Petition for Writ of Certiorari — Apotex Inc., et al., Petitioners v. Cephalon, Inc., et al.

No. ____

IN THE

Supreme Court of the United States

————

APOTEX INC., APOTEX CORP.,

Petitioners,

v.

CEPHALON, INC., EAGLE PHARMACEUTICALS, INC.,

TEVA PHARMACEUTICALS INTERNATIONAL GMBH,

Respondents.

————

On Petition for a Writ of Certiorari to the

United States Court of Appeals

for the Federal Circuit

————

PETITION FOR A WRIT OF CERTIORARI

————

LAWRENCE ROSENTHAL

Of Counsel

CHAPMAN UNIVERSITY

SCHOOL OF LAW

One University Drive

Orange, California 92866

(714) 628-2650

STEVEN E. FELDMAN

Counsel of Record

DANIEL R. CHERRY

SHERRY L. ROLLO

HAHN LOESER & PARKS LLP

200 West Madison Street

Suite 2700

Chicago, Illinois 60606

(312) 637-3010

sfeldman@hahnlaw.com

Counsel for Petitioner

December 14, 2021

WILSON-EPES PRINTING CO., INC. – (202) 789-0096 – WASHINGTON, D.C. 20002

i

QUESTION PRESENTED

Whether

claimed

inventions

involving

reformulating and administering an old drug in

ways that are no better than prior techniques, and

which had been taught and suggested in the prior

art, are nevertheless patentable although these

formulations and methods were at least “obvious to

try” under this Court’s decision in KSR, Int’l v.

Teleflex, Inc., merely because the court found that a

person of ordinary skill in the art would not have

been sufficiently motivated to make and administer

the drug in this way.

ii

PARTIES TO THE PROCEEDINGS

The parties are identified in the caption.

Aposherm, Inc. is the parent company of Petitioner

Apotex Corp. and Apotex Pharmaceuticals, Inc. is

the parent company of Petitioner Apotex, Inc. No

publicly traded company owns 10% or more shares

of Apotex Inc., Apotex Corp., or of any of their parent

corporations. In addition to the parties identified in

the caption, the following firms were codefendants

in this consolidated case and are therefore technical

respondents under this Court’s Rule 12.6: Slayback

Pharma LLC, Mylan Laboratories, Ltd., Fresenius

Kabi USA, LLC.

iii

TABLE OF CONTENTS

Page

QUESTION PRESENTED .................................... i

PARTIES TO THE PROCEEDINGS .................. ii

TABLE OF CONTENTS ..................................... iii

TABLE OF AUTHORITIES ................................ iv

OPINIONS BELOW............................................... 1

JURISDICTION ..................................................... 1

STATUTORY PROVISION INVOLVED ............ 1

STATEMENT.......................................................... 2

REASONS FOR GRANTING THE WRIT .......... 9

CONCLUSION ..................................................... 21

APPENDIX

Appendix A, Opinion from the United States

District Court for the District of Delaware………1a

Appendix B, Judgment from the United States

Court of Appeals for the Federal Circuit…….…..62a

Appendix C, Judgment from the United States Court

of Appeal for the Federal Circuit Denying Petition for

Rehearing, Rehearing En Banc……………………..64a

iv

TABLE OF AUTHORITIES

CASES

Page

Accorda Therap. v. Roxane Labs.,

903 F.3d 1310 (Fed. Cir. 2018)........................... 12

Eagle Pharm. v. Azar,

952 F.3d 323 (D.C. Cir. 2020) ............................ 15

Graham v. John Deere,

383 U.S. 1 (1966) .................................... 11, 13, 14

In re Stepan,

868 F.3d 1342 (2017) .......................................... 13

Intelligent Bio-Sys., Inc. v. Illumina Cambridge

Ltd.,

821 F.3d 1359 (Fed. Cir. 2016)........................... 13

KSR, Int’l v. Teleflex, Inc.,

550 U.S. 398 (2007) ..................................... passim

Persion Pharmaceuticals LLC v. Alvogen Malta

Operations Ltd.,

945 F.3d 1184 (Fed. Cir. 2019)........................... 13

v

STATUTES

Page

28 U.S.C. § 1254(1)................................................... 1

28 U.S.C. § 1331 ....................................................... 7

28 U.S.C. § 1338a ..................................................... 7

35 U.S.C. § 103(a)..................................................... 2

35 U.S.C. § 271(e)(2) ................................................ 7

OTHER AUTHORITIES

A Prescription for Change: Cracking Down on

Anticompetitive Conduct in Prescription Drug

Markets,

Senate Subcommittee on Competition Policy,

Antitrust, and Consumer Rights (July 13, 2021)

............................................................................. 16

A Prescription for Change: Cracking Down on

Anticompetitive Conduct in Prescription Drug

Markets: Hearing Before the Subcomm. on

Competition Policy, Antitrust, and Consumer

Rights of the S. Comm. on the Judiciary, 117th

Cong. (2021) (testimony of Rachel Moodie, Ph.D.,

Vice President, Biosimilars Patents and Legal,

Fresenius Kabi),

https://www.judiciary.senate.gov

/imo/media/doc/Testimony%20-%20July%2013%

202021_Rachel_Moodie.pdf ................................ 18

vi

Page

Dennis D. Crouch, Wrongly Affirmed Without

Opinion, 52 Wake Forest L. Rev. 561 (2017)..... 15

MAJORITY STAFF OF H.R. COMM. ON OVERSIGHT AND

REFORM, 117TH CONG., DRUG PRICING

INVESTIGATION MAJORITY STAFF REPORT 81

(2021),

https://oversight.house.gov/sites/democrats.oversi

ght.house.gov/files/DRUG%20PRICING%20REP

ORT%20WITH%20APPENDIX%20v3.pdf. ....... 17

Paul Gugliuzza, & Mark Lemley,

Can a Court Change the Law by Saying

Nothing?,

71 Vand. L. Rev. 765 (2018) ............................... 15

Robin Feldman, Why prescription drug prices have

skyrocketed,

Washington Post (Nov. 26, 2018),

https://www.washingtonpost.com/outlook/2018/11

/26/why-prescription-drug-prices-haveskyrocketed/ ........................................................ 18

Thomas Sullivan, “A Tough Road: Cost to Develop

One Drug is $2.6 billion; Approval Rate For

Drugs Entering Clinical Trials is Less Than

12%,”

POLICY AND MEDICINE (May 21, 2019) ............... 16

1

OPINIONS BELOW

The Federal Circuit’s summary affirmance is

reported at 856 Fed.Appx. 309 (Fed. Cir. 2021)

(App., infra, at 62a-63a). The district court’s opinion

(App., infra, at 1a-61a) is reported at 456 F.Supp.3d

594 (D. Del. 2020).

JURISDICTION

The judgment of the court of appeals was entered

on August 13, 2021. App., infra, at 62a-63a. On

October 15, 2021, the court of appeals denied a

timely petition for rehearing en banc. App., infra,

64a-65a. This Court’s jurisdiction is invoked under

28 U.S.C. § 1254(1).

STATUTORY PROVISION INVOLVED

Section 103 of the Patent Act applicable to the

patents at issue here provides, in pertinent part:

(a) 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 to which said subject

matter pertains. Patentability shall

not be negatived by the manner in

which the invention was made.

2

35 U.S.C. § 103(a) (pre-AIA, 2011). 1

STATEMENT

Section 103 of the Patent Act provides, in

straightforward terms, that “[a] patent may not be

obtained . . . if the differences between the subject

matter sought to be patented and the prior art are

such that the subject matter as a whole would have

been obvious at the time the invention was made to

a person having ordinary skill in the art to which

said subject matter pertains.” 35 U.S.C. § 103(a)

When this Court decided KSR, Int’l v. Teleflex, Inc.,

550 U.S. 398 (2007), it corrected the Federal

Circuit’s significant departure from the text of 35

U.S.C. §103, and restored the proper balance

between patentable “real innovation” and minor

manipulations of the prior art that are the product

of ordinary skill and common sense, which although

not identical to the prior art remain part of the

public domain because they are merely obvious

variants of the prior art. In so doing, this Court

rejected the Federal Circuit’s overly rigid and

formulaic obviousness test, which required finding

an explicit teaching, suggestion, or motivation

(“TSM test”), in the prior art before an invention

could be declared obvious.

The current language of 35 U.S.C. § 103 is not

materially different from the text applicable to the

patents in suit.

1

3

Unfortunately over the ensuing decade-and-a-half,

the Federal Circuit has again strayed from this

Court’s guidance and reverted to its old rigid ways,

except now it has made the motivation part of its old

test the arbiter of patentability.

Under the Federal Circuit’s current obviousness

test, and contrary to KSR, express prior art

teachings and suggestions to do what the patentee

did, which even under the Federal Circuit’s old TSM

standard would have resulted in a conclusion of

obviousness, now can be overcome by a supposed

lack of motivation to do what had already been

taught or suggested, or minor variations thereof,

which should have been accessible to all as part of

the public domain.

This case stems from respondent Eagle

Pharmaceuticals’ efforts to patent a reformulation of

an old cancer drug called bendamustine. 2 Eagle’s

liquid bendamustine formulation is marketed under

the tradename Bendeka®.

App, infra, at 4a.

Bendamustine is an old drug, developed in East

Germany in the 1960s, which has been used to treat

various cancers including Chronic Lymphocytic

Leukemia and Non-Hodgkin’s Lymphoma, which

are Bendeka®’s FDA-approved indications. App,

infra, at 3a-4a. Bendamustine was marketed in

Germany, before being introduced to the U.S.

market in the early 2000’s by Respondent Cephalon

as the drug Treanda®. App, infra, at 4a. Cephalon

Our statement is based entirely on the findings of

the district court contained in our appendix.

2

4

later was acquired by Respondent Teva. App, infra,

at 4a. Eagle reformulated Bendamustine so it could

be administered as a liquid rather than a lyophilized

or freeze-dried powder that must be reconstituted as

an injectable liquid before it can be administered to

patients. Id. As the district court observed: “Aware

that bendamustine’s toxicity made it potentially

dangerous for medical staff to reconstitute the drug,

Eagle began in 2009 to develop a liquid

bendamustine formulation that ultimately became

Bendeka®.” Id.

The patents and products at issue here are

concentrated liquid bendamustine formulations that

do not need to be reconstituted. App, infra, at 4a.

Because bendamustine was known to be unstable in

water, Eagle formulated its product using “polyols”

(a type of alcohol). App, infra, at 4a, 13a. Three

polyols are commonly used in liquid injectable

formulations - polyethylene glycol (PEG), propylene

glycol (PG) and glycerol. App, infra, at 18a. The

patented formulations use two of them: PEG and

PG. App, infra, at 18a-19a.

Prior art dating back to 1981 (Olthoff) already

taught how to make stable, liquid bendamustine

formulations using polyols, which overcame the

inconvenience

of

lyophilized

powders

and

bendamustine’s water instability. App, infra, at

14a, 18a-19a. As the district court observed, Olthoff

“claimed a stable, non-aqueous liquid injection

solution of between 25 and 100 mg/mL

bendamustine . . .” App, infra, at 14a. It added:

“Olthoff’s objective was to ‘produce a stable and

ready-to-use injection solution out of N[itrogen]-

5

mustard compounds, avoiding the Technical

solution of a dry ampoule [i.e., lyophilization].’”

App., infra, at 14a (internal citations omitted).

Indeed, “Olthoff specifically proposed dissolving

bendamustine in ‘polyols, particularly 1,2-propylene

glycol [i.e., PG].’” App., infra, at 14a (internal

citations omitted).

A patent for a second prior art liquid bendamustine

formulation (Drager), was applied for and patented

by Cephalon/Teva just prior to Eagle filing for its

patent. This formulation also disclosed polyolbased, non-aqueous liquid formulations, including

PEG and PG, at concentrations up to 90%. App.,

infra, at 19a-20a. All polyols include multiple

“hydroxyl” groups (-OH). App., infra, at 14a. PEG

is a relatively low-OH solvent. App., infra, at 20a.

According to Drager, the presence of these hydroxyl

groups caused an unwanted degradation reaction

called esterification to occur with bendamustine.

App., infra, at 15a. Drager found that improved

stability could be achieved by reducing the

concentration of -OH groups by including an

additional solvent called an aprotic solvent. App.,

infra, at 15a. Aprotic solvents do not include any

hydroxyl groups. App., infra, at 15a. Drager’s

preferred aprotic solvent was DMA. App., infra, at

20a. Drager also disclosed that antioxidants could

be included in its formulations. App., infra, at 24a25a, n.3.

Later, Eagle filed additional patent applications

directed to administering the concentrated liquid

formulations described in its now prior art

formulation patents (Palepu 2011), to patients in 10-

6

15 minutes as low volume (50-100ml) infusions. Two

prior art publications (Preiss 1985, 1998) already

had administered bendamustine to cancer patients

in 3-10 minute infusions or bolus injections. App.,

infra, at 33a-34a. “Preiss 1998 concluded that ‘only

mild toxicity occurred even at high doses (>

200mg/m2

b[endamustine]-hydrochloride

per

cycle).’” App., infra, at 34a.

As the district court observed: “It is undisputed

that a POSITA would have wanted to use a stable

and ready-to-use formulation as part of an improved

administration method.” App., infra, at 36a. In

particular, the district court observed that Eagle’s

prior art Palepu 2011 patent application

“established a motivation to use its formulations”

because it touted the advantages of its concentrated

formulations stating “that they have substantially

improved long term stability when compared to

currently available formulations,” and “are

advantageously ready to use or ready for further

dilution” and thus “[r]econstitution of lyophilized

powder is not required.” App., infra, at 36a. Thus:

“A POSITA [person having ordinary skill in the art]

also would have been motivated to combine Palepu

2011 with the Treanda® Label to come up with the

claimed doses and dosing schedule.” App., infra, at

36a. “Palepu 2011 instructed administering its

formulations in accordance with the Treanda®

dosing schedule.” App., infra, at 36a. “And the

Treanda® Label taught similar doses and the same

dosing schedules as those in the asserted

administration claims.” App., infra, at 36a.

7

Petitioners are generic pharmaceutical companies

that filed abbreviated new drug applications

(“ANDA”) with the FDA seeking approval to sell

generic bendamustine liquid dosage forms. App.,

infra, at 3a-6a. Respondent brought suit against

petitioners for infringement of thirteen patents and

over 250 claims, which Eagle obtained and Teva

licensed, pursuant to 35 U.S.C. § 271(e)(2). Id.

Jurisdiction was based on 28 U.S.C. § 1331 and

1338a.

The at-issue patents fall into two categories. The

formulation patents are directed to non-aqueous,

ready-to-dilute, liquid bendamustine concentrates

(25mg/ml-50mg/ml) that utilize a polyol-based

solvent system (Polyethylene glycol (95%-75%):

Propylene glycol (5%-25%)) and a “stabilizing

amount”

of

an

antioxidant,

including

monothioglycerol, and certain resulting impurity

levels. App., infra, at 12a.

The district court acknowledged that “[v]iewed in

isolation, Olthoff would have led a person having

ordinary skill in the art to use PEG and PG in a

liquid bendamustine formulation. Olthoff provided

a short, finite list of solvent options that included

PEG and PG. Specifically, Olthoff reported that

bendamustine is stable in monovalent alcohols and

polyols, and the disclosure of “polyols” would have

given an ordinarily skilled person just three polyol

options: PEG, PG, and glycerol.” App., infra, at 18a

(internal citations omitted). “By providing a finite

list, Olthoff would have made using PEG and PG

obvious to try because a [person having ordinary

skill in the art] would face only ‘a finite number of

8

identified, predictable solutions.’” App., infra, at 19a

(quoting KSR, 550 U.S. 398 at 421). Nevertheless,

the district court concluded that the Olthoff patent

application did not make the use of PEG and PG

obvious because the Drager application “teaches

away from Olthoff’s teaching of using polyols such as

PEG and PG” because “Drager determined that the

results described in [Olthoff] were not reproducible.”

App., infra at 19a (internal quotations and record

citations omitted). For this reason, the district court

ruled that there was insufficient proof that the “prior

art . . . would have motivated a [person having skill

in the art] to reach the claimed formulations”, and

held the claims unobvious. App., infra, at 29a.

The administration patents are directed to diluting

and infusing the concentrated liquid bendamustine

formulations of the formulation patents (which were

prior art to the administration patents) in

convenient 50-100ml bags over 10-15 minutes to

treat two types of cancer, chronic lymphocytic

leukemia (CLL) and non-Hodgkin’s lymphoma

(NHL), and certain resulting diluted concentrations,

utilizing the same dosing schedules established by

the prior art powder bendamustine formulations.

App., infra, at 12a, 36a-37a.

The district court found that an ordinarily skilled

person would have been motivated to use the

formulation described in the Palepu 2011 patent

application, and to administer it using the same

dosing schedule as was used in the prior art as

reflected in the Preiss references and the subsequent

Schoffski articles, which disclosed high doses of

bendamustine to cancer patients as infusions or

9

bolus injections in 3-10 minutes. App., infra, at 33a34a (“Preiss 1998 administered three-to-ten-minute

onetime infusions of bendamustine in doses ranging

from 54 to 226 mg/m2. . . . Preiss 1998 concluded that

‘only mild toxicity occurred even at high doses (>

200mg/m2 b-hydrochloride per cycle).’”). The district

court concluded that the Preiss studies “were not

designed to evaluate safety” and “did not provide

enough data points or information,” App., infra at

39a, subsequent studies by the Preiss researchers

recommended longer infusion times, App., infra at

41a-42a, and the Schoffski articles “did not compare

the overall incidence or severity of side effects in the

two infusion protocols.” App., infra at 41a. The

district court reached this conclusion despite

acknowledging that “in support of its request for

permission to test Bendeka®, Eagle submitted to the

FDA a Detailed Review of Literature that relied in

part on data from the Preiss and Schöffski

references.” App., infra at 44a-45a.

The court found no unexpected results, no teaching

away, no longfelt need, no failure of others and no

commercial success that bear on the obviousness of

what is claimed for either set of patents. App, infra,

at 28a-29a, 46a-50a.

REASONS FOR GRANTING THE WRIT

1. The district court’s ruling, summarily affirmed

by the court of appeals, represents a wholesale

rejection of the approach to patentability that this

Court adopted in KSR. As the district court

acknowledged, the precise formulation of liquid

bendamustine that respondents were able to patent,

10

as well as the same method for administering the

drug, had been disclosed in prior art. Olthoff had

come up with the formulation, and the Preiss

researchers had come up with the method of

administration. Yet, the district court concluded

that because Drager had criticized Olthoff and

developed what it characterized as an improved

formulation to that of Olthoff’s, and because more

data was necessary before the Preiss researchers’

conclusions could be accepted as conclusive,

respondents’ patents were valid.

A patent is awardable only for true innovation, not

for an option within the grasp of the ordinarily

skilled person that turned out to work as expected.

As this Court explained in KSR:

When there is a design need or market pressure

to solve a problem and there are a finite number

of identified, predictable solutions, a person of

ordinary skill has good reason to pursue the

known options within his or her technical grasp.

If this leads to the anticipated success, it is likely

the product not of innovation but of ordinary skill

and common sense. In that instance the fact that

a combination was obvious to try might show that

it was obvious under § 103.

550 U.S. at 421. That holding fits this case to a tee.

The district court found there was a compelling

need to develop a liquid formulation for

bendamustine to avoid the potential for toxicity

created when a powder must be reconstituted. The

prior art disclosed both a formulation that had, in

11

Olthoff’s study, proved successful, and a method for

administration that the Preiss researchers had

found, at a minimum, quite promising. It was

accordingly obvious to try the approaches reflected

in that prior art. One is not entitled to a patent

monopoly for trying what is obvious to try.

There is, moreover, no question of deference to the

district court’s finding, which we have accepted in

their entirety. That is because “[t]he ultimate

judgment of obviousness is a legal determination.”

KSR, 550 U.S. at 427.

2. Despite the clarity of the district court’s error,

the court of appeals summarily affirmed. That

result is distressing, but unsurprising given the

Federal Circuit’s longstanding resistance to a

faithful application of KSR.

In KSR, this Court explained the established fourfactor legal standard for assessing obviousness

harkening back to Graham v. John Deere, 383 U.S.

1, 17-18 (1966):

[T]he scope and content of the prior

art are . . . determined; differences

between the prior art and the claims at

issue are . . . ascertained; and the level

of ordinary skill in the pertinent art

resolved. Against this background, the

obviousness or nonobviousness of the

subject matter is determined. Such

secondary

considerations

as

commercial success, long felt but

unsolved needs, failure of others, etc.,

12

might be utilized to give light to the

circumstances surrounding the origin

of the subject matter sought to be

patented.”

While the sequence of these

questions might be reordered in any

particular case, the factors continue to

define the inquiry that controls.

550 U.S. at 406-07.

Despite this Court’s approach to obviousness, the

Federal Circuit seems to believe that if there is any

uncertainty about whether an obvious-to-try

approach will succeed, that potentially compromises

the motivation to try an obvious solution to a

pressing problem, and therefore produces patent

monopolies for what is obvious to try. Indeed, so

ingrained has the motive-to-try-what-is-likely-tosucceed test now become in the Federal Circuit’s

obviousness psyche, that the Federal Circuit now

sometimes includes motivation as a fifth Graham

factor:

“[O]bviousness is a question of law

based on underlying questions of fact,

including the level of ordinary skill in

the art, the scope and content of the

prior art, the differences between the

claims and the prior art, motivation to

modify or combine with a reasonable

expectation of success, and objective

indicia of nonobviousness.”

Accorda Therap. v. Roxane Labs., 903 F.3d 1310,

1328 (Fed. Cir. 2018) (emphasis added) (citing KSR,

13

among other authorities). Accord, e.g., Persion

Pharmaceuticals LLC v. Alvogen Malta Operations

Ltd., 945 F.3d 1184, 1189 (Fed. Cir. 2019)

(“Obviousness is a question of law with underlying

factual findings relating to the scope and content of

the prior art; differences between the prior art and

the claims at issue; the level of ordinary skill in the

pertinent art; the presence or absence of a

motivation to combine or modify with a reasonable

expectation of success; and any objective indicia of

non-obviousness.”).

In other cases, the Federal Circuit has dispensed

with discussing the Graham factors entirely, instead

jumping straight to its motivation analysis. In re

Stepan, 868 F.3d 1342, 1345-46 (Fed. Cir. 2017) (“An

obviousness determination requires finding both

‘that a skilled artisan would have been motivated to

combine the teachings of the prior art ... and that the

skilled artisan would have had a reasonable

expectation of success in doing so.’” (internal citation

omitted, quoting Intelligent Bio-Sys., Inc. v.

Illumina Cambridge Ltd., 821 F.3d 1359, 1367–68

(Fed. Cir. 2016)).

To be sure, when prior art powerfully suggests

that a particular invention is likely to fail, few are

likely to be motivated to invest their time and

resources in such an approach, which would, for that

reason, make the invention nonobvious should it

succeed, despite the apparent long odds as reflected

in prior art. This relationship between prior art and

motivation may constitute a helpful insight, but as

this Court observed in KSR as it repudiated the

Federal Circuit’s previous “‘teaching, suggestion, or

14

motivation’ test,”: “Helpful insights, however, need

not become rigid and mandatory formulas.” 550 U.S.

at 407, 419.

Using a known formulation for a known purpose,

pursuant to a known dosing schedule, with a

protocol taught and suggested by the prior art that

obtains an expected result is not patentable. KSR,

550 U.S. at 417. The district court plainly employed

its motivation test, never codified in any statute,

although it is utterly at odds with KSR, to disguise

the basic reality that anyone familiar with prior art

would have known that Olthoff had taught that

polyols could be used to make a stable liquid

bendamustine and that Preiss had found that

bendamustine could be administered to patients in

short, low volume infusions. Perhaps there was no

certainty that Olthoff and Preiss were correct, but it

was surely obvious to try to replicate their results.

As noted in KSR and Graham, so-called secondary

considerations of non-obviousness such as

unexpected results, longfelt need, failure of others or

commercial success can sometimes overcome a

prima facie showing of obviousness. But here, such

secondary considerations cannot remedy the district

court’s legal errors because the court found none.

App., infra, at 28a-29a, 46a-50a. The absence of

secondary considerations in a case where the court

finds there is a teaching-away is implausible and

likely unprecedented. If it were true that the prior

art taught away, then the absence of unexpected

results and the other secondary considerations of

nonobviousness cannot be explained.

15

3. The Federal Circuit’s summary affirmance is

troubling for another reason; it reflects a disturbing

pattern in that court. A number of commentators

have observed that the Federal Circuit has relied on

summary affirmance to a far greater extent than any

other court of appeals, and has done so in a manner

that often obscures dubious appellate outcomes.

See, e.g., Dennis D. Crouch, Wrongly Affirmed

Without Opinion, 52 Wake Forest L. Rev. 561 (2017);

Paul Gugliuzza & Mark Lemley, Can a Court

Change the Law by Saying Nothing?, 71 Vand. L.

Rev. 765 (2018).

4. The Federal Circuit’s campaign of resistance to

KSR has special significance in the area of

pharmaceutical patents, in which the regulatory

exclusivities

conferred

on

patent

holders

incentivizes such minor variations over the expense

and effort needed to develop truly new

pharmaceutical compounds and treatments. In

addition to a patent with its twenty-year exclusivity,

companies that file new drug applications also can

obtain certain regulatory exclusivities just by

tweaking an old formulation. Thus, drug companies

are highly motivated to make minor variations,

especially if they can attach a regulatory exclusivity

to it. For example, in this case, Eagle also obtained

an Orphan Drug Exclusivity and its associated

seven-year marketing exclusivity. See Eagle Pharm.

v. Azar, 952 F.3d 323, 342 (D.C. Cir. 2020) (Williams,

J, dissenting).

The Federal Circuit’s obviousness test rewards

what amounts to a lack of meaningful innovation by

granting exclusionary patent rights on top of the

16

regulatory exclusivities for minor variations on old

drugs or formulations patentable that are no better

than their processors and offer no additional

therapeutic benefit to patients, much less any

synergistic or unexpected benefit, simply because

scientifically and technically there is little incentive

to make such changes. Truly new drugs cost

hundreds of millions or even billions of dollars to

develop. See Sullivan, Thomas, “A Tough Road:

Cost to Develop One Drug is $2.6 billion; Approval

Rate For Drugs Entering Clinical Trials is Less

Than 12%,” POLICY AND MEDICINE (May 21, 2019). If

a drug company can get the same exclusionary

patent and regulatory benefit with an investment

that is orders of magnitude less, this disincentivizes

the types of true innovations needed to fight the next

generation of viruses and other maladies.

The Federal Circuit’s dramatic lowering of the

patentability bar also promotes the creation of

patent thickets, which require generic competitors

to navigate dozens of patents and hundreds of claims

all directed to such minor variations. The ability of

drug companies to obtain a dozen or more patents on

the same basic “invention” itself is a red flag

suggesting that there is something amiss in the

patent system. These patent thickets have been the

subject of recent Congressional hearings. E.g., A

Prescription for Change: Cracking Down on

Anticompetitive Conduct in Prescription Drug

Markets, Senate Subcommittee on Competition

Policy, Antitrust, and Consumer Rights (July 13,

2021).

17

Patent thickets have also been scrutinized by the

other chamber of Congress. After a nearly threeyear investigation into the pharmaceutical industry,

the Majority Staff of the House of Representatives

Committee on Oversight and Reform found that:

Secondary patents make up the majority of

the

pharmaceutical

industry’s

patent

portfolio – lengthening the monopoly periods

for lucrative drugs and suppressing generic

competition. The Committee’s investigation

has

shown

that,

in

many

cases,

pharmaceutical companies have obtained

secondary patents covering topics that are not

particularly innovative.

MAJORITY STAFF OF H.R. COMM. ON OVERSIGHT AND

REFORM,

117TH

CONG.,

DRUG

PRICING

INVESTIGATION MAJORITY STAFF REPORT 81 (2021),

https://oversight.house.gov/sites/democrats.oversigh

t.house.gov/files/DRUG%20PRICING%20REPORT

%20WITH%20APPENDIX%20v3.pdf.

The Majority Staff Report also observed that “[t]he

U.S. patent system’s allowance of weak patents

impedes innovation” and that “permissive patent

practices in the United States have incentivized

companies to devote resources to extending

monopolies on existing products.” Id. at 87.

One of the root causes that permit these patent

thickets to develop is the Federal Circuit’s

misapplication of the obviousness law, which

incentivizes this behavior by rewarding these minor

manipulations as if they were truly innovative new

18

drugs. The public suffers the consequences with a

host of “me-too” drugs and formulations that are no

better than their predecessors, rather than truly

innovative drugs with improved therapeutic

benefits. Robin Feldman, Why prescription drug

prices have skyrocketed, WASHINGTON POST (Nov. 26,

2018),

https://www.washingtonpost.com/outlook/2018/11/2

6/why-prescription-drug-prices-have-skyrocketed/

(“78 percent of the drugs associated with new

patents were not new drugs coming on the market

but existing ones. The cycle of innovation, reward,

then competition is being distorted into a system of

innovation, reward, then more reward.”); see also A

Prescription for Change: Cracking Down on

Anticompetitive Conduct in Prescription Drug

Markets: Hearing Before the Subcomm. on

Competition Policy, Antitrust, and Consumer Rights

of the S. Comm. on the Judiciary, 117th Cong. (2021)

(testimony of Rachel Moodie, Ph.D., Vice President,

Biosimilars Patents and Legal, Fresenius Kabi),

https://www.judiciary.senate.gov

/imo/media/doc/Testimony%20-%20July%2013%

202021_Rachel_Moodie.pdf (“Because of the misuse

of so-called “patent thickets” and rebates as

marketing tools, and the use of product hopping as

an additional tool used to prevent competition, the

U.S. branded pharmaceutical industry is not

currently operating in a true free market system

with downward pressure at the appropriate time.”).

Section 103 and this Court’s precedent reflected in

KSR and a host of prior cases, recognize that minor

tweaks to the prior art within the level of an

ordinarily skilled artisan, that result in something

19

that was no better than the prior art are not deemed

worthy of a patent because the differences between

what was claimed and the prior art were so minor

that they were obvious. However, under the Federal

Circuit’s current obviousness standard, minor

tweaks are rewarded to the same degree as the

discovery of a truly new drug compound so long as

the patentee can show that an ordinarily skilled

person would not have been sufficiently motivated to

make that minor change, even in the absence of

unexpected results or other secondary indicia of

nonobviousness.

As this Court has repeatedly made clear, and

contrary to the Federal Circuit’s current test,

assessing obviousness, the issue is not whether a an

ordinarily skilled person would have done what the

patentee did – but rather whether the differences

between what the patentee invented and the prior

art are substantial enough to merit a patent

monopoly.

We build and create by bringing to

the tangible and palpable reality

around us new works based on instinct,

simple logic, ordinary inferences,

extraordinary ideas, and sometimes

even genius. These advances, once part

of our shared knowledge, define a new

threshold from which innovation starts

once more. And as progress beginning

from higher levels of achievement is

expected in the normal course, the

results of ordinary innovation are not

the subject of exclusive rights under

20

the patent laws. Were it otherwise

patents might stifle, rather than

promote, the progress of useful arts.

See U.S. Const., Art. I, § 8, cl. 8.

550 U.S. at 427.

5. This case is a prime candidate for summary

reversal. Our submission does not ask this Court to

address a conflict in the circuits nor to resolve any

unsettled issue of patent law. Our submission is

instead that this Court should use its supervisory

power to direct the court of appeals to apply with

integrity KSR and its holding that what is obviousto-try and hence unpatentable.

21

CONCLUSION

The petition for a writ of certiorari should be

granted, and the judgment of the court of appeals

should be summarily reversed.

Respectfully submitted.

LAWRENCE ROSENTHAL

Of Counsel

One University Drive

Orange, California 92866

(714) 628-2650

STEVEN E. FELDMAN

Counsel of Record

DANIEL R. CHERRY

SHERRY L. ROLLO

HAHN LOESER & PARKS, LLP

200 W. Madison Street,

Suite 2700

Chicago, Illinois 60606

(312) 637-3000

Attorneys for Petitioners

APPENDIX

APPENDIX TABLE OF CONTENTS

Page

Appendix A, Opinion from the United

States District Court for the District of

Delaware .......................................................

1a

Appendix B, Judgment from the United

States Court of Appeals for the Federal

Circuit ...........................................................

62a

Appendix C, Judgment from the United

States Court of Appeal for the Federal

Circuit Denying Petition for Rehearing,

Rehearing En Banc ......................................

64a

1a

APPENDIX A

IN THE UNITED STATES DISTRICT COURT

FOR THE DISTRICT OF DELAWARE

[Filed April 27, 2020]

————

Civil Action No. 17-1154-CFC

CONSOLIDATED

————

CEPHALON, INC., et al.,

v.

Plaintiffs,

SLAYBACK PHARMA LIMITED LIABILITY CO., et al.,

Defendants.

————

John W. Shaw, Karen Keller, Nathan Hoeschen,

SHAW KELLER LLP, Wilmington, Delaware; David I.

Berl, Adam Harber, Elise Baumgarten, Shaun Mahaffy,

Ben Picozzi, Matthew Lachman, WILLIAMS &

CONNOLLY LLP, Washington, District of Columbia

Counsel for Plaintiffs

Eve Ormerod, Neal Belgam, SMITH, KATZENSTEIN,

& JENKINS LLP, Wilmington, Delaware; Beth

Finkelstein, Constance Huttner, Frank Rodriguez,

James Barabas, BUDD LARNER, P.C., Short Hills,

New Jersey

Counsel for Slayback Pharma Limited Liability

Company

2a

Jeremy Cole, Damien Tancredi, Jeffrey Cohen,

FLASTER GREENBURG, P.C., Wilmington, Delaware;

John Cravero, Sherry Rollo, Steven Feldman, HAHN

LOESER & PARKS LLP, Chicago, Illinois

Counsel for Apotex Inc.

Brian Farnan, Michael Farnan, FARNAN LLP,

Wilmington, Delaware; Arun Mohan, SCHIFF HARDIN

LLP, New York, New York; Helen Ji, Kevin Nelson,

Imron Aly, SCHIFF HARDIN LLP, Chicago, Illinois

Counsel for Fresenius Kabi USA, LLC

James Lennon, DEVLIN LAW FIRM LLC,

Wilmington, Delaware; David Steuer, Nicole Stafford,

Shyamkrishna Palaiyanur, WILSON SONSINI

GOODRICH & ROSATI, Austin, Texas; Rhyea Malik

WILSON SONSINI GOODRICH & ROSATI, San

Diego, California

Counsel for Mylan Laboratories Limited

————

OPINION

April 27, 2020

Wilmington, Delaware

/s/ Colm F. Connolly

COLM F. CONNOLLY

UNITED STATES DISTRICT JUDGE

3a

Plaintiffs Teva Pharmaceuticals International GmbH,

Cephalon, Inc., and Eagle Pharmaceuticals, Inc. have

sued Defendants Apotex Inc. and Apotex Corp.,

Fresenius Kabi USA, LLC, Mylan Laboratories Ltd.,

and Slayback Pharma LLC under the Hatch-Waxman

Act, 35 U.S.C. § 271(e)(2)(A). Defendants seek to bring

to market generic versions of Plaintiffs’ Bendeka®, a

drug indicated for the treatment of chronic lymphocytic leukemia (CLL) and indolent B-cell non-Hodgkin

lymphoma (NHL). D.I. 1 ¶¶ 1, 12.1 Plaintiffs allege

infringement of U.S. Patent Nos. 9,265,831 (the #831

patent), 9,572,797 (the #797 patent), 9,144,568 (the

#568 patent) and 9,597,399 (the #399 patent) by all

defendants and infringement of U.S. Patent No.

9,572,887 (the #887 patent) by Slayback. Defendants

have stipulated to infringement of the asserted claims

with two exceptions outlined below. Defendants argue

that all asserted claims of the asserted patents are

invalid.

I held a seven-day bench trial, and, as required by

Federal Rule of Civil Procedure 52(a)(1), I have set

forth separately below my findings of fact and

conclusions of law.

I. BACKGROUND

Plaintiffs sell Bendeka® under New Drug Application No. 208194. D.I. 1 ¶ 13. Eagle is the owner and

assignee of the asserted patents and has listed them

in connection with Bendeka® in the Orange Book

maintained by the Food and Drug Administration

(FDA). Teva Pharms. Intl GmbH v. Apotex Inc., No. 171164 (D. Del. 2017), D.I. 1 ¶¶ 27-3 5. Cephalon holds

1

All docket citations are to the docket for C.A. No. 17-1154

unless stated otherwise.

4a

an exclusive license to the asserted patents and has

assigned to Teva its rights under the license, including

the right to sue for infringement. Id., D.I. 1 ¶¶ 38-39.

Bendeka®’s active ingredient is bendamustine hydrochloride (referred to by the parties as bendamustine),

a nitrogen mustard chemotherapy drug that was first

developed in East Germany in the 1960s. D.I. 334 at

2; D.I. 364 ¶ 1.

In 2008, Cephalon launched the first U.S. bendamustine product, Treanda®. Tr. 403:18-22. Cephalon

initially sold Treanda® in a lyophilized, or freezedried, form. Tr. 404:7-11, 1357:13-19. Lyophilized

drugs must be reconstituted into an injectable liquid

before they can be administered to patients. Tr.

404:7-18, 405:8-06:4. Aware that bendamustine’s toxicity makes it potentially dangerous for medical staff

to reconstitute the drug, Eagle began in 2009 to

develop a liquid bendamustine formulation that ultimately became Bendeka®. Tr. 83:7-84:13, 86:3-19.

In November 2014, Cephalon launched its own liquid version of Treanda®. Tr. 981:25-82:2, 1657:10-11.

In 2015, Teva acquired Cephalon, Tr. 1660:10-14,

and Cephalon thereafter commercialized Bendeka®

as permitted by its exclusive license agreement with

Eagle, PTX-0408; Tr. 1660:10-24, 1795:4-9.

On December 7, 2015, the FDA approved Bendeka®,

D.I. 307-1 ¶152, and on January 27, 2016, Teva

launched Bendeka®, DTX-0500; Tr. 984:17-85:23,

1006:6-07:5. Bendeka® subsequently received orphan

drug exclusivity, a seven-year period during which

the FDA is precluded from approving any other manufacturer’s application to market the same drug to

treat the same rare disease. Eagle Pharm., Inc. v.

5a

Azar, 2018 WL 3838265, at *1 (D.D.C. June 8, 2018),

aff’d, 952 F.3d 323 (D.C. Cir. 2020); Tr. 1725:15-19.

In March of 2016, Teva stopped selling liquid

Treanda®. DTX-0500_0001; Tr. 1623:7-8.

In July and August of 2017, Defendants each filed

an Abbreviated New Drug Application (ANDA) with

Paragraph IV certifications under § 505(j) of the

Federal Food, Drug and Cosmetic Act to gain FDAapproval for the commercial manufacture, use, and

sale of a generic version of Bendeka®. E.g., D.I. 1 ¶ 15.

In August of 2017, Plaintiffs filed these suits alleging

that Defendants’ ANDA filings with Paragraph IV

certifications constituted acts of infringement. E.g.,

D.I. 1. These cases were consolidated for all purposes.

See December 13, 2017 Order.

At trial, Plaintiffs accused all Defendants other than

Slayback of infringing six formulation claims in two of

the asserted patents: claims 2, 3, and 5 of the #831

patent; and claims 9 and 11 of the #797 patent.

Plaintiffs also alleged infringement of six administration claims in four of the asserted patents: claims

11, 18, and 22 of the #568 patent and claim 15 of the

#399 patent (by all Defendants); claim 13 of the #399

patent (by Apotex only); and claim 13 of the #887

patent (by Slayback only). Defendants countered that

(1) the asserted formulation and administration

claims are invalid for obviousness under 35 U.S.C.

§ 103; (2) the asserted formulation claims are invalid

for indefiniteness under 35 U.S.C. § 112; (3) the

asserted formulation claims are invalid for lack of

enablement under 35 U.S.C. § 112; and (4) claim 9

of the #797 patent is invalid for lack of written

description. Defendants stipulated that they infringe

or induce infringement of each of the asserted claims

with two exceptions: Apotex, Fresenius Kabi, and

6a

Mylan argue that (1) their ANDA products do not

contain “a stabilizing amount of an antioxidant” as

the asserted formulation claims require; and (2) they

do not induce infringement of claim 9 of the #797

patent.

II. OBVIOUSNESS

A. Legal Standards for Obviousness

Under § 103 of the Patent Act, codified at 35 U.S.C.

§ 1 et seq., 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 [POSITA] to which said subject

matter pertains.” 35 U.S.C. § 103. As the Supreme

Court explained in the seminal case, Graham v. John

Deere Co., 383 U.S. 1 (1966), under § 103, “[a]n invention which has been made, and which is new in the

sense that the same thing has not been made before,

may still not be patentable if the difference between

the new thing and what was known before is not

considered sufficiently great to warrant a patent.” Id.

at 14. Section 103 ensures that “the results of ordinary

innovation are not the subject of exclusive rights

under the patent laws.” KSR Intern. Co. v. Teleflex

Inc., 550 U.S. 398, 427 (2007). “Were it otherwise

patents might stifle rather than promote, the progress

of useful arts.” Id. (citing U.S. Const. art. I, § 8, cl. 8).

The Court reaffirmed in KSR that the “framework”

set out in the following paragraph from Graham

governs the application of § 103, id. at 406:

While the ultimate question of patent validity

is one of law, the [§] 103 condition [of

patentability], . . . lends itself to several basic

7a

factual inquiries. Under [§] 103, the scope

and content of the prior art are to be determined; differences between the prior art and

the claims at issue are to be ascertained; and

the level of ordinary skill in the pertinent art

resolved. Against this background, the obviousness or nonobviousness of the subject matter is determined. Such secondary considerations as commercial success, long felt but

unsolved needs, failure of others, etc., might

be utilized to give light to the circumstances

surrounding the origin of the subject matter

sought to be patented. As indicia of obviousness or nonobviousness, these inquiries may

have relevancy.

Graham, 383 U.S. at 14-15 (citations omitted).

It is clear that under this framework, a district

court must consider in an obviousness inquiry the

three primary factors identified by the Court in

Graham: (1) the scope and content of the prior art, (2)

the differences between the prior art and the claims at

issue, and (3) the level of ordinary skill in the pertinent art. Less clear is the role, if any, secondary

considerations should play in the analysis.

The logical—some would say necessary—implication of the Court’s use of the word “secondary” in

Graham and its holding that the secondary considerations “might be utilized” and “may have relevancy”

is that a district court is permitted—but not required

in all cases—to examine such considerations in evaluating an obviousness-based invalidity challenge. The

Court seemed to confirm as much in KSR, when it

noted that “Graham set forth a broad inquiry and

invited courts, where appropriate, to look at any

8a

secondary considerations that would prove instructive.” KSR, 550 U.S. at 415 (emphasis added).

But a district court ignores Graham’s “invitation”

to examine secondary considerations at its peril.

One legal scholar, Harmon, has observed that under

Federal Circuit law “[w]e are able now safely to strike

the ‘may’ in the . . . sentence” in Graham in which

the Court stated that secondary “indicia of obviousness and nonobviousness . . . may have relevancy.”

Robert Harmon, Cynthia Homan, Laura Lydigsen,

Patents and the Federal Circuit 245 (13th ed. 2017).

Harmon correctly notes that “[t]he Federal Circuit

has emphatically and repeatedly held that objective

evidence of non-obviousness [i.e., the “secondary considerations” identified in Graham] must be taken into

account always and not just when the decisionmaker

is in doubt.” Id. In Stratoflex, Inc. v. Aeroquip Corp.,

713 F.2d 1530 (Fed. Cir. 1983), for example, the

Federal Circuit held that “evidence rising out of the

so-called ‘secondary considerations’ must always

when present be considered en route to a determination of obviousness.” Id. at 1538. And in In re

Cyclobenzaprine Hydrochloride Extended-Release

Capsule Patent Litigation, 676 F.3d 1063 (Fed. Cir.

2012), the Federal Circuit reaffirmed that holding, id.

at 1079, and went on to say that the Supreme Court in

Graham “did not relegate . . . to ‘secondary status’ the

“objective factors” the Supreme Court had explicitly

identified in Graham as “secondary considerations,”

id. at 1078.

It is true that less than a month after In re Cyclobenzaprine, a different Federal Circuit panel held in

Otsuka Pharmaceutical Co. v. Sandoz, Inc., 678 F.3d

1280 (Fed. Cir. 2012) that because it found that the

defendants had “failed to prove that [the challenged

9a

patent claim] would have been prima facie obvious

over the asserted prior art,” it “need not address” the

“objective evidence” of commercial success, long-felt

need, and the failure of others. Id. at 1296. But the

safer course for a district court faced with an obviousness challenge (and looking to avoid reversal by the

Federal Circuit) is to treat Graham’s “invitation” to

look at secondary considerations like a subpoena.

Obviousness is assessed based on the perspective of

a POSITA at the time of the invention. Unigene Labs.,

Inc. v. Apotex, Inc., 655 F.3d 1352, 1360 (Fed. Cir.

2011). The court therefore needs to guard against

“hindsight bias” that infers from the inventor’s success

in making the patented invention that the invention

was obvious. In re Cyclobenzaprine, 676 F.3d at 1079.

The ultimate question in the obviousness analysis is

“whether there was an apparent reason [for a

POSITA] to combine [at the time of the invention] the

known elements in the fashion claimed by the patent

at issue.” KSR, 550 U.S. at 418. “The analysis is

objective.” Id. at 406. Thus, a court must determine

whether a POSITA “would have had reason to combine

the teaching of the prior art references to achieve

the claimed invention, and . . . would have had a

reasonable expectation of success from doing so.” In re

Cyclobenzaprine, 676 F.3d at 1069.

The party challenging the patent’s validity bears

the burden of proving obviousness by clear and convincing evidence. Id. at 1068-69. In weighing the

Graham factors to decide whether the party has met

that burden, the district court must be guided by

common sense. Wyers v. Master Lock Co., 616 F.3d

1231, 1238 (Fed. Cir. 2010). Indeed, “the legal determination of obviousness may include recourse to

logic, judgment, and common sense, in lieu of expert

10a

testimony.” Id. at 1239. In KSR, the Supreme Court

warned lower courts to avoid “[r]igid preventative

rules that deny factfinders common sense” and to

employ instead “an expansive and flexible approach”

under the Graham framework. KSR, 550 U.S. at

415. Thus, the district court may “reorder[ ] in any

particular case” the “sequence” in which it considers

the Graham factors. Id. at 407. And although a court

should consider carefully the published prior art,

“[t]he obviousness analysis cannot be confined by . . .

overemphasis on the importance of published articles

and the explicit content of patents.” Id. at 419.

“[A]ny need or problem known in the field of

endeavor at the time of the invention and addressed

by the patent can provide a reason for combining the

elements in the manner claimed.” KSR, 550 U.S. at

420. And “[t]he combination of familiar elements

according to known methods is likely to be obvious

when it does no more than yield predictable results.”

Id. at 416. “[T]he fact that a combination was obvious

to try might show that it was obvious under § 103.” Id.

at 421. But a combination is obvious to try only

“[w]hen there is a design need or market pressure to

solve a problem and there are a finite number of

identified, predictable solutions” in the prior art at the

time of the invention. Id. And the court must also be

mindful that “when the prior art teaches away from

combing certain known elements, discovery of a successful means of combining them is more likely to be

nonobvious.” Id. at 416.

11a

B. Obviousness of the Asserted Formulation

Claims

1. Findings of Fact

a. The Priority Date

The parties agree that the date of invention (i.e., the

priority date) for the asserted formulation claims is

January 28, 2010. Tr. 403:4-6, 1352:16-21, 2015:3-16;

#831 patent at (60); #797 patent at (60).

b. Definition of the Relevant POSITA

The parties agree that a POSITA would have had

the skills, education, and expertise of a team of

individuals working together to formulate a liquid

injectable drug product. Such a team would have

included individuals with doctoral degrees in chemistry, biochemistry, pharmaceutics, pharmaceutical

sciences, chemical engineering, biochemical engineering or related fields, with at least two years of postgraduate experience in developing liquid injectable

drug products, or master’s or bachelor’s degrees in

similar fields of study, with a commensurate increase

in their years of postgraduate experience. Such a team

also would have been familiar with a variety of issues

relevant to developing liquid injectable drug formulations, including, among other things, solubility,

stability, pharmacokinetics, pharmacodynamics, and

other pharmaceutical characteristics. Such a team

also would have included persons with expertise in

analytical chemistry, including the detection and

measurement of chemical degradants. The team also

would have had access to an individual with a medical

degree with experience in treating patients with CLL

and NHL. PDX-4-2; Tr. 562:1-63:6, 1036:7-37:11,

1353:6-20, 2014:22-15:2.

12a

c. Content of the Asserted Formulation

Claims

The asserted formulation claims teach a non-aqueous

liquid composition that contains (1) bendamustine (or

a pharmaceutically acceptable salt thereof); (2) about

5% to about 10% by volume of the solvent propylene

glycol (PG); (3) the solvent polyethylene glycol (PEG);

(4) one of the following ratios of PEG to PG: about

95:5, about 90:10, about 85:15, about 80:20, and about

75:25; and (5) a stabilizing amount of an antioxidant.

#831 patent at claims 2, 3, 5; #797 patent at claims

9, 11. Two claims also specify components and quantities: (1) claim 11 of the #797 patent requires that

“the antioxidant is thioglycerol or monothioglycerol,”2

and (2) claim 5 of the #831 patent requires that “the

bendamustine concentration is from about 25 mg/mL

to about 50 mg/mL.” Certain claims also recite stability limitations such as “less than or equal to 0.11% PG

esters at about 1 month of storage at about 5°C.” #831

patent at claims 2, 3, 5; #797 patent at claims 9, 11.

d. Bendamustine, PEG, and PG

Bendamustine has two relevant functional groups

at opposing ends of its chemical structure: a nitrogen

mustard group and a carboxylic acid group. Tr. 422:2323:13,430:19-31:6,1038:5-7.

Nucleophiles—such as water, PG, and PEG degrade

bendamustine at its nitrogen mustard group through

reactions in which an aziridinium ring forms. Tr.

407:12-19,564:10-66:12,1038:13-21,1043:23-46:12,1381:

11-18; DTX-0073 at 4:33-37; PTX-1010 at TEVABEN

D00296748. Compounds like PEG and PG that have

2

Thioglycerol or monothioglycerol are used synonymously. Tr.

519:10-15.

13a

hydroxyl (OH) groups also degrade bendamustine at

its carboxylic acid group through a process called

esterification where the carboxylic acid group reacts

with the OH groups to form degradants called esters.

Tr. 431:4-13.

When PEG is combined with bendamustine, a process called PEG oxidation accelerates the esterification reaction. Tr. 484:15-85:11, 1416:11-18:12; PTX0669 at TEVABEND00294275; PTX-0623 at TEVA

BEND00289470. PEG thus causes more degradation

at bendamustine’s carboxylic acid group than the

same amount of PG would cause. Tr. 1054:5-59:11;

PTX-0999 at TEVAVEND00292131; PTX-0997 at

TEVABEND00291955.

Because water causes bendamustine to degrade at

its nitrogen mustard group, the prior art bendamustine formulations used a lyophilized (freeze-dried)

form of bendamustine that required a human operator

to reconstitute it using water shortly before administering it to a patient. DTX-0094_0010; Tr. 404:7-18,

405:8-06:4,408:17-09:1,410:4-5,1357:13-19. Reconstitution by human manipulation had two known disadvantages in 2010: it increased the risk of contamination, Tr. 406:16-20; and, because bendamustine is a

cytotoxic compound, it posed a potential danger to the

operator, Tr. 84:2-13, 406:23-07:3; DTX-0056_0001;

DTX-0056 at 2:33-67; DTX-0094 0011.

e. Content of the Prior Art

Defendants argue that five prior art references

would have motivated a POSITA to arrive at the

asserted formulation claims with a reasonable expectation of success: Olthoff, Drager, Alam, Rowe, and

Boylan. D.I. 378 at 31.

14a

1) Olthoff (DTX-0094)

Olthoff, a 1983 East German patent, claimed a

stable, non-aqueous liquid injection solution of

between 25 and 100 mg/mL bendamustine dissolved

in a solvent consisting of 100% PG. DTX-0094_0016;

Tr. 448:20-25. Olthoff’s objective was to “produce a

stable and ready-to-use injection solution out of

N[itrogen]-mustard compounds, avoiding the technical solution of a dry ampoule [i.e., lyophilization].”

DTX-0094_0012; Tr. 409:18-10:5. Olthoff disclosed

that bendamustine has “a[n] extraordinarily high

chemical stability for the production of injection

solutions in” monovalent alcohols, glycols and polyols.

DTX-0094 0012; Tr. 410:6-11:8. Olthoff specifically

proposed dissolving bendamustine in “polyols, particularly 1,2-propylene glycol [i.e., PG].” DTX0094_0014;

Tr. 412:6-14. Polyols are another name for compounds

that have multiple OH groups. Tr. 412:17-18, 413:1113. Both PEG and PG are polyols. Id.

Olthoff’s examples did not use an antioxidant. DTX0094_0013, 0015; Tr. 1457:5-12.

In the decades between Olthoff’s publication and the

priority date, its formulations were never used. DTX0073 at 2:19-29.

2) Drager (DTX-0073)

About 30 years after Olthoff was published, Drager,

a U.S. patent, issued in 2013. Tr. 434:6-20; D.I. 307-1

¶ 223. (Drager’s priority date is September 25, 2008

making it prior art to the asserted formulation claims.)

Like Olthoff, Drager described stable “liquid pharmaceutical formulations comprising bendamustine.”

DTX-0073 at 2:33-35, Abstract; Tr. 433:23-25. But

Drager determined that the “results described in

[Olthoff] were not reproducible.” DTX-0073 at 2:62-64.

15a

Drager’s data showed that bendamustine in 99% PG

degraded almost completely after eight weeks at

25°C and more than 20% at 5°C after one year. DTX0073 at Fig. 3; Tr. 1378:9-80:5. The reason for that

degradation, according to Drager, was that (1) PG

causes bendamustine to degrade at the nitrogen mustard group, DTX-0073 at 4:19-24, 4:33-37; Tr. 602:1315, and (2) PG’s OH groups cause bendamustine to

degrade at the carboxylic acid group through esterification, DTX-0073 at 5:12-14; Tr. 602:3-6.

As a solution to the degradation problem, Drager

disclosed the use of aprotic solvents, i.e., solvents

containing no OH groups, in a liquid bendamustine

formulation. DTX-0073 at 3:21-25; Tr. 581:19-82:12.

Drager showed that dissolving bendamustine in 100%

DMA, an aprotic solvent, results in no degradation of

bendamustine at the carboxylic acid group. DTX-0073

at Table II; Tr. 432:22-33:7,435:11-36:9.

Drager also taught that protic solvents—i.e., solvents, including PEG and PG, that have OH groups—

are acceptable to use with bendamustine but only

when combined with aprotic solvents. DTX-0073 at

3:3-10,3:36-48,4:18-24; Tr. 601:11-17. Drager showed

that the formulation containing 66% DMA and 34%

PG is stable. DTX-0073 at Table II; Tr. 436:16-37:15.

3) Alam (DTX-0056)

Alam, a U.S. Patent issued on November 7, 1989,

disclosed stable liquid formulations of cyclophosphamide, a compound that, like bendamustine, has a

nitrogen mustard group. DTX-0056 at Abstract, 1:5-8;

Tr. 422:3-9, 424:6-12. Alam tested cyclophosphamide’s

stability in mixtures of three polyols—PG, PEG and

glycerol—and found that the formulation containing

PEG and PG had “less degradation than the others.”

16a

Tr. 424:2-25:5,428:6-12,1421:18-24; DTX-0056 at

Tables 1-5. Alam disclosed using PG at a ratio of from

about 10% to about 90% and PEG at a ratio of from

about 90% to about 10%. DTX-0056 at 4:6-12; Tr.

425:6-14.

Bendamustine and cyclophosphamide have two structural differences that bear on how they degrade when

they are mixed with PEG and PG. First, because cyclophosphamide does not have a carboxylic acid group,

cyclophosphamide does not experience esterification,

i.e., it does not react with compounds such as PEG

and PG that have OH groups to form esters. Tr.

430:22-31:1, 1077:25-78:6. Second, in bendamustine,

the nitrogen mustard group is attached to a benzene

ring, while in cyclophosphamide, the group is attached

to a phosphoramide. Tr. 1075:4-25. Because it is

attached to a benzene ring in bendamustine, a POSITA

would have expected nucleophiles such as PEG and

PG to accelerate degradation at the nitrogen mustard

group via the formation of an unstable aziridinium

ring. Tr. 1037:19-41:16,1058:12-17,1060:2-9; PTX0376 at JDG_BENDA 00002265; PTX-1010 at

TEVABEND00296748. But in cyclophosphamide, the

phosphoramide deactivates the nitrogen mustard

group and cyclophosphamide consequently does not

degrade by forming the aziridinium ring in a liquid

formulation before administration. Tr. 1076:1-77:24;

PTX-0991 at TEVABEND00290978; PTX-0993 at

TEVABEND00291516.

Neither Alam nor Drager used an antioxidant in

their exemplary or preferred formulations. Tr. 1458:258:23.

17a

4) Rowe, Handbook of Pharmaceutical Excipients (DTX-0160)

Rowe’s Handbook of Pharmaceutical Excipients

disclosed that PEG is susceptible to oxidation and that

one can use an antioxidant to prevent such oxidation.

DTX-0160 0011; Tr. 486:7-24.

5) Boylan (DTX-0063)

Boylan disclosed a list of “some of the most commonly used antioxidants in pharmaceutical injectable

formulations” including monothioglycerol. DTX0063_0019, 0020; Tr. 487:12-18. Boylan also disclosed

usual concentrations for each of the listed antioxidants. DTX-0063 0020; Tr. 487:18-19. Monothioglycerol is FDA-approved. Tr. 340:20-23.

2. Conclusions of Law

I find that Defendants have not established by

clear and convincing evidence that a POSITA would

have had reason to combine the limitations recited in

the asserted patents’ formulation claims. Although

Defendants persuaded me that a POSITA would have

had reason to try to develop a non-aqueous liquid

bendamustine formulation, they failed to establish by

clear and convincing evidence that a POSITA would

have used in that formulation the PEG and PG

solvents, PEG:PG ratios, antioxidant, concentrations

of bendamustine, or PG ester stability limitations

recited in the asserted claims. I do not find Plaintiffs’

evidence of secondary considerations to establish

nonobviousness, but I find Defendants’ failure of proof

with respect to Graham’s primary factors in this case

to be dispositive and that therefore the formulation

claims are not invalid under § 103.

18a

a. Non-Aqueous Liquid Bendamustine

Formulation

Every asserted formulation claim requires a nonaqueous liquid formulation. Due to bendamustine’s

instability in water, the prior art used a lyophilized

form of bendamustine. Tr. 404:9-18, 1357:13-19. But,

as discussed above, lyophilization had known disadvantages. To avoid lyophilization while still avoiding

the use of water, a POSITA would have been motivated to create a non-aqueous liquid bendamustine

product. In fact, as can be seen in Olthoff and Drager,

other inventors sought to create non-aqueous liquid

bendamustine formulations before the priority date.

b. Use of PEG and PG

The claimed non-aqueous liquid bendamustine formulations contain the solvents PEG and PG. Defendants argue that Olthoff, Drager, and Alam would

have motivated a POSITA to use PEG and PG with

bendamustine. D.I. 378 at 13, 16.

1) Olthoff and Drager

Viewed in isolation, Olthoff would have led a

POSITA to use PEG and PG in a liquid bendamustine

formulation. D.I. 378 at 13; DTX-0094_0014; Tr. 412:318,413:4-13. Olthoff provided a short, finite list of

solvent options that included PEG and PG. Specifically, Olthoff reported that bendamustine is stable in

monovalent alcohols and polyols, DTX-0094_0012—

13; Tr. 410:6-11:8, 1084:13-86:11; and the disclosure

of “polyols” would have given a POSITA just three

polyol options: PEG, PG, and glycerol, Tr. 413:4-13.

Plaintiffs dispute that assertion, D.I. 371 at 20-23, but

Plaintiffs’ expert himself limited polyols to those

three options in a patent application that he submitted

in 2009, see DTX- 07640011 (“Preferably the water

19a

soluble plasticizer is selected from the group consisting of polyols (glycerin [i.e., glycerol], propylene

glycol, polyethylene glycols) . . . .”). His response when

confronted with that disclosure at trial was: “Yes,

but I didn’t — at that time I didn’t know that I would

be sitting here today.” Tr. 1575:2-76:1. Moreover,

while I agree with Plaintiffs that Olthoff would have

taught a POSITA also to consider monovalent alcohols, D.I. 371 at 21, Plaintiffs only list four monovalent

alcohols that a POSITA would have considered using

with bendamustine, D.I. 361 1173. Olthoff thus would

have left a POSITA with three polyols and four monovalent alcohols as options. By providing a finite list,

Olthoff would have made using PEG and PG obvious

to try because a POSITA would face only “a finite

number of identified, predictable solutions.” KSR, 550

U.S. 398 at 421.

Drager, however, teaches away from Olthoff’s

teaching of using polyols such as PEG and PG alone

with bendamustine. As noted, Drager determined that

the “results described in [Olthoff] were not reproducible.” DTX-0073 at 2:62-64, 3:1-2. And Drager’s data

showed that bendamustine in 99% PG degraded

almost completely after eight weeks at 25°C and more

than 20% at 5°C after one year. DTX-0073 at Fig. 3;

Tr. 1378:9-80:5. As Plaintiffs’ expert, Dr. Siepmann,

credibly testified, a POSITA would have considered

20% degradation after just one year at 5°C to be “not

good.” Tr. 1379:25-80:5.

Drager disclosed combining bendamustine with

aprotic solvents as a means of reducing such degradation. DTX-0073 at 3:3-10, 3:21-25; Tr. 581:19-82:12.

Drager also allowed for combining bendamustine with

a mixture of aprotic solvents and protic solvents,

including PEG and PG. DTX-0073 at 3:3-10, 3:36-48,

20a

4:18-24; Tr. 601:11-17. But Drager stated that the

concentration of protic solvents should be kept at

90%—and preferably lower—to limit degradation.

DTX-0073 at 3:49-4:25; Tr. 1393:3-22. Drager specifically showed that a formulation containing 66% DMA

and 34% PG is stable. DTX-0073 at Table II; Tr.

436:16-37:15.

Defendants assert that Drager taught the use of

aprotic solvents because they have no OH groups and

that, therefore, Drager would have motivated a

POSITA to use solvents with a low number of OHgroups. Tr. 431:20-23,437:8-15. They argue that

“[w]hile Drager claimed a formulation containing a

polar aprotic solvent (DMA) and a polar protic solvent

(PG), a POS[IT]A would be motivated to remove DMA

from the formulation because DMA has been known to

cause problems in formulations.” D.I. 379 If 65; D.I.

378 at 14-15. According to Defendants, because DMA

was the only aprotic solvent listed by Drager that is

“used in FDA products,” D.I. 378 at 15, a POSITA

would turn to protic solvents like PEG that have a

relatively low number of OH groups. D.I. 379 ¶ 67; D.I.

378 at 21.

Drager, however, teaches away from the use of only

protic solvents. Therefore, Drager would not have

motivated a POSITA to replace DMA with a low-OH

protic solvent. Defendants and their expert conceded

that neither Drager’s disclosures nor its examples

taught using exclusively protic solvents. Tr. 583:1—

83:10,1886:17-19. Instead, Drager taught the use of

an aprotic solvent with bendamustine to avoid

degradation by nucleophiles like PEG and PG.

Moreover, Drager disclosed numerous alternative

aprotic solvents that could potentially replace DMA.

DTX-0073 at 3:9-14; Tr. 1395:7-14. And DMA was not

21a

the only aprotic solvent in an FDA-approved product.

The prior art reference Strickley, for example, disclosed that the aprotic solvents NMP and DMSO had

been commercially used. PTX-0569 at JDG_BENDA

00003311-14; Tr. 1390:19-24.

A POSITA in 2010 reading Olthoff and Drager thus

would have found that Olthoff taught combining bendamustine with polyols including PEG and PG, but

that Drager taught away from using protic solvents,

such as PEG and PG, alone with bendamustine.

“Where the prior art contains apparently conflicting

teachings (i.e., where some references teach the combination and others teach away from it) each reference

must be considered for its power to suggest solutions

to an artisan of ordinary skill . . . consider[ing] the

degree to which one reference might accurately discredit another.” Medichem, S.A. v. Rolabo, S.L., 437

F.3d 1157, 1165 (Fed. Cir. 2006) (internal quotation

marks and citation omitted).

After considering the two references, I find that a

POSITA would have credited Drager’s data and conclusions over those in Olthoff. Drager expressly

asserted that the “results described in [Olthoff] were

not reproducible.” DTX-0073 at 2:62-64. And Drager

used high-performance liquid chromatography (HPLC)

to make its determinations while Olthoff used thinlayer-chromatography (TLC). Plaintiffs assert, and

Defendants do not dispute, that HPLC is more reliable than TLC because of its superior sensitivity and

ability to resolve impurities. Tr. 1074:4-75:3,1086:1720,1380:14-25,1511:5-11. Moreover, in the decades

between Olthoff’s publication in 1983 and the priority

date in 2010, Olthoff’s formulations were never used,

suggesting that POSITAs generally did not rely on

Olthoff. DTX-0073 at 2:19-29. “The elapsed time

22a

between [Olthoff] and the [asserted] patent’s filing

date evinces that the [asserted] patent’s claimed

invention was not obvious to try.” Leo Pharm. Prod.,

Ltd. v. Rea, 726 F.3d 1346, 1356 (Fed. Cir. 2013). Thus,

a POSITA looking at Olthoff and Drager would have

followed Drager’s teaching not to use protic solvents

such as PG and PEG alone with bendamustine.

2) Alam

Defendants also argue that Alam’s disclosure of

mixing cyclophosphamide with PEG and PG would

have motivated a POSITA to use those solvents with

bendamustine because both bendamustine and cyclophosphamide have nitrogen mustard groups. D.I.

378 at 16. But two structural differences between

cyclophosphamide and bendamustine that effect how

they degrade when they are combined with PEG and

PG would have discouraged a POSITA from relying

on Alam in formulating bendamustine. First, unlike

bendamustine, cyclophosphamide does not have a

carboxylic acid group and thus does not undergo an

esterification reaction when it is combined with PEG

or PG. Tr. 1077:25-78:6, 1421:1-5. Second, because the

nitrogen mustard group in bendamustine is attached

to a benzene ring, while in cyclophosphamide it is

attached to a phosphoramide, cyclophosphamide

degrades differently at the nitrogen mustard group

than bendamustine does. Tr. 1077:4-1077:24; PTX0991 at TEVABEND00290978; PTX-0993 at TEVA

BEND00291516. Defendants’ expert, Dr. Pinal, did

not point to any prior art references to support his

contrary conclusion that “the nitrogen group in the

two molecules are exactly the same.” Tr. 423:713,504:21-05:5.

I find therefore that a POSITA in 2010 would not

have viewed cyclophosphamide as a relevant compar-

23a

ator for bendamustine reactions, Tr. 1078:7-11, and

would not have considered Alam in formulating a

stable bendamustine formulation, Tr. 1420:10-21:5.

* * * *

In sum, Defendants have not proven by clear and

convincing evidence that Olthoff, Drager, and Alam

would have motivated a POSITA to use PEG and PG

to create a non-aqueous liquid bendamustine formulation. Although Olthoff taught using polyols such as

PEG and PG with bendamustine, Drager teaches

away from the use of protic solvents such as PEG

and PG alone with bendamustine and a POSITA

would credit Drager’s teaching over Olthoff’s. Moreover, a POSITA looking to solve the degradation

problem in bendamustine would not have considered

Alam in formulating a liquid bendamustine product

because Alam concerned a compound that degrades

differently than bendamustine when combined with

PEG and PG.

c. Use of Claimed PEG:PG Ratios

Every asserted formulation claim requires a

PEG:PG ratio that falls between 95:5 and 75:25.

Defendants argue that the claimed PEG:PG ratios

would have been obvious “in light of Alam’s express

disclosure of the entire range from 10:90 to 90:10.” D.I.

378 at 19-20. But as explained above, the prior art

would not have motivated a POSITA to use PEG and

PG in the first place. Also, even if a POSITA had

chosen to use PEG and PG, it would not have relied

on Alam because Alam concerned a compound that

degrades differently than bendamustine in reaction to

PEG and PG. Finally, the claimed formulations use

more PEG than PG whereas Alam preferred using

more PG than PEG, DTX-0056 at 4:6-12, and a

24a

POSITA in 2010 would have known that PEG would

cause more degradation at bendamustine’s nitrogen

mustard group than PG due to PEG oxidation. Tr.

1054:5-59:11; PTX-0999 at TEVAVEND00292131;

PTX-0997 at TEVABEND00291955. Thus, Alam did

not make obvious the PEG:PG ratios recited in the

asserted formulation claims.

d. Use of An Antioxidant

Every asserted claim requires an antioxidant and

one asserted claim requires that the antioxidant be

monothioglycerol. Assuming a POSITA had chosen to

use a 90% PEG and 10% PG bendamustine formulation, that POSITA would have been motivated to curb

PEG oxidation: a process in which PEG accelerates the

esterification reaction. Tr. 484:15-85:11, 1416:1118:12; PTX-0669 at TEVABEND00294275; PTX-0623

at TEVABEND00289470.

Defendants argue that Boylan and Rowe would

have motivated a POSITA to solve the oxidation

problem with an antioxidant. D.I. 378 at 22-23. They

assert that Rowe taught a POSITA to inhibit the

oxidation of PEG with the inclusion of a suitable

antioxidant and that Boylan taught using specific

antioxidants, including monothioglycerol. D.I. 378 at

23; Tr. 486:7-24, 488:7-9, 505:11-06:7, 543:2-5; DTX0160_0011; DTX-00630020. Defendants also note that

monothioglycerol is “very commonly used,” and is

FDA-approved for injectable products. D.I. 378 at 23.3

3

Defendants also assert that Drager taught “the use of antioxidants in the formulation.” D.I. 378 at 22. They did not,

however, request a finding of fact on this point and none of

Drager’s preferred or exemplary formulations contained an antioxidant. Drager mentioned that the invention may include other

25a

Other prior art references, however, teach away

from the use of antioxidants. See Tr. 1452:20-53:21;

Note for Guidance, European Agency for the Evaluation of Medicinal Products, PTX-0629 at TEVA

BEND00290713, TEVABEND00290720 (“Antioxidants

should only be included in a formulation if it has

been proven [t]hat their use cannot be avoided.”);

Pharmaceutical Preformulation and Formulation,

Interpharm, PTX-0391 at JDG_BENDA_00000415

(stating that antioxidant use “is now in decline” and

that “[a] preferred method of preventing oxidation

[over antioxidants] is simply to exclude oxygen”).

Moreover, none of the four approved injectable products in the prior art that contained PEG included an

antioxidant. Tr. 600:4-6, 1454:24-55:17; PTX-0722

(Ativan); PTX-0718 (Busulfex); PTX-0720 (Robaxin);

PTX-0569 at JDG_BENDA 00003308 (VePesid). In

addition, the liquid bendamustine examples in Defendants’ prior art references do not include antioxidants:

Olthoff’s liquid bendamustine formulation with PG

had no antioxidant, DTX-0094 at JDG BENDA

00002313; Tr. 1457:5-12, and neither Alam nor Drager

used an antioxidant in their exemplary formulations,

Tr. 1458:258:23. Accordingly, I find that Defendants

did not establish by clear and convincing evidence

that the combination of Boylan and Rowe would have

motivated a POSITA to use an antioxidant.

e. Use of the Claimed Bendamustine

Concentrations

Claim 5 of the #831 patent requires a bendamustine

concentration of “from about 25 mg/mL to about

50 mg/mL.” DTX-0006_0009. Defendants argue that

excipients such as an antioxidant, DTX-0073 at 7:1-18, claim 5,

but it did not encourage a POSITA to use an antioxidant.

26a

“[t]here was nothing special or unobvious about [that]

concentration range” in view of the Treanda® Label

and Olthoff. D.I. 378 at 25.

First, Defendants assert that the lyophilized

Treanda® Label would have motivated a POSITA to

use the claimed concentrations because a POSITA

would have multiplied the 120 mg/m2 dose for NHL

patients disclosed in the lyophilized Treanda® Label,

DTX-0848_0001, by the average body-surface-area of

a human, 2.0 m2, to get a 240 mg total dosage, D.I. 378

at 25-26. According to Defendants, the POSITA then

would have placed that dose in a common vial size of

either 5 mL or 10 mL to arrive at a concentration of

either 24 or 48 mg/mL. D.I. 378 at 26. Defendants,

however, offered no evidence establishing why a

POSITA would have combined a dosage for a lyophilized bendamustine formulation with a particular vial

size when making a liquid bendamustine formulation.

Second, Defendants argue that Olthoff would have

motivated a POSITA to reach the claimed concentration because “Olthoff disclosed and claimed [PG-only]

liquid bendamustine formulations containing ‘concentrations of 25 mg/m[L] to 100 mg/m[L],”‘ D.I. 378 at 25,

and Olthoff disclosed that bendamustine’s solubility in

PG was very high, 125 mg/mL, D.I. 378 at 26.

Defendants assert that “[w]hile the prior art did not

disclose bendamustine’s solubility in PEG, . . .

solubility is an inherent (i.e. intrinsic) property” that

can be discovered through routine testing, and given

the high 125 mg/mL solubility in PG, a POSITA

“would understand that by adding PEG to PG, the

solubility would drop from 125 to a lower value, and

that at ten percent PG and 90 percent PEG, it would

be possible to make a solution with a concentration

of 25 milligrams per milliliter.” D.I. 378 at 26-27.

27a

But as explained above, Defendants have not

established a motivation to use PEG and PG in the

first place. Thus, even assuming that a POSITA could

have found bendamustine’s solubility in PEG through

routine testing, Defendants did not establish by clear

and convincing evidence that a POSITA would have

been motivated to conduct such testing. As Plaintiffs

note, Defendants’ expert “testified only that the

POS[IT]A would have considered it ‘possible’ to

dissolve 25 mg/mL bendamustine in 90:10 PEG:PG at

room temperature, far short of establishing motivation” to use PEG. D.I. 371 at 43.

Moreover, Defendants fail to explain why a POSITA

would believe that bendamustine would have a lower

solubility in PEG and PG as opposed to in PG alone

based only on bendamustine’s high solubility in PG.

In choosing a concentration, a POSITA would have

required that the bendamustine concentration remain

below the formulation’s bendamustine solubility limit

so that the bendamustine would completely dissolve

and dangerous precipitation would not occur. Tr.

591:19-92:7, 593:23-94:4, 1434:13-35:9, 1435:10-25,

1472:12-14; PTX-0667 at TEVABEND00293319.

Because a POSITA would want to avoid such precipitation, it would likely not combine bendamustine

with a 90% PEG and 10% PG formulation based on

bendamustine’s solubility in PG alone.

f. PG Ester Stability Limitations

Finally, certain asserted formulation claims contain

a stability limitation, i.e., a maximum amount of

degradants called PG esters that the composition can

have after storage for a set time period at a set temperature. For example, claims 2, 3, and 5 of the #831

patent recite compositions having “less than or equal

28a

to 0.11% PG esters at about 1 month of storage at

about 5°C.” #831 patent at claims 2, 3, 5.

Defendants argue that the stability limitations are

an inherent property because at least one obvious

formulation in the asserted claims would naturally

result in the required PG ester levels. D.I. 378 at 27.

But “[t]o prove that a claim limitation is inherent in

the prior art, [the challenger] must show . . . [not only]

that the limitation at issue is necessarily present, or

the natural result of the combination of elements,” but

also that the combination of elements that naturally

result in the limitation is “explicitly disclosed by the

prior art.” Par Pharm., Inc. v. Twi Pharm., Inc., 120 F.

Supp. 3d 468, 473 (D. Md.), aff’d, 624 F. App’x 756

(Fed. Cir. 2015) (emphasis added) (internal quotation

marks omitted); see also D.I. 378 at 28 (“Once an

embodiment is shown to be obvious, any corresponding

data can be used to show that the stability property

is inherent.” (emphasis added)). Because I find that

the combination of elements that Defendants allege

inherently result in the stability limitations is not

obvious, such limitations are not obvious through

inherency.

g. Secondary Considerations

The parties adduced at trial evidence of only one

secondary consideration that bears on the formulation

claims—commercial success. D.I. 371 at 79-80.

Plaintiffs argue that “[s]ales of Bendeka® exceed $2

billion,” and that “Bendeka® halted the downward

trend in bendamustine sales, despite increasing competition.” D.I. 371 at 79. But such evidence does not

support a finding of nonobviousness. First, Bendeka®

sells at a lower price than the prior art lyophilized

Treanda® product. Tr. 1641:25-42:3, 1680:2-12,

1798:8-99:2. Second, Plaintiffs’ cluster of exclusivities

29a

has blocked others from entering the market.4 Tr.

1723:24-26:1, 1730:3-7. “Where market entry by

others was precluded . . . the inference of nonobviousness of the asserted claims, from evidence of commercial success, is weak.” Galderma Labs., L.P. v. Tolmar,

Inc., 737 F.3d 731, 740 (Fed. Cir. 2013) (internal

quotation marks, alterations, and citations omitted).

* * * *

Although the evidence of commercial success does

not support a finding of nonobviousness, I still find

that Defendants have not shown by clear and convincing evidence that the prior art they cited would

have motivated a POSITA to reach the claimed

formulations. As discussed above, a POSITA would

have credited Drager over Olthoff, and Drager teaches

away from the use of protic solvents such as PG and

PEG alone with bendamustine. Moreover, a POSITA

would not have relied on Alam in formulating

bendamustine. Finally, clear and convincing evidence

does not show that a POSITA would have relied on

Boylan and Rowe as motivation to use an antioxidant

because of the references that teach away from the use

of antioxidants in injectable formulations. And the

Treanda® Label and Olthoff would not have motivated

a POSITA to reach the claimed concentrations.

4

Cephalon had an exclusive license from Fujisawa to develop

bendamustine in the U.S. DTX-1230_0001, 0002, 0019; Tr.

1226:24-27:1, 1263:21-25, 1233:18-34:25. Also, in 2008, lyophilized Treanda® obtained seven years of orphan drug exclusivity

(ODE) and an additional six months of pediatric exclusivity. Tr.

1723:24-26:1. Bendeka® also received ODE. Eagle Pharm., 2018

WL 3838265, at *1. Thus, Bendeka® received seven years of

exclusivity that would prevent generics from entering the market

until 2022. Tr. 1723:24-26:1.

30a

C. Obviousness of the Asserted Administration

Claims

1. Findings of Fact

a. The Priority Date

The parties agree that the priority dates for the

asserted administrations claims are (1) March 20,

2012 for claim 22 of the #568 patent, and (2) July 10,

2012 for the remaining administration claims. D.I.

332; Tr. 2015:10-16.

b. Definition of the Relevant POSITA

The parties agree that a POSITA would have

had the skills, education, and expertise of a team of

individuals working together to develop a safe and

effective administration protocol for a cytotoxic parenteral5 drug product. Such a team would have

included individuals with doctoral degrees in pharmaceutics, pharmaceutical sciences, pharmacology,

pharmacokinetics, pharmacodynamics, or related

fields, with at least two years of post-graduate

experience in developing protocols for pharmaceutical

administration, or master’s or bachelor’s degrees in

similar fields of study, with a commensurate increase

in their years of post- graduate experience. Such a

team would have been familiar with a variety of

issues relevant to administering liquid injectable drug

products, including, among other things, toxicity,

solubility, pharmacokinetics, and pharmacodynamics.

Such a team would have included at least one

individual with a medical degree with experience in

5

In the pharmaceutical field, “parenteral” typically refers to

products that are administered by injection. Tr. 407:6-8.

31a

treating patients with CLL and NHL. PDX-2-4; Tr.

1112:4-20, 1293:22-94:9, 1233:1-17, 2014:22-15:2.

c. Content of the Asserted Administration Claims

The asserted administration claims recite methods

of treating CLL or NHL6 with a liquid bendamustine

composition. #568 patent at claims 11, 18, 22; #887

patent at claim 13. Certain claims require administering the bendamustine composition on days one and

two of a 21-day cycle for NHL, #568 patent at claim 18,

or on days one and two of a 28-day cycle for CLL,

#568 patent at claim 11. One claim requires a

bendamustine dose of “about 25 mg/m2 to about 120

mg/m2.” #887 patent at claim 13.

The asserted administration claims also specify

administration times, the longest time being “about 15

minutes or less.” See e.g., #568 patent at claim 22;

#887 patent at claim 13. They also specify administration volumes that are all 100 mL or less. See e.g.,

#399 patent at claim 13. Finally, certain claims specify

post- dilution bendamustine concentrations ranging

from 0.05 mg/mL to 12.5 mg/mL. See e.g., #568 patent

at claims 11, 18.

d. Content of the Prior Art

Defendants argue that eight prior art references

would have motivated a POSITA to combine the

elements of the claimed administration with a reasonable expectation of success: Palepu 2011, the

Treanda® Label, Preiss 1985, Preiss 1998, Schöffski

6

Two claims recite, more generally, a “method of treating

cancer or malignant disease.” #399 patent at claims 13, 15.

32a

2000a, Schöffski 2000b, Barth, and Glimelius.7 D.I.

378 at 53.

1) Palepu 2011 (DTX-0984)

Palepu 2011 is the published application that led

to the asserted formulation patents. Tr. 546:25-47:17.

The parties have stipulated that Palepu 2011 disclosed the formulations claimed in the asserted formulation and administration claims. D.I. 320 ¶6.

2) Treanda® Label (DTX-0993 and

DTX-1202)

The Treanda® Label, published in April 2009, D.I.

307-1 ¶ 247, disclosed two FDA-approved liquid

bendamustine composition dosing schedules: (1) for

CLL, intravenous (IV) infusion at a dose of 100 mg/m2

over 30 minutes on days one and two of a 28-day

cycle for up to six cycles, Tr. 648:3-9; DTX-0993_0001;

DTX-1202_001; and (2) for NHL, IV infusion at a dose

of 120 mg/m2 over 60 minutes on days one and two of

a 21-day cycle for up to eight cycles, DTX-09930001;

DTX- 1202001; Tr. 648:3-9.

The Treanda® Label required the administration of

Treanda® in a volume of 500 mL, Tr. 652:13-16; DTX1202_002, with a post-dilution bendamustine concentration of 0.2-0.6 mg/mL bendamustine, DTX0993_0002; DTX-1202_003; Tr. 652:21-23.

7

Defendants also cite Olthoff to argue that the asserted

administration claims were obvious, but the arguments regarding Olthoff were advanced only by Dr. Yates, an admitted nonformulator, and an expert that all Defendants but Apotex

rejected. Tr. 918:11-17, 920:19-22:13. Dr. Yates is a professional

witness with limited relevant experience who has testified

repeatedly for Apotex. Tr. 908:17-13:12. I did not find his testimony credible and do not rely on it.

33a

3) Preiss 1985 (DTX-0320; DTX-0985)

Preiss 1985 disclosed the results of a pharmacokinetic analysis of bendamustine. DTX-0320 0002; Tr.

658:25-59:2, 1119:18-20. A pharmacokinetic analysis

is a preliminary study in which a new drug is administered to a small number of patients to determine

the Cmax and area under the curve (AUC). The Cmax

is the peak concentration of the drug in the bloodstream; the AUC is the patient’s total exposure to the

drug. Tr. 659:3-15, 847:8-24, 1114:2-7, 1120:18-25.

Pharmacokinetic studies are not designed to assess a

drug’s safety. Tr. 724:7-12, 1120:8-25.

Preiss 1985 administered bendamustine intravenously for three minutes to seven patients with

various cancers. DTX-0320_0002; Tr. 659:23-60:2,

723:16-24:3. Preiss 1985 administered an average

total dose of 280 to 375 mg. Preiss 1985 reported “only

rather mild side effects” at those doses. DTX0320_0006; Tr. 664:6-20, 1123:9-22.

4) Preiss 1998 (DTX-0991)

Preiss 1998 investigated bendamustine’s clinical

pharmacology and defined bendamustine’s maximum

tolerated dose (MTD) and dose limiting toxicities

(DLT). DTX-0991_0002; Tr. 674:16-25. The MTD of

a drug is a tolerable dose without severe or lifethreatening toxicities; it differs from a recommended

dose for clinical use. Tr. 1126: 9-11. DLTs are severe

or life-threatening side effects. Tr. 674:23-75:1,

1126:12-23. Preiss 1998 administered bendamustine

to more than 50 patients with various cancers. DTX0991002. Preiss 1998 was not designed to evaluate

the safety of an infusion protocol. Tr. 730:22-31:1,

731:8-21.

34a

Preiss 1998 administered three-to-ten-minute onetime infusions of bendamustine in doses ranging from

54 to 226 mg/m2. It also administered three-to-tenminute infusions on four consecutive days in doses

ranging from 20 to 88 mg/m2. DTX-0987_005. Preiss

1998 concluded that “only mild toxicity occurred

even at high doses (> 200mg/m2 b-hydrochloride per

cycle).” DTX-0991_0004; Tr. 676:19-25. Preiss 1998

reported “disorientation” and a “vegetative neurotoxic

effect” after the one-time infusions of 175 mg/m2 and

215 mg/m2 doses. DTX-991_0004, 0005.

5) Schöffski 2000a (DTX-0987)

Schöffski 2000a administered bendamustine over

30 minutes and compared its results to the three-toten-minute infusions disclosed in Preiss 1998. DTX0987_0002,_0005; Tr. 678:4-14. Schöffski 2000a

reported that some side effects from its 30-minute

infusions were comparable to those observed with

the three-to-ten-minute infusions in Preiss 1998. DTX0987_0005,_0006; Tr. 678:10-79:5.

6) Schöffski 2000b (DTX-0988)

Schöffski 2000b administered 60 to 80 mg/m2 of

bendamustine in 30 minutes. DTX-0988 0001-03; Tr.

679:20-22. Schöffski 2000b observed side effects that

were comparable to those observed in Schöffski 2000a.

DTX-0988 0005. Schöffski 2000b’s authors did not

“observe confusion or other signs of neurotoxicity

when giving the drug as a repeated 30-min i.v.

infusion.” DTX-0988 0005.

7) Barth 2010 (DTX-1004)

Barth suggested administering bendamustine in a

solvent volume of 100 to 250 mL. DTX-1004 0005; Tr.

658:12-20, 681:21-83:8. Barth explained that

35a

[t]he 30-minute short infusion [of bendamustine] that is practiced in Germany can

be readily achieved with infusion volumes of

100 to 250 m[L] 0.9% NaCl.

It is unclear why the American prescribing

information specifies 500 m[L] 0.9% NaCl or

a final concentration of 0.2-0.6 mg/m[L] . . . .

A short infusion with such volume is difficult

to implement.

DTX-1004_0005; Tr. 682:9-83:2. Barth did not disclose

any study or data. DTX- 10040005; Tr. 1157:22-59:18.

8) Glimelius (DTX-0079)

Glimelius disclosed the administration of 5Fluorouracil to treat colorectal cancer as an infusion

lasting ten to 20 minutes using a 50 to 100 mL minibag. DTX-0079 0001, _0002. Mini-bags are small

standard size bags. Tr. 554:2-9.

2. Conclusions of Law

Defendants did not establish by clear and convincing evidence that a POSITA would have been motivated to combine the prior art references to arrive at

the claimed administrations with a reasonable expectation of success. Although the prior art would have

motivated a POSITA to reach the claimed formulation,

dose, and dosing schedule, and although Plaintiffs’

proffered secondary indicia of nonobviousness were of

little or no probative value, I find that the prior art

would not have motivated a POSITA to reach the

remaining claim limitations, and thus the claims as a

whole are not obvious.

36a

a. Formulation,

Schedule

Dose,

and

Dosing

The parties agree that Palepu 2011, the published

application that led to the asserted formulation

patents, disclosed before the priority date the formulations found in the asserted administration claims.

D.I. 320 If 6. But Plaintiffs argue that Defendants

have not shown that a POSITA would have been

motivated to select Palepu 2011’s formulations for

the administrations recited in the asserted claims.

D.I. 371 at 48. Palepu 2011 itself, however, established

a motivation to use its formulations: it touted

advantages of its disclosed formulations including

“that they have substantially improved long term

stability when compared to currently available formulations” and that they “are advantageously ready to

use or ready for further dilution” and thus “[r]econstitution of lyophilized powder is not required.” DTX0984_0002 at [0007]; Tr. 889:8-90:3. It is undisputed

that a POSITA would have wanted to use a stable and

ready-to-use formulation as part of an improved

administration method.

A POSITA also would have been motivated to

combine Palepu 2011 with the Treanda® Label to

come up with the claimed doses and dosing schedule.

Palepu 2011 instructed administering its formulations

in accordance with the Treanda® dosing schedule.

DTX-0984_0004 at [0044]; Tr. 856:8-9. And the

Treanda® Label taught similar doses and the same

dosing schedules as those in the asserted administration claims. DTX-09930001, DTX-12020001, Tr.

654:18-21, 695:10-20. The required dose found in the

claims is about 25 mg/m2 to about 120 mg/m2 and the

Treanda® Label requires doses of 100 mg/m2 or 120

mg/m2. #887 patent at claim 13; DTX-0993_0001;

37a

DTX-1202_0001. Also, the dosing schedule recited in

the claims is the same as the Treanda® Label’s

schedule: (1) for CLL, infusion on days one and two of

a 28-day cycle, #568 patent at claim 18; DTX-0993

0001; DTX-1202 001; Tr. 648:3-9; and (2) for NHL, IV

infusion on days one and two of a 21-day cycle, #568

patent at claim 11; DTX-09930001; DTX-1202 001; Tr.

648:3-9.

That said, the asserted administration claims

require administering each bendamustine dose in faster times, in lower volumes, and at higher post-dilution

concentrations than the Treanda® Label requires. The

question thus remains whether a POSITA would have

been motivated to reach the claimed administration

times, volumes, and concentrations.

b. Administration Times, Volumes, and

Post-Dilution Concentrations

All asserted claims require administering bendamustine in 15 minutes or less, with some requiring ten

minutes or less. All asserted claims also require

administering bendamustine in a volume of 100 mL or

less, with some claims requiring about 50 mL. Finally,

all but one of the asserted administration claims

require post-dilution bendamustine concentrations

ranging from 0.05 to 12.5 mg/mL.8

Defendants argue that the claimed administration

times were obvious under the Preiss and Schöffski

studies; that the claimed administration volumes are

obvious under the Preiss studies, Barth, and

8

Claim 13 of the #887 patent, the only claim asserted against

Slayback, does not have a concentration limitation. D.I. 362 at 3.

38a

Glimelius; and that the claimed post-dilution concentrations are obvious under the Preiss studies and

the Treanda® Label. Defendants also contend that

Eagle’s post-invention statements corroborate Defendants’ assertion that the Preiss studies would have

motivated a POSITA to use shorter administration

times, lower volumes, and higher concentrations.

9

1) The Preiss Studies

Defendants argue that the Preiss studies support a

finding that the claimed administration times,

volumes, and concentrations are obvious. First,

Defendants argue that a POSITA would have been

motivated to administer bendamustine in 15 minutes

or less because Preiss 1985 and Preiss 1998 disclosed

that administration of bendamustine in three-to-ten

minutes was well-tolerated in humans and Schöffski

2000a and 2000b disclosed that the safety results of

30-minute bendamustine administrations were consistent with Preiss’s three-to-ten-minute infusions.

D.I. 378 at 39-40. Second, Defendants assert that the

Preiss studies render the claimed volumes of 100 mL

or less obvious because, although the Preiss references

did not disclose a volume, a POSITA would have

known based on Preiss’s three-to-ten-minute time

constraint and typical infusion rates that the studies

infused similar volumes. D.I. 378 at 42. Third,

Defendants contend that Preiss rendered the claimed

concentrations of 0.05 to 12.5 mg/mL obvious because

9

Relying on the testimony of Dr. Yates, Defendants also cite

Olthoff to argue that the claimed volumes were obvious. D.I. 378

at 43. As noted above, I did not find Dr. Yates’s testimony to be

credible and will not rely on it. Moreover, Olthoff’s example

bendamustine formulation did not use PEG and, as explained

above, Drager discredited Olthoff’s data. DTX-0094_0015; Tr.

923:14-24.

39a

Preiss 1985 likely used a concentration of 5.6 mg/mL.

D.I. 378 at 46.

I find, however, that the Preiss studies would not

have motivated a POSITA to reach the claimed

administration times, volumes, or concentrations

because (1) a POSITA would not have relied on the

Preiss studies to determine a safe and effective infusion time, volume, or concentration for bendamustine,

(2) subsequent prior art taught away from Preiss’s

three-to-ten-minute infusions, and (3) Defendants

only hypothesize that the Preiss studies used volumes

and concentrations similar to those in the claimed

administrations.

a) A POSITA would not have relied

on the Preiss studies to determine a safe administration.

As an initial matter, Preiss 1985 and Preiss 1988

were not designed to evaluate safety, and thus a

POSITA would not have relied on the Preiss studies

to determine a safe infusion time, volume, or concentration. Tr. 724:7-12, 730:22-31:1, 731:8-21. Moreover, the Preiss studies did not provide enough data

points or information to allow a POSITA to rely on

them for safety information. Preiss 1985 tested only

seven patients with various cancers, DTX-320_0002;

Tr. 723:16-24:3, 1122:20-22; it did not discuss how it

collected side effect information, including the number

or timing of observations, the side effects being

observed, or a grading system, Tr. 724:14-28:16; and it

neither specified which of the seven patients in the

study had side effects nor distinguished between IV

and oral side effects, Tr. 728:8-20. A POSITA would

not have concluded that side effects would not be

present in a larger population, Tr. 1121:1-5, let alone

the relevant population, Tr. 1122:20-23:8, based on a

40a

study that covered only seven patients with various

cancers and offered no explanation of how the side

effects were studied or which patients experienced

the side effects. Preiss 1998 similarly tested patients

with various cancers, Tr. 1125:24-26:1, and it did not

disclose when the side effects it reported were

monitored or how many times side effect information

was collected from patients. Thus, a POSITA would

not have relied on either Preiss study to determine the

safety of a short bendamustine infusion. Tr. 1122:1419,1123:9-22.

In addition, the parties agree that the claimed

administrations require repeated cycles, D.I. 378 at

38; D.I. 371 at 59, but the Preiss studies did not

administer bendamustine in repeated cycles.10 And

according to Defendants’ expert, “bendamustine therapy side effects result from . . . the number of cycles

given” and “these side effects are typically more severe

in subsequent cycles because there are cumulative

effects on bone marrow.” Tr. 736:11-37:20. A POSITA

would therefore not have relied on the Preiss studies

to determine the safety of a short infusion of bendamustine administered in multiple cycles. Tr. 1133:711. Moreover, neither Preiss study administered bendamustine over two consecutive days as the claims

require. Tr. 1129:12-20.

The Schöffski articles also would not have motivated a POSITA to rely on the Preiss studies to

determine the safety of a short infusion time, lower

infusion volume, or higher infusion concentration.

10

Defendants cited no reference that administered bendamustine in ten minutes or less in repeated cycles. Tellingly,

Defendants’ references that did administer bendamustine in

repeated cycles all used 30-minute infusions. DTX-0987_0001;

DTX-0988_0001; DTX-1004_0002, _0005; DTX-0848; PTX-0268.

41a

Schöffski 2000a reported that it observed some side

effects like those in Preiss 1998, but did not compare

the overall incidence or severity of side effects in

the two infusion protocols. DTX 0987 0006,0007; Tr.

1138:21-39:19. Also, Schöffski 2000b stated that it

observed similar side effects to those observed in

Schöffski 2000a, not that it observed the same side

effects as Preiss. And Schöffski 2000b stated that it did

not “observe confusion or other signs of neurotoxicity

when giving the drug as a repeated 30-min i.v.

infusion,” DTX-0988_005, while Preiss 1998 reported

“disorientation” and a “vegetative neurotoxic effect,”

DTX-0991 at JDG BENDA 00006920-21.

b) Subsequent prior art taught

away from the Preiss infusions.

Subsequent prior art also would have dissuaded a

POSITA from relying on the Preiss studies. A POSITA

would not have stopped with Preiss 1985 and Preiss

1998; instead, it would have also considered later

prior art references that used 30 to 60 minute

infusions and a 500 mL volume. “Too often the

obviousness analysis is framed as an inquiry into

whether a person of skill, with two (and only two)

references sitting on the table in front of him, would

have been motivated to combine . . . the references in

a way that renders the claimed invention obvious. The

real question is whether that skilled artisan would

have plucked [those references] out of the sea of prior

art and combined [them].” WBIP, LLC v. Kohler Co.,

829 F.3d 1317, 1337 (Fed. Cir. 2016).

The Preiss researchers themselves conducted later

studies and recommended in subsequent papers an

infusion of at least 30 minutes in 500 mL. DTX09870001; DTX-0988 0001; PTX-0268; DTX-0982

0009; Tr. 1145:13-46:7. Preiss 2003—conducted by the

42a

same research group as Preiss 1985 and 1998—

reported administration over 30 minutes in repeated

cycles. PTX-0268; Tr. 1141:21-43:15. Moreover, the

Ribomustin Monograph—which set forth the prescription information for the German bendamustine product Ribomustin and was developed by a company

that employed scientists involved in the Preiss and

Schöffski studies—recommended a 30 to 60 minute

infusion in 500 mL because of local toxicity concerns.

DTX-0982009; Tr. 1143:17-44:13, 1144:14-45:5,

1146:8-54:4.

c) Defendants only hypothesize

that the Preiss studies used

the claimed volumes and

concentrations.

Finally, Defendants only hypothesize that the

Preiss studies used similar volumes and concentrations as those recited in the asserted claims. With

respect to volume, Defendants assert that although

the Preiss references did not disclose a volume,

“[b]ecause administration time and volume are

related,” a POSITA would have known based on

Preiss’s three-to-ten-minute time constraint and typical infusion rates that the studies infused small

volumes. D.I. 378 at 42 (citations omitted). With

respect to concentration, Defendants contend that

“Preiss 1985 administered bendamustine in a dose of

280-375 mg in a bolus, [i.e., a volume that the]

evidence showed likely meant 50 or 100 mL,” and

diluting 280 mg in 50 mL would result in a

concentration of 5.6 mg/mL. D.I. 378 at 46. Such

speculations about Preiss’s infusion rate and volume,

however, are only based on “conclusory and unsupported expert testimony” and they do not support a

finding of obviousness by clear and convincing evi-

43a

dence. See TQ Delta, LLC v. CISCO Sys., Inc., 942 F.3d

1352, 1361 (Fed. Cir. 2019) (“In cases like InTouch,

Active Video, and DSS, we rejected obviousness determinations based on conclusory and unsupported

expert testimony.”).

Defendants have thus failed to establish by clear

and convincing evidence that the Preiss studies

support a finding that the claimed infusion times,

volumes, and concentrations were obvious. “Whether

a skilled artisan would be motivated to make a combination includes whether he would select particular

references in order to combine their elements,” WBIP,

829 F.3d at 1337, and a POSITA in 2010 would not

have selected the Preiss studies to determine a safe

and effective infusion for a bendamustine formulation.

2) Barth and Glimelius

Defendants also argue that the administration

volumes are obvious under Barth and Glimelius.

They note that Barth recommended a 100 to 250 mL

bendamustine infusion, D.I. 378 at 43, and that a

“POS[IT]A would have known from Glimelius (DTX0079) that minibags, [standard infusion bag sizes of

50 or 100 mL], were typically used for infusions of 1020 min,” D.I. 378 at 44 (citations omitted).

Barth and Glimelius, however, would not have

motivated a POSITA to use the claimed volumes.

First, Barth did not disclose any study or data; it

only suggested hypothetical smaller volumes. DTX1004_0005; Tr. 1159:10-18. And Barth’s 100 to 250 mL

suggestion did not cover the claimed volumes (all

claims require 100 mL or less). DTX-1004_0005; Tr.

1159:3-16. Second, Glimelius did not disclose any

bendamustine administration, Tr. 841:3-42:22, and

the mere availability of a standard IV bag would not

44a

have given a POSITA motivation to use a bag that

size. IV bags of 50 mL were available before the

priority date, but had never been used to deliver

bendamustine. D.I. 371 at 58.

3) The Treanda® Label

Defendants also assert that the Treanda® Label

would have motivated a POSITA to use the claimed

post-dilution concentrations. They argue that the

claimed concentrations are obvious as inherent

because diluting the claimed doses disclosed in the

Treanda® Labe1 in the claimed volume of liquid

necessarily would have resulted in the claimed concentrations of bendamustine, PG, and PEG. D.I. 378

at 44. But because I find that the claimed volumes

are not obvious, it does not follow that the claimed

concentrations are obvious as inherent. Defendants

also state that “on the lower end of the spectrum, the

[claimed] concentration falls within the 0.2-0.6 mg/mL

concentration of the Treanda® Label.” D.I. 378 at 45.

But the Treanda® concentrations only cover a small

portion of the claimed range of 0.05 to 12.5 mg/mL and

thus they do not render the claimed concentrations

obvious.

4) Eagle’s Post-Invention Statements

Defendants further argue that, through postinvention statements, Plaintiffs admitted that the

prior art taught that short infusions in lower volumes

were safe and effective. Defendants point to the fact

that Eagle relied on the conclusions from the Preiss

studies when it told the FDA that its Bendeka®

protocol was safe. D.I. 378 at 51.

It is true that, in support of its request for permission to test Bendeka®, Eagle submitted to the FDA

45a

a Detailed Review of Literature that relied in part on

data from the Preiss and Schöffski references. DTX1041 0175. The literature review stated: “Thus, the

short duration infusion of bendamustine appears to be

well tolerated in this study and a dose of 215 milligrams has been reported in the literature as the

clinically tolerated dose for bolus administration of

bendamustine.” DTX-1041 0175. Later, Eagle made

similar statements to the FDA when drafting its

Investigator’s Brochure to support its requested study

that required administering the Bendeka® formulation in ten minutes. DTX-1061 at 14.

Eagle’s submissions to the FDA, however, also contained non-public, non-prior-art tests and analysis

Eagle had conducted to show those short-infusion

protocols were safe to test in humans. DTX1041_0025-26. And I find that Eagle’s post-invention

discussion of the prior art that is intermingled with

its own non-public data that it developed in inventing

the claimed administration does not show that a

POSITA who did not have Eagle’s non-public data

would have relied on the Preiss studies. Conclusions

drawn from a patentee’s “disclosures to the FDA” risk

being “distorted by hind-sight bias,” especially here

where the FDA submission was dated after the priority dates and thus was written “through the lens of

what [the inventor] had invented.” Neptune Generics,

LLC v. Eli Lilly & Co., 921 F.3d 1372, 1377 (Fed. Cir.

2019).

In sum, Defendants failed to prove by clear and

convincing evidence that a POSITA reading the Preiss

and Schöffski studies, Barth, Glimelius, and the

Treanda® Label would have found the claimed infusion times, volumes, and concentrations obvious.

46a

c. Secondary Considerations

Plaintiffs offered at trial evidence of four secondary

considerations that bear on the administration claims:

skepticism, long-felt need, commercial success, and

industry praise. I did not, however, find this evidence

to be probative indicia of nonobviousness for the

following reasons.

1) Skepticism

Plaintiffs argue that “industry participants” were

skeptical of the claimed invention. D.I. 371 at 77. But

the skepticism they cite was apparently held by a

“couple of nurses, a pharmacist[,] and an oncology

medical resident,” DTX0959_0001, and investors, D.I.

371 at 78. Such “lack of enthusiasm by a few is not

equivalent to skepticism.” BTG Intl Ltd. v. Amneal

Pharm. LLC, 923 F.3d 1063, 1076 (Fed. Cir. 2019).

Plaintiffs also contend that the FDA declined to

allow testing of Eagle’s IV push method of administration because of safety concerns. D.I. 371 at 78. But

the IV push method is not the claimed invention; the

invention is the ten-minute infusion and the FDA told

Eagle to proceed with its ten-minute infusion study.

PTX-0746 at EGL-BENDEKA 00146354; Tr. 1691:314; see also PTX-0747 at EGL-BENDEKA_001463 55

(“[Eagle] stated that they have decided not to evaluate

the IV push method administration. [Eagle] will use

120 mg/m2 over 10 minutes in their bridging study.”).

2) Long-Felt Need

Plaintiffs also argue that Bendeka®’s shorter infusion addressed a “long-felt need to reduce chair time

for chemotherapy, improving patient experience and

allowing more patients to be treated.” D.I. 371 at 79.

The parties offered competing expert testimony on this

47a

point. I found credible only Defendant’s expert, Dr.

Thirman, who testified that Bendeka® does not

meaningfully reduce chair time because patients

receive IV fluids and other drugs simultaneously

with the administration of Bendeka® and the administration of those fluids and other drugs lasts for

much longer than 15 minutes. Tr. 188:20-89:9, 189:2224, 1744:14-51:20,1745:20-46:6,1751:3-51:8,1765:1866:6,1779:11-18; DTX-09680001. For example, Bendamustine is frequently administered with a drug called

Rituxan that has an administration time of four to

eight hours. Tr. 190:24-91:6,191:2-6,713:14-22,1746:1117,1781:14-22.11

11

Plaintiffs’ expert, Dr. Agarwal, was not credible. He testified

that, based on his experience in a “community-based cancer

center,” Tr. 1288:19, there were “always issues with the chair

time” in the oncology field and that Bendeka® resolved the chair

time need, Tr. 1304:7-05:19. My assessment of his lack of credibility was informed by the logic and credible nature of Dr. Thirman’s

testimony and also by Dr. Agarwal’s dissembling with respect to

his billing practices (which might explain why he favored shorter

chair times). Dr. Agarwal initially denied having any idea how

his patients are billed for his work: “I mean, I’m not, I’m not the

biller and I don’t get paid by the amount I bill or anything . . . .

My only concern is the patient’s safety and that’s all I care

about . . . . I have no clue honestly about billing, billing procedures.” Tr. 1339:15-21. He volunteered that “billing, which is a

totally different department, I have no clue how they do it and I

don’t take a look at it. I don’t even know how to look at it.” Tr.

1340:15-17. And when asked how billing relates to infusion time,

Dr. Agarwal claimed to have “no idea how the billing codes work

with the infusion.” Tr. 1344:13-17. But when asked by the Court

if he was “paid by salary,” Dr. Agarwal responded: “So the way it

works is, what they [his practice group] wanted is eat what you

kill. Basically, if I see more patients, I get paid more. If I work

harder, I get more. If I work less, I get paid less.” Tr. 1345:7-11.

He then continued to explain the billing process in detail:

48a

3) Commercial Success

Plaintiffs further argue that Bendeka®’s commercial success is demonstrated by (1) the fact that

“Bendeka® halted the downward trend in bendamustine sales, despite increasing competition,” D.I.

371 at 79, and (2) “Teva’s choice to license Bendeka®

and pay Eagle a portion of the profit for each

Bendeka® sale, when it could keep all profits from

Treanda®,” D.I. 361 ¶ 222. But such evidence does not

support a finding of nonobviousness. Plaintiffs have

not provided evidence to establish that Bendeka®’s

sales and Teva’s decision to license Bendeka® were

linked to Bendeka®’s patented advantages as opposed

to Bendeka®’s exclusivities. See D.I. 371 at 80

So the way it works is, so we have like repeated billing

codes for repeated business, which are from level one

to level four, and that’s very small. You just mark what

billing code you want to put. These are being audited

by McKesson and auditors, that you are not — they

look at our notes. They decide if the doctor is overbilling or underbilling with the code. We have another

code for the new patient.

****

So they have like one to four levels of visit. Depending

on how much time I spend with a patient, either from

15 minutes to 30 minutes, I can go from a level one visit

to a level four visit and that’s what I mark on that. I

think it’s level one to level five. Level five is a very

complex visit where I spend an hour or more with a

patient, and most of the visits are about level three or

1evel four, but these patients that are going to see me,

I just bill level 3 or 4 and then I submit the payment

and that is taken care of by the billing and coding

department.

Tr. 1345:19-46:1, 1346:13-23. Also, when Dr. Agarwal was asked

if he was “familiar with a term called infusion billing,” he

responded “Yes.” Tr. 1338:2-4.

49a

(“Eagle’s patents expire shortly after Teva’s preexisting patents.”); Tr. 1725:25-26:2 (stating that with

the Bendeka® license, Teva has FDA exclusivity until

2022). Also, the “competition” that Plaintiffs cite consists only of Eagle’s Belrapzo®—a drug that shares

Bendeka®’s formulation, but lacks the short-infusion

protocol. D.I. 361 ¶ 219. Because Eagle benefits from

the sales of both Belrapzo® and Bendeka®, it may

have an incentive to market Bendeka® over Belrapzo®,

Tr. 1652:19-53:2, and thus any evidence that Bendeka®

has higher sales has little if any probative value.

4) Praise

Finally, Plaintiffs argue that “Bendeka®’s patented

advantages . . . have received industry praise.” D.I. 371

at 81. In support of this assertion, they cite (1) Veteran’s Administration (VA) newsletter that highlighted

the advantages of Bendeka® as compared to Treanda®,

(2) a study that noted attributes of Bendeka® that

drive Bendeka®’s usage, and (3) Fresenius Kabi’s prelitigation statement that Bendeka® reduced “[p]atient

chair time” and that Bendeka® could “have higher

pricing and still retain volume due to the benefits it

offers.” D.I. 371 at 81; D.I. 361 If 226. Here again, I

find such evidence to have at best marginal probative

value. As an initial matter, the VA does not even use

Bendeka®. Tr. 1777:1-78:16. Second, the study Plaintiffs cite was funded by Teva and provides no connection between the claimed limitations and industry

praise. Tr. 1305:25-07:4. Third, Fresenius Kabi’s

statement merely lists reduced chair time as a fact and

does not exhibit any praise related to the asserted

claims.

* * * *

50a

In sum, the secondary consideration evidence does

not support a finding of nonobviousness. I still find,

however, that the asserted administration claims are

not obvious. Defendants have not shown by clear and

convincing evidence that Palepu 2011, the Treanda®

Label, Preiss 1985, Preiss 1998, Schöffski 2000a,

Schöffski 2000b, Barth, and Glimelius would have

motivated a POSITA to arrive at the claimed administrations with a reasonable expectation of success. A

POSITA would not have been motivated to follow

Preiss’s three-to-ten-minute (and potentially lower

volume and higher concentration) infusions because

(1) a POSITA would not have relied on the Preiss

studies to determine a safe bendamustine infusion

protocol, (2) subsequent prior art taught away from

the three-to-ten-minute infusions, and (3) Defendants

only guess that Preiss used similar volumes and

concentrations to those claimed. Moreover, Barth and

Glimelius would not have motivated a POSITA to

administer bendamustine at lower volumes because

(1) Barth only disclosed hypothetical volumes that did

not even include the claimed volumes of 100 mL or less

and (2) Glimelius did not involve bendamustine.

Finally, the claimed concentrations are not obvious as

inherent or under the prior art.

III. INDEFINITENESS

Defendants argue that the asserted formulation

claims are invalid because they each require “a stabilizing amount of antioxidant”—a requirement Defendants contend is indefinite. D.I. 371 at 2.

A. Legal Standards for Indefiniteness

“[A] patent is invalid for indefiniteness if its claims,

read in light of the specification delineating the

patent, and the prosecution history, fail to inform,

51a

with reasonable certainty, those skilled in the art

about the scope of the invention.” Nautilus, Inc. v.

Biosig Instruments, Inc., 572 U.S. 898, 901 (2014).

“Indefiniteness is a matter of claim construction, and

the same principles that generally govern claim construction are applicable to determining whether allegedly indefinite claim language is subject to construction.” Praxair, Inc. v. ATMI, Inc., 543 F.3d 1306, 1319

(Fed. Cir. 2008), abrogated on other grounds by

Nautilus, 572 U.S. at 901 (rejecting Federal Circuit’s

“insolubly ambiguous” standard for indefiniteness). As

in claim construction, in making an indefiniteness

determination, the district court may make “any

factual findings about extrinsic evidence relevant to

the question, such as evidence about knowledge of

those skilled in the art.” See BASF Corp. v. Johnson

Matthey Inc., 875 F.3d 1360, 1365 (Fed. Cir. 2017).

“Any fact critical to a holding on indefiniteness . . .

must be proven by the challenger by clear and

convincing evidence.” Cox Commc’ns, Inc. v. Sprint

Commc’n Co. LP, 838 F.3d 1224, 1228 (Fed. Cir. 2016)

(alteration in original)).

B. Discussion

Defendants argue that “the claims recite a ‘stabilizing amount’ [of antioxidant] with no guidance,

functional or otherwise, on what degree of stability is

required to obtain some unnamed objective.” D.I. 380

at 3. But this argument conflates (1) whether a given

antioxidant

amount

improves

bendamustine’s

stability with (2) the extent to which that given antioxidant amount improves stability. The written

description defines a “stabilizing amount of antioxidant” as an amount that “increase[s] or enhance[s]

the stability of the bendamustine in the compositions

described herein,” #831 patent at 3:49-54; Tr. 370:25-

52a

71:9. Thus, the “objective” of the antioxidant amount

is not “unnamed” but is instead “to increase or

enhance the stability of the bendamustine in the

compositions” described in the specification.12

Defendants argue that the term is indefinite

because “[t]he specification does not explain how to

determine whether stability has been ‘increased’ or

‘enhanced.’” D.I. 378 at 3. But as Plaintiffs’ expert, Dr.

Siepmann, credibly testified, a POSITA would understand that a stabilizing amount of an antioxidant

includes any amount that decreases the amount of

bendamustine degradation after any time period and

at any temperature. Tr. 1485:4-87:10, 1502:8-12. And

the patents provide a POSITA with a method for

measuring stability: using HPLC to compare the

amount of overal1 bendamustine degradation with

and without the antioxidant. Tr. 1485:14-86:11. Example 3 demonstrates that a POSITA would compare

the amount of bendamustine remaining in the same

formulation, stored under the same conditions, with

and without the antioxidant, #831 patent at 7:59-8:27;

and the specifications describe measuring the remaining bendamustine using HPLC, id. at 2:26-44,2:573:4,4:22-26; Tr. 1487:11-89:11. In addition to providing

12

Section 112(b) of Title 35 provides that “[t]he specification

shall conclude with one or more claims[.]” This language makes

clear that the specification includes the claims asserted in the

patent, and the Federal Circuit has so held. See Markman, 52

F.3d at 979 (“Claims must be read in view of the specification, of

which they are part”). The Federal Circuit and other courts,

however, have also used “specification” on occasion to refer to

the written description of the patent as distinct from the claims.

See, e.g., id. (“To ascertain the meaning of claims, we consider

three sources: The claims, the specification, and the prosecution

history.”). To avoid confusion, I refer to the portions of the specification that are not claims as “the written description.”

53a

exemplary test methods, the specification also lists

“suitable antioxidant amounts” and “antioxidants,”

and provides examples of “stabilizing” amounts. #831

patent at 3:57-4:8, 7:59-9:2; Tr. 371:15-72:18, 1489:2390:4.

In BASF, the Federal Circuit held the term “composition . . . effective to catalyze” not indefinite, even

though the patent did not “recite a minimum level of

function needed to meet this ‘effective’ limitation” or

“a particular measurement method,” because tests for

determining whether a composition was catalyzing

were well-known. 875 F.3d at 1366-68. Here, the term

“stabilizing amount of antioxidant” is like the term

“composition . . . effective to catalyze” and Plaintiffs’

expert, like the expert in BASF, persuasively testified

that a POSITA would know how to determine whether

an amount of antioxidant is stabilizing. Moreover,

unlike in BASF, the asserted patents here provide a

test method.

Finally, Defendants cite the patentee’s removal of

antioxidant and stability limitations during prosecution as support for their indefiniteness argument. D.I.

378 at 5-6. But the removal of those limitations

undercuts Defendants’ argument because it confirms

that the “examiner understood” the claims without

those limitations. See Sonix Tech. Co. v. Publ’ns Intl,

Ltd., 844 F.3d 1370, 1379-80 (Fed. Cir. 2017).

I thus find that the term “stabilizing amount of antioxidant” is not indefinite and I construe it as: any

amount of an antioxidant that decreases the amount

of bendamustine degradation after any time period

and at any temperature.

54a

IV. ENABLEMENT

Defendants assert that the asserted formulation

claims are invalid for lack of enablement because

the formulation patents disclosed neither the use of

sodium hydroxide (NaOH) or of “other undisclosed

variables.” D.I. 378 at 59.

A. Legal Standards for Enablement

“Claims are not enabled when, at the effective filing

date of the patent, one of ordinary skill in the art

could not practice their ful1 scope without undue

experimentation.” Wyeth & Cordis Corp. v. Abbott

Labs., 720 F.3d 1380, 1384 (Fed. Cir. 2013) (citation

omitted). “That some experimentation is necessary

does not preclude enablement; the amount of experimentation, however, must not be unduly extensive.”

Atlas Powder Co. v. E.I. du Pont De Nemours & Co.,

750 F.2d 1569, 1576 (Fed. Cir. 1984) (citations

omitted). A challenger must prove invalidity based

on non-enablement by clear and convincing evidence.

MagSil Corp. v. Hitachi Glob. Storage Techs., Inc., 687

F.3d 1377, 1380 (Fed. Cir. 2012). Enablement is a

question of law based on underlying facts. Abbott

Labs., 720 F.3d at 1384 (citations omitted).

B. Discussion

Defendants argue that the asserted formulation

claims are not enabled because the claims do not contain NaOH and “a pH adjuster like NaOH is necessary

to obtain the PG ester levels claimed in the [a]sserted

[f]ormulation [c]laims.” D.I. 378 at 59. Defendants

note that “Eagle’s later-filed [#]879 application . . .

explains [that] ‘the control samples, which did not

include NaOH did not provide long term storage

stability,’ and ‘exhibited more than 28% total esters

55a

compared to initial after six months of storage at 25°

C.’” D.I. 378 at 60 (citation omitted).

Evidence that some claimed formulations did not

result in the PG ester limitations, however, does not

establish that the claims are not enabled. Defendants

have not presented any evidence to show that a

POSITA would have had to undertake undue experimentation to alter the formulation to obtain the PG

ester limitations. That some formulations with the

claimed ingredients do not satisfy the PG ester

limitations does not support non-enablement unless

the number of such formulations is significant enough

to have required a POSITA to experiment unduly. See

Atlas Powder, 750 F.2d at 1576-77 (“Even if some

of the claimed combinations were inoperative, the

claims are not necessarily invalid . . . . Of course, if the

number of inoperative combinations becomes significant, and in effect forces one of ordinary skill in the

art to experiment unduly in order to practice the

claimed invention, the claims might indeed be invalid.

That, however, has not been shown to be the case

here.” (citations omitted)). Defendants presented no

evidence showing that the number of unsuccessful

formulations is significant enough to require undue

experimentation. Accordingly, they failed to establish

by clear and convincing evidence that the asserted

claims are invalid for lack of enablement.

V. WRITTEN DESCRIPTION

Apotex argues that claim 9 of the #797 patent is

invalid for lack of written description. D.I. 378 at 60.

It asserts that “the absence of any mention of a pH

adjuster like NaOH in the [#]797 patent demonstrates

that the inventors did not have possession of it at

that time, as confirmed by their later filing of another

patent application that discloses and claims it.” D.I.

56a

378 at 61 (citations omitted). “But written description

is about whether the skilled reader of the patent

disclosure can recognize that what was claimed

corresponds to what was described . . . .” Alcon

Research Ltd. v. Barr Labs., Inc., 745 F.3d 1180, 1191

(Fed. Cir. 2014). And Apotex never cites the intrinsic

record to show that the asserted formulation patents

claim something that they do not describe in their

written descriptions. Instead, Apotex improperly cites

extrinsic evidence—the later-filed Eagle patent

application. Apotex has thus failed to establish that

claim 9 is invalid for lack of written description.

VI. INFRINGEMENT

Defendants stipulated to infringement of the

asserted claims with two exceptions. Apotex, Fresenius

Kabi, and Mylan argue that (1) they do not infringe

the asserted formulation claims because their ANDA

products do not contain “a stabilizing amount of an

antioxidant” as the asserted formulation claims

require, D.I. 369 at 2; and (2) they do not directly

infringe or induce infringement of claim 9 of the #797

patent, which requires that the “bendamustinecontaining composition ha[ve] less than or equal to

0.43 % total PG esters at about 3 months of storage at

a temperature of about 25°C,” because their proposed

labeling does not direct physicians to store their

ANDA products for about 3 months at about 25°C, D.I.

369 at 4-5.

A. Legal Standards for Infringement

A defendant is liable for patent infringement if it

files an ANDA “for a drug claimed in a patent or the

use of which is claimed in a patent.” 35 U.S.C.

§ 271(e)(2)(A). To establish infringement based on the

filing of an ANDA under § 271(e)(2)(A), a patentee

57a

must show that “if the drug were approved based

upon the ANDA, the manufacture, use, or sale of that

drug would infringe the patent in the conventional

sense.” Glaxo, Inc. v. Novopharm, Ltd., 110 F.3d 1562,

1569 (Fed. Cir. 1997).

“Conventional” infringement includes direct infringement and inducement. 35 U.S.C. § 271 (a), (b). Direct

infringement requires that “every limitation set forth

in a claim . . . be found in an accused product, exactly.”

Southwall Techs., Inc. v. Cardinal lG Co., 54 F.3d

1570, 1575 (Fed. Cir. 1995) (citation omitted). Inducement requires a showing “that the accused inducer

took an affirmative act to encourage infringement

with the knowledge that the induced acts constitute

patent infringement.” Microsoft Corp. v. Data Tern,

Inc., 755 F.3d 899, 904 (Fed. Cir. 2014) (citation

omitted). A plaintiff can prevail on a claim of inducement only if it establishes direct infringement. See

Limelight Networks, Inc. v. Akamai Techs., Inc., 572

U.S. 915, 921 (2014) (“[I]nducement liability may arise

if, but only if, there is direct infringement.” (internal

quotation marks, alterations, and citation omitted)).

A patentee must prove infringement by a preponderance of the evidence. Envirotech Corp. v. Al George,

Inc., 730 F.2d 753, 758 (Fed. Cir. 1984). “A patentee

may prove infringement by any method of analysis

that is probative of the fact of infringement, and

circumstantial evidence may be sufficient.” Martek

Biosciences Corp. v. Nutrinova, Inc., 579 F.3d 1363,

1372 (Fed. Cir. 2009) (internal quotation marks and

citations omitted).

58a

B. Direct Infringement of the “Stabilizing

Amount of Antioxidant” Limitation

The asserted formulation claims require a “stabilizing amount of an antioxidant,” a term that I construed

as any amount of an antioxidant that decreases the

amount of bendamustine degradation after any time

period and at any temperature.

Defendants’ ANDA products each contain 5 mg/mL

of the antioxidant monothioglycerol, see PTX-0474 at

APOLIQBENDA ANDA 0005427 (Apotex); PTX-0486

at FK_BENDA_00003243, 3245 (Fresenius Kabi);

PTX-0007 at MYLBEN 000248 (Mylan); Tr. 372:1974:13, and the formulation patents’ written description shows that 5 mg/mL of monothioglycerol is a

stabilizing amount. The written description identifies

“5 mg/mL to about 20 mg/mL” as a “preferable” stabilizing amount of antioxidant. #831 patent at 3:49-68;

#797 patent at 3:55-66. The written description also

identifies “thioglycerol (also known as monothioglycerol)” as a preferred antioxidant. #831 patent at 4:1-8;

#797 patent at 4:6-16. Moreover, Example 3 demonstrates that adding “5 mg/m[L] of lipoic acid . . . as a

stabilizing antioxidant” to 20 mg/mL of bendamustine

in PEG decreased the amount of bendamustine

degradation after 15 days at 25°C and 40°C as compared to the same formulation without an antioxidant.

#831 patent at 7:59-8:27; #797 patent at 7:61-8:29; Tr.

371:15-72:18. Example 4 recites dissolving 50 mg/mL

bendamustine in 90% PEG and 10% PG, and adding

“5 mg/m[L] of [mono]thioglycerol, a-lipoic acid or

dihydrolipoic acid,” an amount that it describes as “a

stabilizing amount of an antioxidant.” #831 patent at

8:29-65; #797 patent at 8:32-66.

Circumstantial evidence can establish infringement; and here, the asserted formulation patents’

59a

disclosures that 5 mg/mL of an antioxidant (and

specifically monothioglycerol) is stabilizing shows that

the 5 mg/mL of monothioglycerol that Defendants use

in their ANDA products decreases the amount of

bendamustine degradation as compared to the same

formulation without an antioxidant. Finally, Fresenius

Kabi and Mylan represented to the FDA that 5 mg/mL

monothioglycerol was sufficient to ensure that the

amount of bendamustine in their ANDA products did

not fall below specification limits. See PTX-0054 at FK

BENDA 00000543 (Fresenius Kabi); PTX-0201 at

MYL-BEN 005258 (Mylan); Tr. 374:14-77:1.

C. Direct and Induced Infringement of Claim 9

of the #797 Patent

Claim 1 of the #797 patent recites a “method of

treating leukemia, Hodgkin’s disease, or multiple

myeloma” comprising “administering” the specified

“liquid bendamustine-containing composition.” #797

patent at 12:43-46 (claim 1). Claim 9 recites the

method of claim 1, wherein the “bendamustinecontaining composition has less than or equal to 0.43%

total PG esters at about 3 months of storage at a

temperature of about 25° C.” #797 patent at claim 9.

Defendants stipulate that their ANDA Products have

“less than or equal to 0.43% total PG esters at about

3 months of storage at a temperature of about 25° C,”

but contend that they do not directly infringe or

induce infringement of claim 9 because their proposed

labeling does not recommend storing their ANDA

Products for “about 3 months” at “a temperature of

about 25° C.” D.I. 307-4 ¶ La; D.I. 320 ¶ 3.

I find, however, that even though Defendants’

labeling does not mention storage, Defendants’ ANDA

products directly and indirectly infringe claim 9

because the PG ester limitation does not require the

60a

user to store the products for three months at 25°C.

Claim 9’s PG ester limitation describes a characteristic of the claimed formula; it is not a method step and

thus, does not require action to infringe. The claim

does not recite testing for the PG ester limitation; it

just describes a composition that would have less than

0.43% PG esters if one were to test for them after

storing the composition for three months at 25°C.

Defendants’ proposal to construe the PG ester

limitation as a method step that requires actual storage under the specified conditions also fails because it

“renders [claim 9] nonsensical.” See Becton, Dickinson

& Co. v. Tyco Healthcare Grp., LP, 616 F.3d 1249, 1255

(Fed. Cir. 2010) (“A claim construction that renders

asserted claims facially nonsensical cannot be correct.”

(internal quotation marks and citations omitted)).

Although claim 1 of the #797 patent requires the

composition to have “less than or equal to 0.11% total

PG esters at about 1 month of storage at a temperature

of about 5° C,” claim 9 requires the same composition

to have “less than or equal to 0.43% total PG esters at

about 3 months of storage at a temperature of about

25° C.” #797 patent at 12:61-63 (claim 1), 13:22-25

(claim 9). Under Defendants’ proposed construction, to

infringe, the user would need to store the composition

simultaneously at different temperatures, which is

impossible.

Defendants therefore directly infringe and induce

infringement of claim 9 of the #797 patent. With

respect to direct infringement, Defendants agree that

their products have less than or equal to 0.43% total

PG esters after storing them for three months at a

temperature of about 25°C and, other than with

respect to a stabilizing amount of an antioxidant, they

stipulated to direct infringement of the remaining

61a

limitations. D.I. 320 ¶ 3. With respect to induced

infringement, Defendants will encourage others to

administer their ANDA products through their proposed labels. Although Defendants’ proposed labeling

does not mention the claimed PG ester limitations,

Defendants know “that [their ANDA products] meet

all of the claim limitations and, through [their] proposed label[s], encourage[] patients to administer

[their ANDA products] in a manner that infringes the

claimed method.” Orexigen Therapeutics, Inc. v.

Actavis Labs. FL, Inc., 282 F. Supp. 3d 793, 816 (D.

Del. 2017), rev’d in part on other grounds sub nom.

Nalpropion Pharm., Inc. v. Actavis Labs. FL, Inc., 934

F.3d 1334 (Fed. Cir. 2019). “Whether the [user] who

performs the method by administering the [products]

knows that the [products] meet the [PG ester limitations] is irrelevant for the purposes of infringement.”

Id.

VII. CONCLUSION

For the foregoing reasons, I find that all asserted

claims of the asserted patents are not invalid and that

Defendants infringe and induce infringement of each

of the asserted claims.

The parties will be directed to submit a proposed

order by which the Court may enter final judgment

consistent with this Opinion.

62a

APPENDIX B

NOTE: This disposition is nonprecedential.

UNITED STATES COURT OF APPEALS

FOR THE FEDERAL CIRCUIT

[Filed August 13, 2021]

————

2020-2134, 2020-2137

————

CEPHALON, INC., EAGLE PHARMACEUTICALS, INC.,

TEVA PHARMACEUTICALS INTERNATIONAL GMBH,

Plaintiffs-Appellees,

v.

SLAYBACK PHARMA LLC,

FRESENIUS KABI USA, LLC,

Defendants,

APOTEX INC., APOTEX CORP.,

MYLAN LABORATORIES LIMITED,

Defendants-Appellants.

————

Appeals from the United States District Court for the

District of Delaware in Nos. 1:17-cv-01154-CFC,

1:17-cv-01164-CFC, 1:17-cv-01201-CFC,

1:17-cv-01790-CFC, Judge Colm F. Connolly.

————

JUDGMENT

————

63a

DAVID I. BERL, Williams & Connolly LLP,

Washington, DC, argued for all plaintiffs-appellees.

Plaintiffs-appellees

Cephalon, Inc., Teva Pharmaceuticals International

GmbH also represented by ADAM HARBER, MATTHEW

LACHMAN, SHAUN PATRICK MAHAFFY, BEN PICOZZI.

DANIEL BROWN, Latham & Watkins LLP, New York,

NY, for plaintiff-appellee Eagle Pharmaceuticals, Inc.

Also represented by GABRIEL K. BELL, Washington,

DC; KENNETH G. SCHULER, MARC NATHAN ZUBICK,

Chicago, IL.

STEVEN ERIC FELDMAN, Hahn Loeser & Parks, LLP,

Chicago, IL, argued for defendants-appellants Apotex

Inc., Apotex Corp. Also represented by DANIEL RONALD

CHERRY, JOHN CRAVERO, SHERRY LEE ROLLO.

NICOLE W. STAFFORD, Wilson, Sonsini, Goodrich &

Rosati, Austin, TX, argued for defendant-appellant

Mylan Laboratories Limited. Also represented by

ADEN M. ALLEN; DENNIS DONALD GREGORY, New York,

NY; DAVID S. STEUER, Palo Alto, CA.

THIS CAUSE having been heard and considered, it is

ORDERED and ADJUDGED:

Per Curiam (Newman, Clevenger, and Taranto,

Circuit Judges).

AFFIRMED. See Fed. Cir. R. 36.

ENTERED BY ORDER OF THE COURT

August 13, 2021

Date

/s/ Peter R. Marksteiner

Peter R. Marksteiner

Clerk of Court

64a

APPENDIX C

NOTE: This order is nonprecedential.

UNITED STATES COURT OF APPEALS

FOR THE FEDERAL CIRCUIT

[Filed October 15, 2021]

————

2020-2134, 2020-2137

————

CEPHALON, INC., EAGLE PHARMACEUTICALS, INC.,

TEVA PHARMACEUTICALS INTERNATIONAL GMBH,

Plaintiffs-Appellees

v.

SLAYBACK PHARMA LLC,

FRESENIUS KABI USA, LLC,

Defendants

APOTEX INC., APOTEX CORP.,

MYLAN LABORATORIES LIMITED,

Defendants-Appellants

————

Appeals from the United States District Court for the

District of Delaware in Nos. 1:17-cv-01154-CFC,

1:17-cv-01164-CFC, 1:17-cv-01201-CFC,

1:17-cv-01790-CFC, Judge Colm F. Connolly.

————

ON PETITION FOR REHEARING EN BANC

————

65a

Before NEWMAN, LOURIE, CLEVENGER1, DYK, PROST,

O’MALLEY, REYNA, TARANTO, CHEN, HUGHES,

STOLL, and CUNNINGHAM, Circuit Judges*.

PER CURIAM.

ORDER

Apotex Inc., Apotex Corp., and Mylan Laboratories

Limited filed a petition for rehearing en banc. The

petition was first referred as a petition for rehearing

to the panel that heard the appeal, and thereafter

the petition for rehearing en banc was referred to

the circuit judges who are in regular active service.

Upon consideration thereof,

IT IS ORDERED THAT:

The petition for panel rehearing is denied.

The petition for rehearing en banc is denied.

The mandate of the court will issue on October 22,

2021.

FOR THE COURT

October 15, 2021

Date

/s/ Peter R. Marksteiner

Peter R. Marksteiner

Clerk of Court

1

Circuit Judge Clevenger participated only in the decision on

the petition for panel rehearing.

*

Chief Judge Moore did not participate.