapies, Inc. v. Biogen IDEC, Civ. No. WDQ-04-2607, 2012 WL 326491 (D. Md. Aug. 9, 2012) .........................................6

Mayo Collaborative Servs. v. Prometheus Labs., Inc., 132 S. Ct. 1289 (2012) ..................................................................................................... passim

STATUTES

35 U.S.C. § 101 ................................................................................................................................1


1

INTRODUCTION

The Magistrate Judge correctly applied clear Supreme Court precedent in finding in her

Report and Recommendation (“R&R”) that Counts I, III, and IV of Endo’s Complaint regarding

U.S. Patent No. 8,808,737 (“the ’737 patent”) should be dismissed for failure to state a claim

because the ’737 patent claims unpatentable subject matter under 35 U.S.C. § 101. The Supreme

Court in Mayo Collaborative Servs. v. Prometheus Labs., Inc., 132 S. Ct. 1289, 1297 (2012),

held that a patent “could not simply recite a law of nature and then add the instruction ‘apply the

law.’” Endo’s objections to the R&R are inconsistent with clear Supreme Court precedent by

arguing that an instruction to apply a law of nature—which here is taking account of kidney

function in “administering” an old drug for an old purpose—renders patentable natural laws. But

patent eligibility should not “depend simply on the draftman’s art.” Alice Corp. Pty. Ltd. v. CLS

Bank Intern., 134 S. Ct. 2347, 2359 (2014). The ’737 patent does not avoid invalidity simply

because Endo included in the claims an “administering” step that is a trivial addition to the exact

type of subject matter held unpatentable in Mayo, which claimed using a measurement of blood

levels to “indicate a need to decrease the amount of said drug subsequently administered.”

FACTUAL BACKGROUND

In this lawsuit, Endo alleges that Actavis has infringed the ’737 patent and U.S. Patent

8,871,779 (which is not at issue on this motion) by (i) selling an FDA-approved extended-release

formulation of oxymorphone, and (ii) submitting an Abbreviated New Drug Application

(“ANDA”) seeking FDA approval for a different formulation of the same drug. Actavis moved

to dismiss Endo’s claims for direct, contributory, and induced infringement of the ’737 patent,

showing that (1) all claims of the ’737 patent are directed to an unpatentable law of nature under

35 U.S.C. § 101, and (2) the Complaint failed to state a claim for indirect infringement and

cannot state a claim against Actavis for direct infringement. The R&R found that the ’737


2

patent’s claims were unpatentable, and did not reach the issue of whether Endo had adequately

pled indirect infringement.

Claim 1 of the ’737 patent is representative of all of the ’737 patent’s claims:


a. providing a solid oral controlled release dosage form, comprising:

i. about 5 mg to about 8 mg of oxymorphone or a pharmaceutically acceptable salt thereof as the sole active ingredient; and

ii. a controlled release matrix;

b. measuring a creatinine clearance rate of the patient and determining it to be (a) less then about 30 ml/min, (b) about 30 mL/min to about 50 mL/min, (c) about 51 mL/min to about 80 mL/min, or (d) above about 80 mL/min; and

c. orally administering to said patient, in dependence on which creatinine clearance rate is found, a lower dosage of the dosage form to provide pain relief;

wherein after said administration to said patient, the average AUC of oxymorphone over a 12-hour period is less than about 21 ng·hr/mL.

The dependent claims modify either the value or the specified measurement of the final

“wherein” clause, and do not affect the present analyses.

ARGUMENT

I. The R&R correctly concluded that the ’737 patent’s claims were invalid as claiming an unpatentable law of nature

Alice and Mayo set forth a two-part test of patent eligibility. “First, a court must

determine if a relevant claim is ‘directed to one of those patent ineligible concepts,’ i.e., a law of

nature, natural phenomenon, or an abstract idea. If so, then the court must ask, ‘what else is

there in the claims before us?’” D.I. 51 at 9-10 (citing Alice, 134 S. Ct. at 2355).


3

A. The ’737 patent’s claims are directed to the law of nature that bioavailability of oxymorphone is increased in patients with renal impairment

The R&R recognized that Endo conceded in its original opposition brief that the relevant

claims are directed to a law of nature; Endo wrote that “it is true that the claimed inventions

relate to the unexpected discovery that the bioavailability of oxymorphone is increased in

patients with renal impairment.” D.I. 51 at 13 n. 70 (quoting D.I. 18 at 14). Endo’s argument

that the invention is directed instead to a “new and useful regimen for treating pain in a specific

patient population” is flatly contradicted by the ’737 patent specification, which states that

oxymorphone and other morphine derivatives have been used for treating pain for decades (’737

patent at 1:9-32), and that controlled release oxymorphone was approved by the FDA in 2006,

four years before the filing date of the ’737 patent (’737 patent at 3:40-49). The specification

describes the invention in simplest form as nothing more than providing prior art controlled-

release oxymorphones tablet and “informing the patient or the patient’s prescribing physician

that the bioavailability of oxymorphone is increased in patients with renal impairment.” ’737

patent at 2:29-34. There is no question that the claims are directed to the law of nature that “the

bioavailability of oxymorphone is increased in patients with renal impairment.”

That Endo drafted its claims to require administration of a dosage of a drug (D.I. 56 at 3-

4) does not show that the claims are to a new and useful process rather than a law of nature, as

Endo suggests. The claims’ step of “administering” the drug is “insignificant post-solution

activity.” Mayo, 132 S. Ct. at 1298 (quoting Diamond v. Diehr, 450 U.S. 175, 191-92 (1980)).

Mayo held unpatentable claims that included the step of “determin[ing] the level of the relevant

metabolites in the blood, through whatever process the doctor or the laboratory wishes to use,”

because “scientists routinely measured metabolites as part of their investigations into the

relationships between metabolite levels and efficacy and toxicity of thiopurine compounds.” Id.


4

Here, the “administering” step Endo relies on to argue for patent-eligibility calls for an even

more routine activity: giving an old drug (oxymorphone) for its known purpose (reducing pain).

There is nothing “new and useful,” to use Endo’s words (D.I. 56 at 3), about using the smallest

effective dose of a drug, or giving less to patients who need (or can only tolerate) less.

B. The R&R correctly concluded that nothing in the ’737 patent’s claims transforms them into patent-eligible subject matter

The ’737 patent claims: (1) providing a controlled release dosage of oxymorphone; (2)

measuring a creatinine clearance rate, which is used to measure renal impairment; and (3)

administering to the patient a lower dose of oxymorphone dependent on the creatinine clearance

rate measured. Neither Endo’s opposition brief nor its objections to the R&R argue that the

“providing” step or the “measuring” step provide patent-eligible subject matter. D.I. 18 at 14-20;

D.I. 56 at 3-9. Nor do they. Mayo, 132 S. Ct. at 1297-98 (steps directed to routine and

conventional medical activities do not provide patentable subject matter to laws of nature).

The R&R correctly found that the ’737 patent’s “administering” step is analogous to the

“indicates a need” steps in Mayo. The “measuring” and “administering” steps of the ’737 patent

are strikingly similar to the “determining” and “wherein” steps held unpatentable in Mayo, as

shown by the following table:

Claim 1 of the Mayo patent 132 S. Ct. at 1295

Claim 1 of the ’737 patent

(b) determining the level of 6-thioguanine in said subject having said immune-mediated gastrointestinal disorder,

b. measuring a creatinine clearance rate of the patient and

wherein the level of 6-thioguaninine less than about 230 pmol per 8x108 red blood cells

determining it to be (a) less than about 30 mL/min, (b) about 30 mL/min to about 50 mL/min, (c) about 51 mL/in to about 80 mL/min, or (d) above about 80 mL/min; and

indicates a need to increase the amount of said c. orally administering to said patient, in


5

drug subsequently administered to said subject

and

wherein the level of 6-thioguanine greater than about 400 pmol per 8x108 red blood cells indicates a need to decrease the amount of drug subsequently administered to said subject.

dependence on which creatinine clearance rate is found, a lower dosage of the dosage form to provide pain relief

wherein after said administration to said patient, the average AUC of oxymorphone over a 12-hour period is less than about 21 ng·hr/mL.

Both the Mayo claim and the ’737 patent claim providing or administering an old drug for a

known purpose, running lab work, and setting the dose of drug based on the results. The only

distinction is that the lab work in Mayo “indicates a need” to increase or decrease the drug, while

the ’737 patent says to actually do it. But this is a distinction without a difference: there is no

meaningful addition to the law of nature in either claim. Contrary to Endo’s argument that

requiring a physician to “apply that knowledge in [a] practical, tangible way” (D.I. 56 at 5)

renders a claim patentable, the Supreme Court clearly held that “one must do more than simply

state the law of nature while adding the words ‘apply it.’” Mayo, 132 S. Ct. at 1294.

The Magistrate Judge also correctly distinguished the Classen series of cases. First,

Endo’s reliance on Classen Immunotherapies, Inc. v. Biogen IDEC, 659 F.3d 1057 (Fed. Cir.

2011) (Classen I), is misplaced because it is no longer good law after Mayo and Alice. It does

not matter that the Federal Circuit suggested in 2011 that stating the abstract idea of comparing

data on vaccination schedules and telling a doctor to “apply it” by administering vaccines

according to the preferred schedule rendered a claim patentable, when the Supreme Court held in

2012 in Mayo that merely adding an application step does not render a claim patentable. Indeed,

Classen I expressly relied on principles that Mayo rejected, i.e., the proposition that adding a

physical act to an unpatentable scientific principle renders the claim patent-eligible. See Classen

I, 659 F.3d at 1067-68 (“In contrast, the claims of the ’139 and ’739 patents require the further

act of immunization in accordance with a lower-risk schedule, thus moving from abstract


6

scientific principle to specific application.”). And if this was not enough, the Supreme Court’s

admonition in Mayo, 132 S. Ct. at 1299-1300, and Alice, 134 S. Ct. at 2358-59, against finding

claims to be patentable solely due to the inclusion of an application step, thus overturned Classen

I’s suggestion that adding an application step rendered a claim patentable.

Second, the subsequent decision of the District of Maryland on remand in Classen

Immunotherapies, Inc. v. Biogen IDEC, Civ. No. WDQ-04-2607, 2012 WL 326491 at *4-*5 (D.

Md. Aug. 9, 2012) (Classen II), apart from not being binding precedent on this Court,

distinguished Mayo on the ground that the “application” step in Mayo was “well-understood,

routine, conventional activity previously engaged in by scientists who work in the field,”

whereas there was no evidence that the immunization schedules at issue in Classen II were

conventional activity. As the R&R correctly noted, the ’737 patent recognizes that the

administration of oxymorphone for pain relief is well-understood, routine, conventional activity,

making it equivalent to the patent-ineligible claim of Mayo, not the claim held to be patent-

eligible in Classen II. D.I. 51 at 16. Notably, the ’737 patent claim does not require

administration of oxymorphone on any particular schedule or in any particular unusual way; it

merely requires the step of “administering to said patient, in dependence on which creatinine

clearance rate is found, a lower dosage of the dosage form to provide pain relief.” Mayo

similarly warned that its “determining” step was “set forth in highly general language covering

all processes that make use of the correlations after measuring metabolites, including later

discovered processes that measure metabolite levels in new ways. 132 S. Ct. at 1302.

C. The R&R correctly found that the ’737 patent claims would preempt future inventions and discoveries in the field

Endo claims that the ’737 patent is “limited to a specific method of treating a very

particular patient population (renally impaired patients) using a very particular drug (controlled


7

release oxymorphone) in a very particular way (reducing the dosage in dependent [sic] upon the

patients’ creatinine clearance rate).” D.I. 56 at 9. So, too the Mayo patent was limited to a

specific method of treating a very particular patient population (patients with immune-mediated

gastrointestinal disorder) using a very particular drug (6-thioguanine) in a very particular way

(increasing or reducing the dosage dependent on whether the patient’s 6-thioguanine level was

below or above the range of 230-400 pmol per 8x108 red blood cells). 132 S. Ct. at 1295. The

Supreme Court explicitly rejected the exact same argument Endo makes here:

In any event, our cases have not distinguished among different laws of nature according to whether the principles they embody are sufficiently narrow. And this is understandable. Courts and judges are not institutionally well suited to making the kinds of judgments needed to distinguish among different laws of nature. And so the cases have endorsed a bright-line prohibition against patenting laws of nature, mathematical formulas and the like, which serves as a somewhat more easily administered proxy for the underlying “building-block” concern.

132 S. Ct. at 1303 (citations omitted).

The ’737 patent, if it were held patentable, would dangerously preempt good

pharmaceutical and good medical practice. In the ’737 patent, Endo did nothing more than

observe how a drug was metabolized in patients with kidney disease, and attempt to claim a

monopoly on good medical practice (adjusting the dosage of medicine in patients who need or

can tolerate less). The ’737 patent seeks to prevent doctors from applying the good medical

practice of adjusting the dosage of an opiate painkiller to reduce side effects while maintaining

efficacy, and to prevent generic pharmaceutical companies from providing doctors with basic

medical information that can be helpful to their prescribing practices. These are among the

policy concerns that the patentable subject matter doctrine, and its focus on preemption, are

designed to address. See Mayo, 132 S. Ct. at 1302.


8

The Court in Mayo recognized the problem, raised by amici including the American

Medical Association and the American Hospital Association, that if “claims to exclusive rights

over the body’s natural responses to illness and medical treatment are permitted to stand, the

result will be a vast thicket of exclusive rights over the use of critical scientific data that must

remain widely available if physicians are to provide sound medical care.” 132 S. Ct. at 1304.

Putting medical information on the label of a drug, getting a patent, and then suing others for

infringement because they include that information on their labels is at the core of such concerns.

D. The R&R’s reasoning would not lead to invalidation of all method-of-treatment patents

As explained in this brief and the R&R, the ’737 patent’s claims are not patent-eligible

subject matter—and can be found to be patent-ineligible on a motion to dismiss—because the

patent itself states that all of the claim elements other than the law of nature are routine and

conventional activity. Endo’s “sky is falling” argument is largely nonsense. An inventor can

still discover that a known drug has some hitherto-unknown uses (as for different indications)

and claim a method of using that drug for the new use. The R&R stands only for the

unremarkable proposition that one cannot observe the way the body metabolizes an old drug

used for an old purpose, and seek to patent the use of that knowledge.

II. If the Court finds that the R&R is in error, the Court should remand Actavis’s motion to dismiss to the Magistrate Judge for further consideration of the alternate ground of no induced infringement

Actavis’s motion to dismiss raised two grounds for dismissal: (1) invalidity of the ’737

patent for claiming unpatentable subject matter, and (2) failure to state a claim of induced

infringement against Actavis. The Magistrate Judge, having found the patent invalid, did not

need to reach the issue of inducement. D.I. 51 at 18. Accordingly, if the Court does not adopt

the R&R, the motion to dismiss will not have been resolved completely, and the issue of whether


9

Endo sufficiently pled infringement of the ’737 patent should be returned to the Magistrate Judge

(or decided in the first instance by the Court as it sees fit).

CONCLUSION

For the foregoing reasons, Actavis respectfully urges the Court to adopt the Magistrate

Judge’s Report and Recommendations and dismiss Counts I, III, and IV of the Complaint.

Of Counsel: HOLLAND & KNIGHT LLP Charles A. Weiss 31 West 52nd Street New York, NY 10019 (212) 513-3551 [email protected] Dated: October 30, 2015

YOUNG CONAWAY STARGATT & TAYLOR, LLP /s/ Robert M. Vrana Adam W. Poff (No. 3990) Robert M. Vrana (No. 5666) Rodney Square 1000 North King Street Wilmington, DE 19801 (302) 571-6600 [email protected] [email protected] Attorneys for Defendants Actavis Inc. and Actavis South Atlantic LLC

01:17916345.1


01:16529567.1


I, Robert M. Vrana, hereby certify that on October 30, 2015, I caused to be electronically




Jack B. Blumenfeld, Esquire Morris Nichols Arsht & Tunnell LLP 1201 North Market Street P.O. Box 1347 Wilmington, DE 19899-1347 [email protected] Attorneys for Plaintiffs

I further certify that on October 30, 2015, I caused a copy of the foregoing document


Jonathan D.J. Loeb, Esquire Dechert LLP 2440 W. El Camino Real Suite 700 Mountain View, CA 94040 [email protected] Martin J. Black, Esquire Sharon K. Gagliardi, Esquire Julie M. Latsko, Esquire Joseph J. Gribbin, Esquire Dechert LLP Circa Centre 2929 Arch Street Philadelphia, PA 19104 [email protected] [email protected] [email protected] [email protected]


2 01:16529567.1

Robert D. Rhoad, Esquire Brian Goldberg, Esquire Dechert LLP 902 Carnegie Center, Suite 500 Princeton, NJ 08540 [email protected] [email protected] Blake B. Greene, Esquire Dechert LLP 300 W. 6th Street, Suite 2010 Austin, TX 78701 [email protected] Attorneys for Plaintiff Endo Pharmaceuticals Inc. Jeffrey J. Toney, Esquire Marcus A. Barber, Esquire Kasowitz, Benson, Torres & Friedman LLP 333 Twin Dolphin Drive, Suite 200 Redwood Shores, CA 94065 [email protected] [email protected] Rodney R. Miller, Esquire Paul G. Williams, Esquire Kasowitz, Benson, Torres & Friedman LLP 1349 W. Peachtree Street, N.W., Suite 1500 Atlanta, GA 30309 [email protected] [email protected] Attorneys for Plaintiff Mallinckrodt LLC

Dated: October 30, 2015 YOUNG CONAWAY STARGATT & TAYLOR, LLP

/s/ Robert M. Vrana Adam W. Poff (No. 3990) Robert M. Vrana (No. (5666) Rodney Square 1000 N. King Street Wilmington, Delaware 19801 [email protected] Attorneys for Defendants


Briefs in Support of Motion to Dismiss for invalidity unpatentable subject matter under 35 U.S.C...

Documents

Transcript of Briefs in Support of Motion to Dismiss for invalidity unpatentable subject matter under 35 U.S.C...