Petition for Writ of Certiorari — Norwich Pharmaceuticals Inc., Petitioner v. Salix Pharmaceuticals, Ltd., et al.

No. 24In the

Supreme Court of the United States

NORWICH PHARMACEUTICALS INC.,

Petitioner,

v.

SALIX PHARMACEUTICALS, LTD., et al.,

Respondents.

On Petition for a Writ of Certiorari to the United

States Court of A ppeals for the Federal Circuit

PETITION FOR A WRIT OF CERTIORARI

Ian Swan

A xinn, Veltrop &

Harkrider LLP

1901 L Street NW

Washington, DC 20036

Thomas K. Hedemann

Counsel of Record

Matthew J. Becker

Matthew S. Murphy

A xinn, Veltrop &

Harkrider LLP

90 State House Square

Hartford, CT 06103

(860) 275-8100

thedemann@axinn.com

Counsel for Petitioner

332793

A

(800) 274-3321 • (800) 359-6859

i

QUESTION PRESENTED

Congress created the Hatch-Waxman Act with the

purpose of hastening the introduction of less-costly generic

drugs while safeguarding the legitimate patent rights of

innovator companies. The lower court’s interpretation

of 35 U.S.C. § 271(e)(4)(A) – the remedy provision in the

Hatch-Waxman Act – is contrary to this purpose because

it requires blanket injunctions on FDA approval of generic

drug applications that may be far broader in scope than

the underlying infringement finding. It is also contrary

to the general patent-law principle that injunctive relief

must be tailored to the infringement and avoid blocking

conduct not found infringing.

The question presented is:

Whether 35 U.S.C. § 271(e)(4)(A) requires courts to

issue injunctive orders that are broader in scope than the

underlying infringement, thereby delaying FDA approval

of generic drug applications for indications that have not

been found to infringe any valid patent.

ii

PARTIES TO THE PROCEEDING

Petitioner is Norwich Pharmaceuticals, Inc., the

defendant-cross-appellant in the court of appeals.

Respondents are Salix Pharmaceuticals, Ltd., Salix

Pharmaceuticals, Inc., Alfasigma S.p.A., and Bausch

Health Ireland Ltd., the plaintiffs-appellants in the court

of appeals.

iii

CORPORATE DISCLOSURE STATEMENT

Norwich Pharmaceuticals, Inc. is wholly owned by

Alvogen Pharma US, Inc. Alvogen Pharma US, Inc. is

wholly owned by Alvogen Group, Inc. Alvogen Group, Inc.

is wholly owned by Alvogen Holdings (Hungary) LLC.

Alvogen Holdings (Hungary) LLC is wholly owned by

Alvogen Pharma Ltd. Malta (which is wholly owned by

Alvogen Lux Holdings S.à.r.l.)

iv

RELATED PROCEEDINGS

Salix Pharms., Ltd. v. Norwich Pharms., Inc., No. 20-430,

U.S. District Court for the District of Delaware. Judgment

entered Aug. 10, 2022;

Salix Pharms., Ltd. v. Norwich Pharms., Inc., No. 222153, U.S. Court of Appeals for the Federal Circuit.

Judgment entered Apr. 11, 2024;

Salix Pharms., Ltd. v. Norwich Pharms., Inc., No. 231952, U.S. Court of Appeals for the Federal Circuit.

Judgment entered Apr. 11, 2024;

Norwich Pharms., Inc. v. Becerra, No. 23-1611, U.S.

District Court for the District of Columbia. Judgment

entered Nov. 1, 2023;

Norwich Pharms., Inc. v. Becerra, No. 23-5311, U.S.

Court of Appeals for the District of Columbia. Currently

held in abeyance.

v

TABLE OF CONTENTS

Page

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

PARTIES TO THE PROCEEDING . . . . . . . . . . . . . . . . ii

CORPORATE DISCLOSURE STATEMENT . . . . . . iii

RELATED PROCEEDINGS . . . . . . . . . . . . . . . . . . . . . iv

TABLE OF CONTENTS . . . . . . . . . . . . . . . . . . . . . . . . . v

TABLE OF APPENDICES . . . . . . . . . . . . . . . . . . . . . . vii

TABLE OF AUTHORITIES . . . . . . . . . . . . . . . . . . . . viii

PETITION FOR A WRIT OF CERTIORARI . . . . . . . 1

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

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

STATUTORY AND REGULATORY PROVISIONS

INVOLVED . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1

INTRODUCTION . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 5

STATEMENT OF THE CASE . . . . . . . . . . . . . . . . . . . . 6

A. Statutory Background . . . . . . . . . . . . . . . . . . . . . . 6

B. Proceedings Below . . . . . . . . . . . . . . . . . . . . . . . . . 9

REASONS FOR GRANTING THE PETITION . . . . 11

vi

Table of Contents

Page

I.

Certiorari Is Required to Prevent 271(e)

Orders From Delaying Approval of Generic

Drugs for Unpatented Indications . . . . . . . . . . . 12

A. The plain statutory language requires

courts to tailor 271(e) orders to the

underlying infringement . . . . . . . . . . . . . . . 12

B. 271(e) orders must be tailored to the

infringement to comport with rather

than undermine the purpose of the

Hatch-Waxman Act . . . . . . . . . . . . . . . . . . . 14

C. 271(e) orders must be tailored to

the infringement to avoid nullifying

FDA’s implementing regulation . . . . . . . . . 16

D. 271(e) orders must be tailored to the

infringement to comport with patent

law . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 17

II. The Cor rect Implementation of the

Remedy Provision in the Hatch-Waxman

Act Is Vital to the Act’s Purpose of

Incentivizing Generic Drugs and Containing

the Cost of Prescription Drugs . . . . . . . . . . . . . 18

III. This Case Is Well-Situated to Address the

Question Presented . . . . . . . . . . . . . . . . . . . . . . . 20

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

vii

TABLE OF APPENDICES

Page

A P P E N DI X A — O P I N ION O F T H E

UNITED STATES COURT OF APPEALS

FOR THE FEDERAL CIRCUIT, FILED

APRIL 11, 2024 . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1a

APPENDIX B — TRIAL OPINION OF THE

UNITED STATES DISTRICT COURT FOR

THE DISTRICT OF DELAWARE, FILED

AUGUST 10, 2022 . . . . . . . . . . . . . . . . . . . . . . . . . . . 34a

APPENDIX C — DENIAL OF REHEARING

OF THE UNITED STATES COURT OF

APPEALS FOR THE FEDERAL CIRCUIT,

FILED JUNE 13, 2024 . . . . . . . . . . . . . . . . . . . . . . 94a

A PPEN DI X D — S TAT U T E S A N D

PROVISIONS . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 96a

viii

TABLE OF CITED AUTHORITIES

Page

Federal Cases

In re Barr Lab’ys, Inc.,

930 F.2d 72 (D.C. Cir. 1991) . . . . . . . . . . . . . . . . . . . . 15

Caraco Pharm. Lab’ys, Ltd. v.

Novo Nordisk A/S,

566 U.S. 399 (2012) . . . . . . . . . . . . . . . . . . . . . . . 7, 8, 15

Duncan v. Walker,

533 U.S. 167 (2001) . . . . . . . . . . . . . . . . . . . . . . . . . . . 14

Durel Corp. v. Sylvania, Inc.,

No. 95-1750, 2000 WL 33687212

(D. Ariz. Apr. 13, 2000) . . . . . . . . . . . . . . . . . . . . . . . . 17

FDA v. Brown & Williamson Tobacco Corp.,

529 U.S. 120 (2000) . . . . . . . . . . . . . . . . . . . . . . . . 12, 13

Johns Hopkins University v. CellPro, Inc.,

152 F.3d 1342 (Fed. Cir. 1998) . . . . . . . . . . . . . . . . . . 17

Johnson v. United States,

529 U.S. 694 (2000) . . . . . . . . . . . . . . . . . . . . . . . . . . . 14

Joy Techs., Inc. v. Flakt, Inc.,

6 F.3d 770 (Fed. Cir. 1993) . . . . . . . . . . . . . . . . . . . . . 17

Teva Pharms. USA, Inc. v.

Novartis Pharms. Corp.,

482 F.3d 1330 (Fed. Cir. 2007) . . . . . . . . . . . . . . . . 6, 15

ix

Cited Authorities

Page

Warner-Lambert Co. v. Apotex Corp.,

316 F.3d 1348 (Fed. Cir. 2003) . . . . . . . . . . . . . . . . 6, 14

Federal Statutes

21 U.S.C. § 355(a) . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 6

21 U.S.C. § 355(b) . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 6, 7

21 U.S.C. § 355(j) . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2, 7, 8

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

35 U.S.C. § 271(e) . . . . . . . . . . . . . . . . . . . . . . 1, 7-17, 19, 20

35 U.S.C. § 283 . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 17

Regulations

21 C.F.R. § 314.53 . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 7

21 C.F.R. § 314.94(a) . . . . . . . . . . . . . . . . . . . . . . . 3, 7, 8, 16

21 C.F.R. § 314.107(b) . . . . . . . . . . . . . . . . . . . . . . . . . . 4, 16

Other Authorities

Comment of the Federal Trade Commission, FTC,

Docket No. PTO-P-2024-0003 (July 9, 2024) . . . . . . 19

1

PETITION FOR A WRIT OF CERTIORARI

Norwich Pharmaceuticals, Inc. respectfully petitions

for a writ of certiorari to review the decision of the United

States Court of Appeals for the Federal Circuit in this

case.

OPINIONS BELOW

The opinion of the Federal Circuit Court of Appeals

is reported at Salix Pharms., Ltd. v. Norwich Pharms.

Inc., 98 F.4th 1056 (Fed. Cir. 2024), and reproduced at Pet.

App. 1a-33a. The order denying rehearing or rehearing en

banc is unreported and reprinted at Pet. App. 94a-95a. The

district court’s opinion is reported at Salix Pharms., Ltd.

v. Norwich Pharms., Inc., No. 20-430, 2022 WL 3225381

(D. Del. Aug. 10, 2022), and reprinted at Pet. App. 34a-93a.

JURISDICTION

The court of appeals entered judgment on April

11, 2024 and denied a timely petition for rehearing or

rehearing en banc on June 13, 2024. Pet. App. 95a. This

Court has jurisdiction under 28 U.S.C. § 1254.

STATUTORY AND REGULATORY

PROVISIONS INVOLVED

35 U.S.C. § 271(e) provides in relevant parts:

(2) It shall be an act of infringement to submit –

(A) an application under section 505(j) of the

Federal Food, Drug, and Cosmetic Act . . . for

2

a drug claimed in a patent or the use of which

is claimed in a patent. . . .

***

(4) For an act of infringement described in paragraph (2) –

(A) the court shall order the effective date of

any approval of the drug . . . involved in the

infringement to be a date which is not earlier

than the date of the expiration of the patent

which has been infringed. . . .

21 U.S.C. § 355(j)(2) provides in relevant parts:

(A) An abbreviated application for a new drug shall

contain—

***

(vii) a certification, in the opinion of the

applicant and to the best of his knowledge, with

respect to each patent which claims the listed

drug referred to in clause (i) or which claims a

use for such listed drug for which the applicant

is seeking approval under this subsection and

for which information is required to be filed

under subsection (b) or (c)—

(I) That such patent information has

not been filed,

(II) That such patent has expired,

3

(III) Of the date on which such patent

will expire, or

(IV) That such patent is invalid or

w ill not be infr inged by the

manufacture, use, or sale of the

new drug for which the application

is submitted; and

(viii)

if with respect to the listed drug

referred to in clause (i) information was filed

under subsection (b) or (c) for a method of use

patent which does not claim a use for which

the applicant is seeking approval under this

subsection, a statement that the method of use

patent does not claim such a use.

The Secretar y may not require that an

abbreviated application contain information in

addition to that required by clauses (i) through

(viii).

21 C.F.R. § 314.94(a)(12)(viii) provides in relevant part:

(A) After Finding of Infringement. An applicant who has

submitted a paragraph IV certification and is sued

for patent infringement must submit an amendment

to change its certification if a court enters a final

decision from which no appeal has been or can be

taken, or signs and enters a settlement order or

consent decree in the action that includes a finding

that the patent is infringed, unless the final decision,

settlement order, or consent decree also finds the

patent to be invalid. In its amendment, the applicant

4

must certify under paragraph (a)(12)(i)(A)(3) of this

section that the patent will expire on a specific date

or, with respect to a patent claiming a method of use,

the applicant may instead provide a statement under

paragraph (a)(12)(iii) of this section if the applicant

amends its ANDA such that the applicant is no longer

seeking approval for a method of use claimed by the

patent. Once an amendment for the change has been

submitted, the ANDA will no longer be considered

to contain a paragraph IV certification to the patent.

If a final judgment finds the patent to be invalid and

infringed, an amended certification is not required.

21 C.F.R. § 314.107(b)(1) provides in relevant part

(ii) Immediately, if the applicant submits an appropriate

statement under § 314.50(i) or § 314.94(a)(12) explaining

that a method-of-use patent does not claim an indication

or other condition of use for which the applicant is seeking

approval, except that if the applicant also submits a

paragraph IV certification to the patent, then the 505(b)

(2) application or ANDA may be approved as provided in

paragraph (b)(1)(i)(C) of this section.

5

INTRODUCTION

This year marks the 40th anniversary of the landmark

Drug Price Competition and Patent Restoration Act

of 1984, commonly referred to as the Hatch-Waxman

Act. The Act’s purpose was to hasten the introduction

of inexpensive generic drugs while still ensuring that

innovator drug companies retain the profitability required

to bring new drugs to market. The Act has largely

delivered on this purpose, having paved the way for

generic drugs that have saved patients and the health care

system more than two trillion dollars in the past decade

alone. At the same time, the pharmaceutical industry has

maintained high profit margins and continues to introduce

new drugs.

The key to the Act’s success is its careful balance

between provisions that encourage generic entry and

provisions that protect innovator drugs. That balance

has now been distorted by the lower court’s incorrect

interpretation of the remedy provision that sits at the

heart of the Act. Under that statutory interpretation,

courts are required to issue orders that broadly prohibit

FDA from approving a proposed generic product for any

indication even when the underlying infringement finding

is limited to a method-of-use patent that covers only one

of multiple approved indications. Such broad injunctive

orders are contrary to Congress’ intended balance

because the Act explicitly permits approval of generic

drugs that seek approval for unpatented indications. They

are also contrary to the basic principle of patent law that

injunctions must be tailored to the infringement so that

they do not bar products and activities that have not been

found infringing. Congress could not have intended for

6

the remedy provision in the Hatch-Waxman Act to have

a broader injunctive scope than permitted by ordinary

patent law. Indeed, no public interest is served by granting

brand companies a monopoly on marketing drugs for

unpatented indications.

This Court’s intervention is required to correct the

lower court’s interpretation of the Act and thereby restore

the balance that Congress put in place and that is vital to

the Act’s proper functioning.

STATEMENT OF THE CASE

A. Statutory Background

The Federal Food Drug & Cosmetic Act (“FDCA”)

establishes the requirements for marketing drugs in the

United States. In 1984, Congress amended the FDCA with

the Hatch-Waxman Act, a central purpose of which is “to

enable competitors to bring cheaper, generic . . . drugs to

market as quickly as possible.” Teva Pharms. USA, Inc.

v. Novartis Pharms. Corp., 482 F.3d 1330, 1344 (Fed. Cir.

2007) (quoting 149 Cong. Rec. S15885 (Nov. 25, 2003)).

Before marketing a new drug, a drug company must

submit a New Drug Application (“NDA”) to FDA, and

FDA must approve it. See 21 U.S.C. § 355(a), (b). “FDA

does not grant across-the-board approval to market a drug

[but rather] to make, use, and sell a drug for a specific

purpose for which that drug has been demonstrated to

be safe and efficacious.” Warner-Lambert Co. v. Apotex

Corp., 316 F.3d 1348, 1356 (Fed. Cir. 2003).

7

“To facilitate the approval of generic drugs as soon as

patents allow, the Hatch–Waxman Amendments and FDA

regulations direct brand manufacturers to file information

about their patents.” Caraco Pharm. Lab’ys, Ltd. v. Novo

Nordisk A/S, 566 U.S. 399, 405 (2012). Specifically, the

NDA applicant must identify each patent that claims

the drug or a method of using the drug. See 21 U.S.C.

§ 355(b)(1)(A)(viii); 21 C.F.R. § 314.53. With respect to

method-of-use patents, the applicant submits “use codes”

that describe the use or indication covered by the patent.

Upon approval of the NDA, FDA publishes the patent

information in a publication known as the “Orange Book.”

See 21 U.S.C. § 355(b)(1)(A)(viii); 21 C.F.R. § 314.53(e).

Pursuant to the Hatch-Waxman Act, generic drug

applicants can submit an Abbreviated New Drug

Application (“ANDA”) that relies on the safety and efficacy

data for the approved brand drug (i.e., the reference-listed

drug, or “RLD”). An ANDA applicant must submit one

of four patent certifications for each patent listed in the

Orange Book for the RLD. The pertinent certification here

is the so-called “Paragraph IV certification,” which states

that the patent is invalid, unenforceable, or will not be

infringed by the manufacture, use, or sale of the generic

drug. See 21 C.F.R. § 314.94(a)(12)(i)(A)(4)(i).

The Hatch-Waxman Act made the submission of

an ANDA with a Paragraph IV certification an act of

infringement, see 35 U.S.C. § 271(e)(2)(A), and further

provided a 30-month stay of FDA’s ability to approve the

ANDA if the patent owner files an infringement suit. See

21 U.S.C. § 355(j)(2)(B)(iii), 355(j)(5)(B)(iii). If a court finds

that the ANDA submission infringes the patent, the Act

requires the court to order that FDA may not approve

8

“the drug . . . involved in the infringement” before the

patent’s expiration (a “Section 271(e) order”). 35 U.S.C.

§ 271(e)(4)(A).

There is one exception to the patent certifications.

As discussed, FDA may approve drugs for more than one

indication. To avoid delaying the introduction of generic

drugs for unpatented indications, the Act permits generic

applicants to submit a “section viii statement” rather than

a patent certification, which declares that the ANDA is

not seeking approval for a patented indication. 21 U.S.C.

§ 355(j)(2)(A)(viii). FDA may then approve the ANDA

product for only the unpatented indication(s). See Caraco,

566 U.S. at 415 (“The Hatch-Waxman Amendments

authorize the FDA to approve the marketing of a generic

drug for particular unpatented uses; and section viii

provides the mechanism for a generic company to identify

those uses, so that a product with a label matching them

can quickly come to market.”).

Following a final court decision of infringement for a

method of use claimed in an Orange Book-listed patent

from which no appeal is or can be taken, FDA regulation

provides that an ANDA applicant may either (1) forego

approval for the patented method of use until the relevant

patent expires, or (2) “amend[] its ANDA such that the

applicant is no longer seeking approval for a method of

use claimed by the patent,” i.e., convert the Paragraph

IV certification to a section viii statement. 21 C.F.R.

§ 314.94(a)(12)(viii)(A).

9

B. Proceedings Below

Salix Pharmaceuticals, Inc. (“Salix”) is the holder of

NDA No. 021361 for rifaximin tablets under the brand

name Xifaxan®, which is currently the only rifaximin

product available on the market. Xifaxan 550 mg rifaximin

tablets are indicated for the treatment of IBS-D in adults

(the “IBS-D Indication”) and for the reduction of the risk

of overt HE recurrence in adults (the “HE Indication”).

In February 2020, Norwich submitted ANDA No.

214369 seeking approval to market generic 550 mg

rifaximin for both the IBS-D and HE Indications. The

ANDA provided Paragraph IV certifications for each of

Salix’s Orange Book-listed patents. In March 2020, based

on the Paragraph IV certifications, Salix filed a patent

suit against Norwich in the District of Delaware under

35 U.S.C. § 271(e)(2). Salix’s suit triggered a now-expired

30-month stay on FDA approval of the ANDA.

The patents Salix asserted at trial fell into three

categories: claims directed to the HE Indication (the “HE

Patents”); claims directed to the IBS-D Indication (the

“IBS-D Patents”); and claims directed to the crystalline

form of rifaximin (the “Polymorph Patents”). After trial,

the court ordered the parties to propose a final judgment

finding the HE Patents infringed and the Polymorph and

IBS-D Patents invalid. Oral Order, No. 20-430 (D. Del.

July 28, 2022), ECF No. 189. Norwich proposed a judgment

with a Section 271(e) order stating that “any final approval

by FDA of Norwich’s ANDA with proposed labeling

containing the [HE Indication] shall be a date not earlier

than the latest expiration of the [HE Patents].” Joint

Letter, No. 20-430 (D. Del. Aug. 15, 2022), ECF No. 196

10

at 3. Salix argued that Norwich’s proposal was “improper

because under § 271(e)(4)(A), the date of approval is tied

to the drug product, not an indication.” Id. at 1.

On August 10, 2022, the court issued a final judgment

finding the IBS-D and Polymorph Patents invalid, and

the HE Patents infringed by the ANDA seeking approval

for the HE Indication. Accepting Salix’s argument that

Section 271(e)(4)(A) requires an order tying the date of

approval to the drug product, the court ordered “that the

effective date of any final approval by [FDA] of Norwich’s

ANDA No. 214369 is to be a date not earlier than the date

of expiration of the last to expire of the [HE Patents]

(currently October 2 2029). . . .” Final Judgment, No. 20430 (D. Del. Aug. 10, 2022), ECF No. 193 at 2.

Nor wich subsequently amended the ANDA by

removing the HE Indication from the proposed label and

providing section viii statements in place of Paragraph

IV certifications for the HE Patents. Norwich also filed

a motion asking the court to modify the 271(e) order to

make it clear that pertains to an ANDA with Paragraph

IV certifications to the HE Patents. Motion to Modify

Judgment, No. 20-430 (D. Del. Sept. 7, 2022), ECF No.

205. The court denied Norwich’s motion. Memorandum

Order, No. 20-430 (D. Del. May 17, 2023), ECF No. 222.

On June 2, 2023, FDA granted tentative approval to

the amended ANDA but declined to grant final approval.

Motion to Expedite, No. 22-2153 (Fed. Cir. June 14, 2023),

ECF No. 23, Zaku Decl., Ex. A. Despite acknowledging

that Salix’s HE Patents “do not claim any indication for

which [Norwich is] seeking approval,” the agency stated

that “final approval cannot be granted until October 2,

2029 as specified in the court order.” Id. at 3-4.

11

Norwich appealed the 271(e) order to the Federal

Circuit, arguing that the district court’s statutory

interpretation is contrary to the plain language, the

section viii mechanism in the Hatch-Waxman Act,

the Act’s overall purpose of hastening generic drugs,

FDA’s implementing regulation, and the basic patentlaw principle that injunctions must be tailored to the

underlying infringement. The Federal Circuit affirmed

the 271(e) order but did so without conducting a substantive

review of the district court’s statutory interpretation,

noting only that the order does not prevent approval of “a

new non-infringing ANDA.” Pet. App. 23a The parties had

never questioned the self-evident fact that the order does

not block an ANDA assigned a different ANDA number

by FDA, however. But submitting a new ANDA simply

to obtain a different ANDA number is not a solution to

the district court’s erroneous statutory interpretation

that requires 271(e) orders that block approval of generic

drugs for indications that are not covered by a patent. The

Federal Circuit denied Norwich’s petition for rehearing

or rehearing en banc.

REASONS FOR GRANTING THE PETITION

The plain language of Section 271(e)(4)(A) requires

that courts issue 271(e) orders that tie the restriction

on FDA approval to the indication for which the ANDA

seeks approval when that indication is the source of

the infringement under Section 271(e)(2)(A). That

straightforward application of the statutory language

is also necessary to avoid conflict with the section viii

mechanism that Congress provided in the Hatch-Waxman

Act to permit approval of generic drugs for uses that are

not covered by a valid patent. It is further mandated by

the basic principle of patent law that injunctive relief may

12

only encompass the specific infringing conduct and no

other conduct.

The district court’s 271(e) order here was based on

an erroneous interpretation of Section 271(e)(4)(A) under

which such orders must be tied to the “drug” regardless

of the underlying infringement. The absurd result of this

interpretation is that FDA is barred from approving the

first generic rifaximin product for IBS-D – an indication

that is unquestionably in the public domain following the

invalidation of Salix’s IBS-D Patents – despite the section

viii mechanism that Congress put in place precisely

to ensure that generic drugs could be marketed for

unpatented indications. With the Federal Circuit having

affirmed the order, the district court’s interpretation will

be the law in all ANDA cases unless this Court grants

review.

I.

Certiorari Is Required to Prevent 271(e) Orders

From Delaying Approval of Generic Drugs for

Unpatented Indications

A.

The plain statutory language requires courts

to tailor 271(e) orders to the underlying

infringement

Section 271(e)(4) directs that “[f ]or an act of

infringement described in paragraph (2) — (A) the court

shall order the effective date of any approval of the drug

. . . involved in the infringement” to be later than the

expiration of the infringed patent. 35 U.S.C. § 271(e)(4)(A).

Because the provision explicitly points to the definition of

infringement in Section 271(e)(2)(A), it must be read in that

context. See FDA v. Brown & Williamson Tobacco Corp.,

13

529 U.S. 120, 133 (2000) (“It is ‘a fundamental canon of

statutory construction that the words of a statute must be

read in their context and with a view to their place in the

overall statutory scheme.’”) (quoting Davis v. Michigan

Dept. of Treasury, 489 U.S. 803, 809 (1989)).

Section 271(e)(2)(A) defines “an act of infringement”

to be the submission of 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) (emphasis added). Thus, the infringement

for which Section 271(e)(4)(A) provides a remedy can refer

to infringement of a patent claiming the drug itself or

infringement of a method patent claiming the appliedfor indication. Here, for example, the district court found

induced infringement of the HE Patents under Section

271(e)(2)(A) solely because the ANDA sought approval for

the HE Indication. Supra at 10.

Upon finding an act of infringement, Section 271(e)

(4)(A) requires the court to issue an order restricting

the approval not merely of “the drug” but of “the drug

. . . involved in the infringement.” 35 U.S.C. § 271(e)(4)

(A). Here, rifaximin – “the drug” – is only “involved in

the infringement” when it is used for the HE Indication.

Conversely, rifaximin is not “involved in the infringement”

when it is sold or used for the IBS-D Indication because the

IBS-D Patents covering that indication were held invalid.

The term “the drug . . . involved in the infringement”

therefore serves to ensure that the scope of the 271(e) order

is commensurate with the underlying act of infringement

and does not prevent approval of the ANDA product for

uses that have not been found infringing.

14

Rather than adhere to the plain statutory language,

the lower court adopted Salix’s contention that Section

271(e)(4)(A) ties “the date of approval . . . to the drug

product, not an indication.” Supra at 10. It then

implemented this reading by issuing an order that

put a blanket ban of approval on “ANDA No. 214369”

irrespective of whether it seeks approval for any patented

indication. This interpretation reduces the term “involved

in the infringement” to serve only to identify the drug to

which the order should be directed. As a mere identifier

the term is wholly redundant, however, because the

infringing drug (and drug application) is already

identified in Section 271(e)(2)(A), which itself is explicitly

referenced in the first sentence of Section 271(e)(4)(A). An

interpretation that renders statutory language redundant

or mere surplusage is contrary to the “cardinal principle

of statutory construction” of “giv[ing] effect, if possible,

to every clause and word of a statute.” Duncan v. Walker,

533 U.S. 167, 174 (2001) (citation omitted).

B. 271(e) or der s must b e t a ilore d t o the

infringement to comport with rather than

undermine the purpose of the Hatch-Waxman

Act

Correct statutory interpretation seeks to “give effect

to congressional purpose so long as the congressional

language does not itself bar that result.” Johnson v.

United States, 529 U.S. 694, 710 n.10 (2000). See also

Warner-Lambert, 316 F.3d at 1355 (Courts interpreting

statutory language look to “the objects and policy of the

law, as indicated by its various provisions, and give it such

a construction as will carry into execution the will of the

Legislature.”) (quoting Kokoszka v. Belford, 417 U.S. 642,

650 (1974)).

15

Congress enacted the Hatch-Waxman Act with the

goal of bringing “‘generic … drugs to market as quickly as

possible.’” Teva Pharms. USA, 482 F.3d at 1344 (quoting

Sen. Kennedy Remarks, 149 Cong. Rec. S15885 (Nov. 25,

2003)). See also In re Barr Lab’ys, Inc., 930 F.2d 72, 76

(D.C. Cir. 1991) (“Congress sought to get generic drugs

into the hands of patients at reasonable prices – fast.”).

Consistent with that goal, Congress included the section

viii mechanism that permits approval of generic drugs for

unpatented indications even when other indications for

the same drug are covered by patents. As this Court has

observed, “[t]he Hatch-Waxman Amendments authorize

the FDA to approve the marketing of a generic drug for

particular unpatented uses; and section viii provides the

mechanism for a generic company to identify those uses,

so that a product with a label matching them can quickly

come to market.” Caraco Pharm. Lab’ys,, 566 U.S. at 415.

Reading Section 271(e)(4)(A) as requiring courts to

tailor 271(e) orders to the underlying act of infringement

gives effect to the overarching purpose of Act and

its section viii mechanism because it permits generic

applicants to carve out an infringing indication from an

ANDA and obtain approval for an unpatented indication.

By contrast, the reading applied by the district court

requires blanket 271(e) orders that prohibit FDA from

approving ANDAs that have section viii statements

to a patented indication and only seek approval for an

unpatented indication. This means that infringing ANDAs

cannot be amended post-judgment to exclude indications

covered by valid patents. In this case, for example, FDA

declined to approve Norwich’s ANDA because of the

district court’s blanket 271(e) order despite acknowledging

the section viii statements to Salix’s HE Patents. Supra

at 10-11.

16

C.

271(e) or der s must b e t a ilore d t o the

infringement to avoid nullifying FDA’s

implementing regulation

There is no statutory basis for a 271(e) order that

precludes the use of the section viii mechanism after a

finding of infringement. On the contrary, Congress did

not place any temporal limitation on the submission of

a section viii statement, and FDA’s regulation therefore

explicitly permits ANDA applicants to use it to carve out

an indication that has been found infringing:

(A) After finding of infringement. An applicant

who has submitted a paragraph IV certification

and is sued for patent infringement must submit

an amendment to change its certification if

a court enters a final decision from which no

appeal has been or can be taken. . . . [W]ith

respect to a patent claiming a method of use,

the applicant may instead provide a statement

under paragraph (a)(12)(iii) of this section if

the applicant amends its ANDA such that the

applicant is no longer seeking approval for a

method of use claimed by the patent. Once an

amendment for the change has been submitted,

the ANDA will no longer be considered to

contain a paragraph IV certification to the

patent.

21 C.F.R. § 314.94(a)(12)(viii)(A). Other FDA regulation

provides that an ANDA with a section viii statement may

be approved “immediately.” 21 C.F.R. § 314.107(b)(1)(ii).

FDA’s regulations thus aligns with both the letter and

purpose of the Hatch-Waxman Act.

17

Norwich followed the regulation to the letter. After

having undertaken the expense of challenging Salix’s

Orange-Book listed patents, Norwich succeeded in

proving that the Polymorph and IBS-D Patents were

invalid but was held to have infringed the HE Patents

by seeking approval for the HE Indication. As FDA’s

regulation prescribes, Norwich then amended the ANDA

to remove the infringing HE Indication and submit section

viii statements rather than Paragraph IV certifications

to the HE Patents. Supra at 10. Yet the district court’s

271(e) order has denied FDA the ability to follow its own

regulation and approve the amended ANDA. The court’s

interpretation of the Section 271(e)(4)(A) thus effectively

nullifies FDA’s regulation.

D.

271(e) order s must b e t a ilore d t o the

infringement to comport with patent law

It is a basic principle of patent law that “a court may

not enjoin products that have not been found by the jury to

infringe the patents-in-suit, and therefore any injunction

should be specifically tailored to comport with the jury’s

findings.” Durel Corp. v. Sylvania, Inc., No. 95-1750,

2000 WL 33687212, at *1 (D. Ariz. Apr. 13, 2000) (citing

Square Liner 360, Inc. v. Chisum, 691 F.2d 362, 378 (8th

Cir. 1982)). Indeed, the Patent Act only empowers courts

to grant injunctions “to prevent the violation of any right

secured by patent. . . .” 35 U.S.C. § 283. Thus, “[j]udicial

restraint of lawful competitive activities . . . must be

avoided. . . .” Joy Techs., Inc. v. Flakt, Inc., 6 F.3d 770,

777 (Fed. Cir. 1993) (vacating injunction and remanding

to narrow scope precluding non-infringing activities).

See also Johns Hopkins University v. CellPro, Inc., 152

F.3d 1342, 1367-68 (Fed. Cir. 1998) (same). By way of

18

example, no court would countenance an injunction that

broadly bars the sale of “F-150” pickup trucks based on

infringement of a patent covering intermittent windshield

wipers if that injunction would operate to bar F-150 trucks

that are redesigned to not have intermittent windshield

wipers.

There is nothing in the provisions or legislative history

of the Hatch-Waxman Act to suggest that Congress

intended it to alter or abrogate any settled principles of

patent law, let alone the principle that injunctions should

be commensurate in scope with the infringing conduct.

Yet the lower court’s interpretation places the remedy

provision of the Hatch-Waxman Act in the unique position

of requiring orders with an injunctive scope that is broader

than the infringement they are based on. Congress surely

did not intend for the Hatch-Waxman Act to distort this

basic tenet of patent law.

II. The Correct Implementation of the Remedy

Provision in the Hatch-Waxman Act Is Vital to the

Act’s Purpose of Incentivizing Generic Drugs and

Containing the Cost of Prescription Drugs

The Hatch-Waxman Act constitutes an important

part of the legal framework that controls and incentivizes

pharmaceutical industry innovation and competition in

the United States. Given that the annual expenditure on

prescription drugs exceeds half a trillion dollars, it is a

matter of national concern that the Act’s provisions are

correctly interpreted and applied by the courts. Congress

intended the Act to strike a balance between enabling

the swift introduction of less-costly generic drugs and

sufficiently rewarding investment in innovation. The lower

19

court’s erroneous interpretation of Section 271(e)(4)(A)

skews that balance away from generic drugs in a way that

Congress did not intend. Unless rectified, the effects are

unwarranted delay of generic alternatives for unpatented

indications and a disincentive for generic companies to

challenge the ever-growing patent thickets that protect

brand monopolies. See Comment of the Federal Trade

Commission, FTC, Docket No. PTO-P-2024- 0003

(July 9, 2024) (“the Commission . . . shares bipartisan

Congressional concerns that patent thickets erected by

incumbents can delay and frustrate the entry of new

biosimilars and generic drugs, increasing prescription

drug costs and limiting patients’ access to more affordable

options.”).

As of today, FDA has approved well over 200 new

drugs that have at least two indications, and for which

the brand company have listed at least two different use

codes (i.e., patented uses) in the Orange Book. The district

court’s incorrect interpretation of Section 271(e)(4)(A)

thus has the potential to delay generic competition for a

substantial number of branded drugs. Such unwarranted

delay is not limited to the situation where, as here, the

generic applicant successfully challenges the patents on

one indication but is held to infringe the patents on a second

indication. It may also occur when a generic is unsuccessful

in challenging both sets of patents where the two sets have

different expiration dates. Unless the court fashions a

Section 271(e)(4)(A) order that differentiates between the

two indications and patent expiration dates, FDA could

not approve the indication covered by the earlier-expiring

patents until expiration of the later-expiring patents. The

result is, again, an unwarranted extension of the brand’s

monopoly on unpatented indications.

20

Furthermore, unless the Court grants review, the

district court’s interpretation requiring blanket 271(e)

orders will have a chilling effect on the willingness of

generic companies to challenge method-of-use patents

covering approved indications. Where there is more than

one such approved indication, generics will be strongly

incentivized to only seek approval for one, because an

adverse infringement finding on any one indication is a

death knell for the entire ANDA. This will be true even

when the generic perceives the patents for both indications

to be equally susceptible to challenge.

The cost of the delay in generic alternatives will be

borne by patients and the health care system that will

pay monopoly prices for indications that are either not

covered by a valid patent or that are covered by patents

that would have been proven invalid or not infringed by a

generic alternative. And the excess profits enjoyed on the

branded side cannot be justified as reward for investment

in innovation and intellectual property. Here, for example,

Salix’s IBS-D Patents were shown to be invalid for

obviousness and thus not representative of innovation.

Furthermore, 271(e) orders are issued at the end of an

ANDA litigation and the brand company has therefore

enjoyed the statutory 30-month stay of FDA approval of

the ANDA that the Hatch-Waxman Act provides. There

is no justification for any further extension of the brand

monopoly on an unpatented indication.

III. This Case Is Well-Situated to Address the Question

Presented

This case is a good vehicle to address the proper

interpretation of the Section 271(e)(4(A) – the remedy

21

provision in the Hatch-Waxman Act that is invoked in

every ANDA litigation after a finding of infringement.

The issue is purely one of statutory interpretation with no

patent merit disputes remaining. Specifically, Norwich has

forgone its right to appeal the district court’s infringement

finding with respect to the HE Patents, and the Federal

Circuit has affirmed that the IBS-D and Polymorph

Patents are invalid.

CONCLUSION

The petition for a writ of certiorari should be granted.

Respectfully submitted,

Ian Swan

A xinn, Veltrop &

Harkrider LLP

1901 L Street NW

Washington, DC 20036

Thomas K. Hedemann

Counsel of Record

Matthew J. Becker

Matthew S. Murphy

A xinn, Veltrop &

Harkrider LLP

90 State House Square

Hartford, CT 06103

(860) 275-8100

thedemann@axinn.com

Counsel for Petitioner

September 11, 2024

APPENDIX

i

TABLE OF APPENDICES

Page

A P P E N DI X A — O P I N ION O F T H E

UNITED STATES COURT OF APPEALS

FOR THE FEDERAL CIRCUIT, FILED

APRIL 11, 2024 . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1a

APPENDIX B — TRIAL OPINION OF THE

UNITED STATES DISTRICT COURT FOR

THE DISTRICT OF DELAWARE, FILED

AUGUST 10, 2022 . . . . . . . . . . . . . . . . . . . . . . . . . . . 34a

APPENDIX C — DENIAL OF REHEARING

OF THE UNITED STATES COURT OF

APPEALS FOR THE FEDERAL CIRCUIT,

FILED JUNE 13, 2024 . . . . . . . . . . . . . . . . . . . . . . 94a

A PPEN DI X D — S TAT U T E S A N D

PROVISIONS . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 96a

1a

APPENDIX A — Appendix

OPINIONAOF THE UNITED

STATES COURT OF APPEALS FOR THE

FEDERAL CIRCUIT, FILED APRIL 11, 2024

UNITED STATES COURT OF APPEALS

FOR THE FEDERAL CIRCUIT

2022-2153, 2023-1952

SALIX PHARMACEUTICALS, LTD., SALIX

PHARMACEUTICALS, INC., BAUSCH HEALTH

IRELAND LTD., ALFASIGMA S.P.A.,

Plaintiffs-Appellants,

v.

NORWICH PHARMACEUTICALS INC.,

Defendant-Cross-Appellant.

April 11, 2024, Decided

Appeals from the United States District Court for the

District of Delaware in No. 1:20-cv-00430-RGA, Judge

Richard G. Andrews.

Before Lourie, Chen, and Cunningham, Circuit Judges.

Opinion for the court filed by Circuit Judge Lourie.

Opinion dissenting-in-part filed by Circuit Judge

Cunningham.

2a

Appendix A

Lourie, Circuit Judge.

Salix Pharmaceuticals, Ltd., Salix Pharmaceuticals,

Inc., Bausch Health Ireland Ltd., and Alfasigma S.P.A.

(collectively, “Salix”) appeal from a final judgment of the

United States District Court for the District of Delaware

holding claim 2 of U.S. Patent 8,309,569, claim 3 of U.S.

Patent 10,765,667, claim 4 of U.S. Patent 7,612,199, and

claim 36 of U.S. Patent 7,902,206 invalid as obvious. See

Salix Pharms., Ltd. v. Norwich Pharms., Inc., No. 20-cv430, 2022 U.S. Dist. LEXIS 142335, 2022 WL 3225381 (D.

Del. Aug. 10, 2022) (“Decision”).

Norwich Pharmaceuticals Inc. (“Norwich”) crossappeals from an order that issued after the district court

concluded that Norwich infringed claim 8 of U.S. Patent

8,624,573, claim 6 of U.S. Patent 9,421,195, and claims 11

and 12 of U.S. Patent 10,335,397 and had failed to prove

that those claims were invalid. That order, contained

within the final judgment, instructed the FDA that

the effective approval date of Norwich’s Abbreviated

New Drug Application (“ANDA”) may not precede the

expiration dates of those claims. J.A. 51. Norwich also

cross-appeals from a denial of its motion to modify the final

judgment. See Salix Pharms., LTD v. Norwich Pharms.,

Inc., No. 20-430, 2023 U.S. Dist. LEXIS 86257, 2023 WL

3496373 (D. Del. May 17, 2023) (“Rule 60(b) Order”).

For the following reasons, we affirm.

3a

Appendix A

Background

Rifaximin, the active ingredient in Salix’s commercial

product Xifaxan®, has been widely used as an antibiotic

for decades, having been first synthesized in the early

1980s in Italy and approved there as an antibiotic in 1985.

Decision, 2022 U.S. Dist. LEXIS 142335, [WL] at *8; J.A.

2532. The FDA approved Xifaxan nearly 20 years later,

in 2004, as 200 mg tablets for the treatment of travelers’

diarrhea. Decision, 2022 U.S. Dist. LEXIS 142335, [WL]

at *1. The FDA subsequently approved 550 mg tablets for

hepatic encephalopathy (“HE”) in 2010 and for irritable

bowel syndrome with diarrhea (“IBS-D”) in 2015. Id.

Norwich sought to market a generic version of

rifaximin and, in 2019, filed an ANDA for 550 mg tablets

with the same indications as Xifaxan, certifying pursuant

to 21 U.S.C. § 355(j)(2)(A)(vii)(IV) that Salix’s rifaximin

patents were invalid. Salix timely sued, asserting that

Norwich’s ANDA infringed dozens of valid, Orange Booklisted patents. By the time of trial, the case had been

streamlined to three groups of patents:

• the ’573, ’195, and ’397 patents, directed to

treating HE (“the HE patents”);

• the ’569 and ’667 patents, directed to

treating IBS-D with 550 mg rifaximin three

times a day (1,650 mg/day) for 14 days (“the

IBS-D patents”); and,

• the ’199 and ’206 patents, directed to

rifaximin form β (“the polymorph patents”).

4a

Appendix A

Following a bench trial, the district court held that

Norwich infringed the HE patents’ claims and had failed

to establish their invalidity. Decision, 2022 U.S. Dist.

LEXIS 142335, [WL] at *10-11. Norwich did not appeal

those holdings. The court also held that Norwich’s ANDA

infringed the IBS-D and polymorph patents, but that

those patents’ claims would have been obvious over certain

prior art. 2022 U.S. Dist. LEXIS 142335, [WL] at *2-3,

16-17. Salix appealed those invalidity holdings.

As part of the entered judgment, the district court

ordered that the effective date of a final approval of

Norwich’s ANDA should not precede October 2029,

which is the latest expiration date associated with the

HE patents. J.A. 51. Norwich then amended its ANDA

in an attempt to remove the infringing HE indication and

moved to modify the judgment under Federal Rule of Civil

Procedure 60(b), asserting that the amendment negated

any possible infringement. The court denied Norwich’s

motion, and Norwich cross-appealed.

We have jurisdiction under 28 U.S.C. § 1295(a)(1).

Discussion

Salix first contends that the district court’s conclusion

that the asserted claims of the IBS-D patents were invalid

as obvious was reached in error. Subsumed within that

challenge is a question of whether or not a background

reference discussed by the court was properly established

as prior art. Salix also contends that the court erred in

holding that the asserted polymorph patent claims were

5a

Appendix A

invalid as obvious. Norwich’s cross-appeal asserts that the

court erred in the phrasing of its order precluding final

approval of its ANDA until expiration of the HE patents.

Norwich further asserts that the court erred in denying

its motion to modify after the ANDA was amended in an

attempt to avoid infringement. We address each argument

in turn.

I

We turn first to Salix’s contention that the district

court erred in concluding that the asserted claims of the

IBS-D patents would have been obvious over the asserted

prior art.

Whether or not a claim would have been obvious

is a question of law, based on underlying factual

determinations. Hospira, Inc. v. Fresenius Kabi USA,

LLC, 946 F.3d 1322, 1328-29 (Fed. Cir. 2020). We review

the ultimate legal question of obviousness de novo and

the underlying factual determinations for clear error. Id.

at 1328. A finding is clearly erroneous only if we are “left

with a definite and firm conviction that the district court

was in error.” Id. (citations omitted).

The IBS-D patents are directed to treating IBS-D

with 550 mg rifaximin, thrice-daily (1,650 mg/day), for

14 days. For example, claim 2 of the ’569 patent depends

from claim 1 as follows:

1. A method of providing acute treatment for

diar-rhea-associated Irritable Bowel Syndrome

6a

Appendix A

(dIBS) comprising: administering 1650 mg/

day of rifaximin for 14 days to a subject in

need thereof, wherein removing the subject

from treatment after the 14 days results in a

durability of response, wherein the durability of

response comprises about 12 weeks of adequate

relief of symptoms.

2. The method of claim 1, wherein the 1650 mg

is administered at 550 mg three times per day.

’569 patent, col. 30 ll. 4-12 (emphases added); see also ’667

patent, col. 46 ll. 29-33, 39-40 (claims 1 & 3, similar). The

key limitation on appeal is the dosage amount that appears

in the claims: 550 mg, three times per day (“TID”), for a

total of 1,650 mg/day.

Norwich challenged the IBS-D claims’ validity

by asserting as prior art references a clinical trial

protocol that had been published on the ClinicalTrials.

gov website in 2005 (“the Protocol”)1 and a 2006 journal

article (“Pimentel”). 2 The Protocol describes a Phase II

study evaluating twice-daily doses of 550 mg (1,100 mg/

1. Cl i n ica lT r ia ls.gov, Hi st o r y of Ch an ges fo r Stu dy:

NCT00269412, Randomized, Double Blind, Placebo-Controlled

Study to Assess the Efficacy and Safety of Three Different Doses

of Rifaximin Administered BID either Two or Four Weeks in the

Treatment of Patients with Diarrhea-Associated Irritable Bowel

Syndrome (December 22, 2005); J.A. 7047-55.

2. M. Pimentel et al., The Effect of a Nonabsorbed Oral

Antibiotic (Rifaximin) on the Symptoms of the Irritable Bowel

Syndrome, 145 A nn. Intern. Med., 557 (2006); J.A. 4639-46.

7a

Appendix A

day) and 1,100 mg (2,200 mg/day) for 14 and 28 days for

the treatment of IBSD. See J.A. 7051. Pimentel teaches

administering 400 mg, TID (1,200 mg/day), for the

treatment of IBS, 3 but further opines that the “optimal

dosage of rifaximin may, in fact, be higher than that used

in our study.” J.A. 4644.

The district court found that those two references

disclose each and every limitation of the challenged IBS-D

claims, and further found that a skilled artisan would

have been motivated to combine those two references to

arrive at what is claimed with a reasonable expectation of

success. Decision, 2022 U.S. Dist. LEXIS 142335, [WL] at

*17, *19-20. The court then concluded that the challenged

IBS-D claims were invalid as obvious. 2022 U.S. Dist.

LEXIS 142335, [WL] at *17-22. Salix appeals, asserting

that the court erred in finding that a skilled artisan would

have had a reasonable expectation of success in using the

claimed 1,650 mg/day dosage to treat IBS-D. Appellants’

Br. at 39-48. Whether or not there would have been a

reasonable expectation of success is a question of fact,

IXI IP, LLC v. Samsung Elecs. Co., 903 F.3d 1257, 1262

(Fed. Cir. 2018), which we review for clear error, Hospira,

946 F.3d at 1328.

Salix does not appear to dispute the district court’s

finding that the Protocol and Pimentel “disclose all

3. Salix did not argue a difference between a motivation to

use rifaximin to treat IBS versus IBS-D. Decision, 2022 U.S. Dist.

LEXIS 142335, [WL] at *19 n.3. It concedes on appeal that “[r]oughly

one-third of IBS patients suffer from IBS-D,” Appellants’ Br. at 6,

and has not otherwise suggested that treatments for IBS would not

inform treatments of IBS-D.

8a

Appendix A

limitations of the IBS-D claims.” See Decision, 2022 U.S.

Dist. LEXIS 142335, [WL] at *17. Rather, it contends that

even if the asserted combination of references effectively

discloses the claimed 1,650 mg/day dosage, there remains

insufficient evidence to support a finding of a reasonable

expectation of success in using that particular dosage

amount. See, e.g., Appellants’ Br. at 39-40. According to

Salix, the highest prior art dosage amount that could have

been supported with a reasonable expectation of success

was the 1,200 mg/day dose evaluated by Pimentel. Id. at

40. We disagree.

The Protocol provides an outline of a planned Phase

II clinical trial in which “three different doses (275, 550

and 1100 mg) of rifaximin” were to be “administered

BID [i.e., twice-daily] for either two or four weeks in the

treatment of patients with diarrhea-associated irritable

bowel syndrome.” J.A. 7050 (cleaned up). As an outline

of that clinical trial plan, the Protocol provides only that

those three specific, twice-daily dosage regimens were to

be investigated for either two or four weeks. The Protocol

does not include any efficacy or safety data, nor does it

mention a 1,650 mg/day dose or TID dosing.

Although we have rejected the idea that “efficacy

data [are] always required for a reasonable expectation

of success,” OSI Pharms., LLC v. Apotex Inc., 939 F.3d

1375, 1385 (Fed. Cir. 2019), we are hesitant to conclude as

a general matter that the disclosure of a Phase II clinical

trial plan, standing alone, provides an expectation of

success sufficient to render obvious a dosage that was not

included within the planned clinical trial. See Appellants’

9a

Appendix A

Reply Br. at 13?14. But the Protocol was not asserted

alone; it was asserted in combination with Pimentel.

Pimentel teaches that administration of 400 mg

rifaximin, TID (1,200 mg/day), “resulted in greater

improvement in IBS symptoms” and “lower bloating

score[s] after treatment.” J.A. 4639; see also id. at 464243 (providing supporting data). Pimentel explains that

the 400 mg TID regimen was chosen “on the basis of a

previous study that demonstrated the efficacy of rifaximin

in bacterial overgrowth.” Id. at 4640. However, Pimentel

does not merely provide that daily rifaximin doses of 1,200

mg were likely to be successful in the treatment of IBS.

Pimentel further teaches that “[r]ecent data suggest that

the optimal dosage of rifaximin may, in fact, be higher

than that used in our study.” J.A. 4644; Decision, 2022

U.S. Dist. LEXIS 142335, [WL] at *20 (emphases added).

The district court did not clearly err in finding that

a skilled artisan would have looked to both of those

references, considered their limits, and had a reasonable

expectation of success as to the efficacy of 550 mg TID

dosing. The combined message that the skilled artisan

would have discerned from the Protocol and Pimentel is

that the optimal dosage for treating patients suffering

from IBS disorders may be higher than 400 mg TID, and

the next higher dosage unit from the Protocol was 550

mg. We see no clear error in the conclusion that there

would have been a reasonable expectation of success in

administering the claimed 1,650 mg/day to IBS-D patients.

Indeed, certainty and absolute predictability are not

required to establish a reasonable expectation of success.

10a

Appendix A

See Almirall, LLC v. Amneal Pharms. LLC, 28 F.4th 265,

275 (Fed. Cir. 2022) (“A finding of a reasonable expectation

of success does not require absolute predictability of

success.”); Acorda Therapeutics, Inc. v. Roxane Lab’ys,

Inc., 903 F.3d 1310, 1333 (Fed. Cir. 2018) (“This court has

long rejected a requirement of conclusive proof of efficacy

for obviousness.” (cleaned up)).

Moreover, references establishing the background

knowledge of a person of ordinary skill in the art are

consistent with the reasonable expectation of success

provided by the combination of the Protocol with Pimentel.

For example, Cuoco 4 teaches the efficacy of 1,200 mg

rifaximin/ day for 14 days for the treatment of small

intestinal bacterial overgrowth (“SIBO”). J.A. 4533. Salix

has acknowledged that those of ordinary skill in the art

identified “bacterial alterations” as a potential underlying

cause for IBS, Appellants’ Br. at 7, and the literature5

describes SIBO as a condition that is “highly prevalent in

patients with irritable bowel syndrome (IBS),” such that

“SIBO decontamination is associated [with] a significant

improvement of IBS symptoms.” J.A. 4664. We therefore

agree with the district court that references describing

the treatment of SIBO would have been pertinent to the

skilled artisan’s considerations as to what treatments

4. L. Cuoco & M. Salvagnini, Small intestine bacterial

overgrowth in irritable bowel syndrome: a retrospective study

with rifaximin, 52 Minerva Gastroenterol. Dietol. (2006) 89; J.A.

4533-39.

5. E. Scarpellini et al., High dosage rifaximin for the treatment

of small intestinal bacterial overgrowth, 25 A liment. Pharmacol.

Ther. 781 (2007); J.A. 4663-67 (“Scarpellini”).

11a

Appendix A

would have a potential for success in treating individuals

suffering from IBS.

In addition to Cuoco, Lauritano6 teaches an increase in

rifaximin efficacy for the treatment of SIBO as doses were

increased from 600 mg/day to 1,200 mg/day, providing the

trend that Pimentel described as indicating that doses

higher than 1,200 mg/day may be even more optimal for

the treatment of IBS. J.A. 7267 (“Higher doses of rifaximin

lead to a significant gain in terms of therapeutic efficacy

in [SIBO] eradication without increasing the incidence

of side-effects.”); see also id. at 4644. As evidenced by

Scarpellini and Lin,7 those in the art advanced on those

findings, and subsequently evaluated higher doses. For

example, Scarpellini reported that a 1,600 mg/day dose

“showed a significantly higher efficacy” compared with

1,200 mg/day for the treatment of SIBO. J.A. 4663; see also

id. at 4666 (Table 1, noting study patients included those

suffering from IBS-D); id. at 4747 (teaching that “[a]bout

400 to about 600 mg of rifaximin may be administered TID

for about 10 days” (i.e., 1,200 mg/day to 1,800 mg/day) for

the eradication of bacterial overgrowth).

The record further supports the finding that there

would have been a reasonable expectation of success

in administering higher doses of rifaximin without an

intolerable increase in negative side effects. For example,

6. E.C. Lauritano et al., Rifaximin dose-finding study for the

treatment of small intestinal bacterial overgrowth, 22 A liment.

Pharmacol. Ther., 31 (2005); J.A. 7267-71.

7. International Patent Application Publication 2006/102536;

J.A. 4721-47.

12a

Appendix A

Cuoco teaches that rifaximin was understood as having “a

low risk of causing microbial resistance,” J.A. 4533, and

that rifaximin was well known for its “profile of tolerability

and safety widely described in the literature,” id. at 4538.

Scarpellini further reported that the 1,600 mg/day dose

provided a “similar compliance and side-effect profile”

compared with the 1,200 mg/day dose. Id. at 4663. As

the district court noted, the “[w]idespread off-label use”

of rifaximin also supported the conclusion that rifaximin

was safe and effective “for the treatment of IBS-D with

a reasonable expectation of success.” Decision, 2022 U.S.

Dist. LEXIS 142335, [WL] at *19; see also Appellants’ Br.

at 17 (“There is no dispute that skilled artisans knew of

the general concept of trying off-label use of rifaximin to

treat IBS-D.”).

In view of the record before us, we see no clear error

in the finding that a skilled artisan would have had a

reasonable expectation of success in administering the

claimed 1,650 mg/day regimen for the treatment of IBS-D.

We therefore affirm the district court’s holding that the

challenged IBS-D claims would have been obvious over

the cited references. See In re Applied Materials, Inc.,

692 F.3d 1289, 1295 (Fed. Cir. 2012) (“[W]here the general

conditions of a claim are disclosed in the prior art, it is not

inventive to discover the optimum or workable ranges by

routine experimentation.” (citation omitted)).

Salix further contends that a Press Release 8 issued

by Salix in a filing with the Securities and Exchange

8. Salix Pharms., Ltd., Current Report (Form 8-K) (Sept. 5,

2007); J.A. 7477-82.

13a

Appendix A

Commission less than a year before the patents’ priority

date was not prior art because Norwich failed to establish

that it was “by others” as required by pre-AIA 35 U.S.C.

§ 102(a). Appellants’ Br. at 30-39. According to Salix,

the district court’s inclusion of that allegedly non-prior

art reference in its discussion of the skilled artisan’s

expectation of success was harmful error. Id.

Although the district court cited the Press Release

in its discussion of the skilled artisan’s expectations, it

ultimately held that the “Protocol and Pimentel [] disclose

all limitations of the IBS-D claims” and that a skilled

artisan “would have been motivated to combine the . . .

Protocol and Pimentel [] with a reasonable expectation of

success.” Decision, 2022 U.S. Dist. LEXIS 142335, [WL]

at *17. We therefore need not decide whether or not the

Press Release was prior art because, even assuming that

it was not, the Protocol and Pimentel alone established

the obviousness of the claims.

We accordingly affirm the district court’s determination

that Norwich established that the IBS-D claims would

have been obvious in view of the Protocol and Pimentel.

II

We next turn to Salix’s contention that the district

court clearly erred in finding that there would have been

a reasonable expectation of success in obtaining the

rifaximin form β recited in the polymorph patents’ claims.

Whether or not there would have been a reasonable

expectation of success is a question of fact, IXI IP, LLC

14a

Appendix A

v. Samsung Elecs. Co., 903 F.3d 1257, 1262 (Fed. Cir.

2018), which we review for clear error, Hospira, 946 F.3d

at 1328. We review the ultimate conclusion of obviousness

de novo. Id.

The polymorph patents are directed to rifaximin form

β. For example, claim 4 of the ’199 patent recites:

4. Rifaximin in polymorphic form β, wherein

the rifaximin has x-ray powder diffraction

pattern peaks at about 5.4°; 9.0°; and 20.9°2θ

and wherein the rifaximin has a water content

of greater than 5%.

’199 patent, col. 10 ll. 24-27; see also ’206 patent, col. 11 ll.

33-37, 41-43 (claims 34 & 36, similar).

Norwich challenged the polymorph claims’ validity

by asserting, inter alia, Cannata,9 which discloses that

rifaximin exists in crystalline form with “outstanding

antibacterial properties.” J.A. 4528; Decision, 2022 U.S.

Dist. LEXIS 142335, [WL] at *6. Cannata does not discuss

rifaximin’s crystal structure in detail, but it does disclose

several preparation protocols for rifaximin that include

solvents used for crystallization. J.A. 4529-31; see also

id. at 3408.

The district court held that expert testimony

supported a conclusion that, in view of the prior art, (1) a

skilled artisan would have had good reason to characterize

9. U.S. Patent 4,557,866; J.A. 4526-32.

15a

Appendix A

the crystalline rifaximin obtained by following the

Cannata protocols, (2) that such characterization was

routine and could have been performed “in one day,” and

(3) that doing so would have led the skilled artisan to have

“detected rifaximin β.” Decision, 2022 U.S. Dist. LEXIS

142335, [WL] at *6-7. The district court subsequently

concluded that the challenged polymorph claims would

have been obvious over the asserted prior art in view of

the common knowledge of the skilled artisan. 2022 U.S.

Dist. LEXIS 142335, [WL] at *7-8.

Salix first challenges the district court’s conclusion

of obviousness by asserting that Grunenthal GMBH v.

Alkem Laboratories Ltd., 919 F.3d 1333 (Fed. Cir. 2019)

and Pharmacyclics LLC v. Alvogen, Inc., No. 2021-2270,

2022 U.S. App. LEXIS 31479, 2022 WL 16943006 (Fed.

Cir. Nov. 15, 2022) compel the opposite result. Appellants’

Br. at 49-51. Salix further contends that the court “applied

the wrong test” by not following a rationale provided in

the district court opinion from Pharmacyclics. Id. at 5557. We disagree.

In Grunenthal, we held that it was not clear error for

the district court to find that the record failed to establish

by clear and convincing evidence a reasonable expectation

of success in preparing the claimed polymorphic Form A

of tapentadol hydrochloride. See 919 F.3d at 1341. In that

case, the synthesis of tapentadol hydrochloride known in

the prior art produced a particular form—Form B. Id. The

district court found that there was a lack of evidence that

a prior art synthesis would have resulted in the claimed

Form A and that no prior art guidance existed to establish

16a

Appendix A

“what particular solvents, temperatures, agitation rates,

etc., were likely to result” in the claimed polymorph. Id.

at 1343. We found no clear error in that analysis. Id. at

1344-45.

We also affirmed a conclusion of non-obviousness of a

claimed polymorph in our non-precedential Pharmacyclics

decision, which issued after the district court released its

decision in this case. See 2022 U.S. App. LEXIS 31479,

2022 WL 16943006, at *10-11. But the court here acted

within its discretion when it declined to follow the district

court decision in Pharmacyclics as though it was binding

precedent. See Decision, 2022 U.S. Dist. LEXIS 142335,

[WL] at *7 n.1 (“Plaintiffs call to my attention [the district

court’s decision in] Pharmacyclics LLC v. Alvogen Pine

Brook LLC. I have considered that case but I do not agree

with it on this point.”). And our later affirmance of the

factual findings in Pharmacyclics did not retroactively

override the district court’s analysis here.

Moreover, a lack of clear error in Grunenthal and

Pharmacyclics does not compel a conclusion of nonobviousness here. Indeed, Grunenthal underscored the

factual nature of these types of inquiries and expressly

held that it did “not rule out the possibility that polymorph

patents could be found obvious.” 919 F.3d at 1344-45.

“The determination of obviousness is dependent on the

facts of each case.” Sanofi-Synthelabo v. Apotex, Inc.,

550 F.3d 1075, 1089 (Fed. Cir. 2008); see also Pfizer, Inc.

v. Apotex, Inc., 480 F.3d 1348, 1366 (Fed. Cir. 2007). In

Grunenthal and Pharmacyclics, the issue was whether a

skilled artisan would have had a reasonable expectation

17a

Appendix A

of success in producing a crystalline form of a compound.

See 919 F.3d at 1341-43; 2022 U.S. App. LEXIS 31479, 2022

WL 16943006, at *10-11. Here, the prior art included a

process to produce a crystalline form of rifaximin, and the

dispute centered around characterizing the crystalline

form resulting from that process. See Decision, 2022

U.S. Dist. LEXIS 142335, [WL] at *13-14. These distinct

factual predicates support the district courts’ factual

findings in each of these three cases under the clear error

standard of review.

In Graham v. John Deere Co. of Kansas City, 383

U.S. 1, 86 S. Ct. 684, 15 L. Ed. 2d 545 (1966), the Supreme

Court set forth the background against which obviousness

is to be assessed: “Under § 103, the scope and content

of the prior art are to be determined” and “differences

between the prior art and the claims at issue are to be

ascertained.” Id. at 17. The scope and content of the prior

art here includes preparations of crystalline rifaximin,

which expert testimony supports would have yielded the

β form of rifaximin. Decision, 2022 U.S. Dist. LEXIS

142335, [WL] at *7; J.A. 3391-92 (“[T]he as-synthesized

form of rifaximin reported by Examples 1, 6, 7, and 9 [of

Cannata] were necessarily rifaximin form Beta, because

of the methods used, the solvent system used, and it was

later confirmed by later work, including work from the

named inventors.”); id. at 3408-09 (similar testimony);

id. at 3393-3404 (discussing the evidence of record that

supports that conclusion); id. at 4700-07, 4846-47, 500714 (providing supporting evidence for that conclusion).

And the parties do not dispute that the methods for

characterizing the resulting crystalline rifaximin were

18a

Appendix A

well known and readily available to the skilled artisan.

Decision, 2022 U.S. Dist. LEXIS 142335, [WL] at *3. The

difference between the prior art and the claims is thus

effectively nothing more than the performance of routine

characterization to identify the polymorphic forms that

result from the known Cannata processes.

In this regard, Salix does not appear to dispute that

there would have been a motivation to explore potential

polymorphic forms of rifaximin. Appellants’ Br. at 4849. Rifaximin was, after all, a known compound with a

known, useful activity. Salix further refers to the district

court’s finding that “polymorph β is a commonly produced

polymorph and the most stable form of rifaximin” as an

“undisputed” fact. Id.; see also Decision, 2022 U.S. Dist.

LEXIS 142335, [WL] at *7. There thus appears to be

no dispute that the claimed polymorph can be readily

produced from the crystallization conditions disclosed

in Cannata and that it would have been well within the

abilities of the skilled artisan to procure and characterize

the β form of rifaximin.

According to Salix, however, rifaximin’s β form

constituted a non-obvious invention because, although

skilled artisans “actually succeed[ed]” in producing and

characterizing it, they would not have “expect[ed] to

succeed” because, as of the critical date, the polymorphic

nature of rifaximin had not yet been reported and the

identity of the β form remained undisclosed. Appellants’

Br. at 49. Salix further argues that there could have been

no expectation of success because the skilled artisan would

not have been able to predict what polymorphic forms

19a

Appendix A

might result from following the preparation protocols

disclosed in the prior art. Id. at 20-21, 50-53. Salix’s

framing of the issue suggests that no unknown entity

could ever be obvious, as one cannot reasonably expect

what was hitherto unknown, which is incorrect.

Here, the district court found a reasonable expectation

of success in characterizing the crystalline product

of Cannata for potential polymorphism using routine,

conventional methods and skill. Decision, 2022 U.S.

Dist. LEXIS 142335, [WL] at *6-7. We see no clear error

in that conclusion. Indeed, Salix has done no more than

combine known elements of the prior art to verify readily

accessible information concerning a compound already in

the hands of those of ordinary skill in the art, and such

routine efforts do not justify removing this polymorph

from the public domain. See KSR Int’l Co. v. Teleflex

Inc., 550 U.S. 398, 427, 127 S. Ct. 1727, 167 L. Ed. 2d 705

(2007); see also Pfizer, 480 F.3d at 1367-68. To be sure, we

do not hold that there is always a reasonable expectation

of success in accessing or characterizing polymorphs. We

are simply reviewing the district court’s decision before

us as to its factual finding of a reasonable expectation of

success, and in so doing, have not been left with a definite

and firm conviction that a mistake was made in reaching

that finding. See Scanner Techs. Corp. v. ICOS Vision Sys.

Corp. N.V., 528 F.3d 1365, 1374 (Fed. Cir. 2008).

Having found no clear error in the district court’s fact

findings as to the existence of a reasonable expectation

of success, we affirm the court’s conclusion that the

polymorph patent claims were invalid as obvious. Because

20a

Appendix A

we affirm the court’s holding that the polymorph patent

claims would have been obvious over the asserted prior

art, we need not consider Norwich’s separate argument

that the polymorph claims would have also been invalid

as inherently anticipated.

III

On cross-appeal, Norwich raises two related but

distinct arguments that arose after the district court

held that Norwich infringed the HE patents and failed to

establish invalidity. See Decision, 2022 U.S. Dist. LEXIS

142335, [WL] at *10-16. Norwich first argues that, in

issuing its final decision, the district court misinterpreted

35 U.S.C. § 271(e)(4)(A), which directs a court, following

a finding of infringement, to order the FDA to defer final

approval of an ANDA until the expiration of the infringed

patent. According to Norwich, that statute precludes

delaying final approval of an entire ANDA, and instead

requires delaying only the approval of the infringing use.

Norwich’s second argument arises from its decision

to amend its ANDA to carve out the infringing HE use

after final judgment. Following that amendment, Norwich

filed a motion to modify the final judgment to allow for

prompt approval of the amended ANDA that purportedly

no longer sought approval for the infringing HE use. The

district court denied that motion, and Norwich crossappealed.

We address both of Norwich’s concerns in turn.

21a

Appendix A

A.

We first address Norwich’s arguments regarding the

district court’s interpretation of 35 U.S.C. § 271(e)(4)(A) in

ordering that a final approval of Norwich’s ANDA could

not be effective before the HE patents expired. J.A. 50-51.

We review issues of statutory interpretation without

deference to the district court’s interpretation. Waymark

Corp. v. Porta Sys. Corp., 245 F.3d 1364, 1366 (Fed.

Cir. 2001). “The starting point in every case involving

construction of a statute is the language itself.” Blue Chip

Stamps v. Manor Drug Stores, 421 U.S. 723, 756, 95 S.

Ct. 1917, 44 L. Ed. 2d 539 (1975) (Powell, J., concurring).

Moreover, we “give effect, if possible, to every clause and

word of [the] statute.” United States v. Menasche, 348 U.S.

528, 538-39, 75 S. Ct. 513, 99 L. Ed. 615 (1955) (citation

omitted). When a statute does not define a given word or

phrase, we presume that Congress intended the word or

phrase to have its ordinary meaning. Asgrow Seed Co. v.

Winterboer, 513 U.S. 179, 187, 115 S. Ct. 788, 130 L. Ed.

2d 682 (1995). However, “[i]n expounding a statute, we

must not be guided by a single sentence or member of a

sentence, but look to the provisions of the whole law, and

to its object and policy.” U.S. Nat’l Bank of Or. v. Indep.

Ins. Agents of Am. Inc., 508 U.S. 439, 455, 113 S. Ct. 2173,

124 L. Ed. 2d 402 (1993) (citation omitted).

Section 271(e)(4)(A) instructs that, following a finding

of infringement, “the court shall order the effective

date of any approval of the drug or veterinary biological

product involved in the infringement to be a date which

22a

Appendix A

is not earlier than the date of the expiration of the patent

which has been infringed.” The order here instructed the

FDA that “the effective date of any final approval . . . of

Norwich’s ANDA No. 214369 is to be a date not earlier

than the date of expiration of the last to expire of [the HE

patents] (currently October 2, 2029).” J.A. 51.

Norwich argues that the language of § 271(e)(4)

requires courts to tie the restriction on FDA approval

to the indication for which the ANDA seeks approval

when that indication was the source of infringement.

Cross-Appellants’ Br. at 14. Norwich’s ANDA originally

sought approval for the treatment of both IBS-D and HE.

Although only the HE indication was found to infringe

a valid patent, the order restricted final approval of the

entire ANDA, including the non-infringing indication,

until 2029. Norwich argues that the statute requires the

district court’s order “to specify that the approval date

pertains to Norwich’s ANDA seeking approval for the

infringing HE Indication.” Id. at 18. But the district court

order concerned only the specific ANDA in question that

included an infringing use, referred to the ANDA by its

number, and enjoined the approval of that ANDA. J.A. 51.

Norwich suggests that the district court order unfairly

precludes it from receiving final approval of a new noninfringing ANDA.10 The district court did no such thing.

10. Norwich notes that on June 2, 2023, FDA tentatively

approved its amended ANDA, which purportedly lacks the HE

indication. Cross-Appellant’s Br. at 6. The tentative approval letter

noted, however, that “final approval cannot be granted until October

2, 2029 as specified in the court order.” Id.

23a

Appendix A

Section 271(e)(4)(A) describes delaying the approval

of “the drug . . . involved in the infringement.” Since the

FDA does not approve drugs in the abstract, but rather

approves drugs for particular uses (indications) of that

drug, the statute is appropriately construed as directed

to approval of particular infringing uses of the drug, not

all uses of the drug including non-infringing uses. The

statutory scheme makes clear that it is not the potential

use of Norwich’s rifaximin for HE that constitutes the

relevant infringement here, nor is it the unpatented drug

compound itself, but rather it is the submission of the

ANDA that included an infringing use. See 35 U.S.C. §

271(e)(2)(A) (making it an “act of infringement to submit”

an ANDA “for a drug claimed in a patent or the use of

which is claimed in a patent”). That the ANDA further

recited a non-patent-protected indication does not negate

the infringement resulting from the ANDA’s submission.

The order thus appropriately delayed the effective final

approval date of “this infringing ANDA” submission.

J.A. 48. The order appropriately said nothing that would

prevent approval of a new non-infringing ANDA.

We therefore affirm the district court’s order setting

the effective approval date of Norwich’s ANDA No. 214369

to be no earlier than the date of expiration of the last to

expire of the HE patents.

B.

Following entry of the final judgment, which included

the resetting order barring final approval of Norwich’s

ANDA until 2029, Norwich amended its ANDA in an

24a

Appendix A

attempt to remove the infringing HE indication. Norwich

then moved to modify the judgment under Federal Rule

of Civil Procedure 60(b), asserting that the amendment

negated any possible infringement, and that the final

approval date of the ANDA, as amended, should not be tied

to the HE patents. See Cross-Appellant’s Br. at 27. The

district court denied that motion, holding that Norwich

“fully litigated the merits of its non-infringement and

invalidity case, lost, and now seeks a way around the final

judgment through Rule 60(b).” Rule 60(b) Order, 2023 U.S.

Dist. LEXIS 86257, [WL] at *2. Norwich cross-appealed.

“Because denial of a Rule 60(b) motion is a procedural

issue not unique to patent law, we apply the rule of the

regional circuit where appeals from the district court

would normally lie,” Amstar Corp. v. Envirotech Corp.,

823 F.2d 1538, 1550 (Fed. Cir. 1987), which, here, is the

Third Circuit. The Third Circuit “review[s] the denial of

Rule 60(b) relief for an abuse of discretion.” Coltec Indus.,

Inc. v. Hobgood, 280 F.3d 262, 269 (3d Cir. 2002); see also

Bohus v. Beloff, 950 F.2d 919, 930 (3d Cir. 1991) (noting

that Rule 60(b) motions are “extraordinary relief which

should be granted only where extraordinary justifying

circumstances are present” (citation omitted)).

“A district court may reconsider its own finding of

infringement in light of an amended ANDA,” but the court

need not do so. Ferring B.V. v. Watson Lab’ys, Inc. Fla.,

764 F.3d 1382, 1391 (Fed. Cir. 2014). Rather, “[a]llowing

an amendment is within the discretion of the district

court, guided by principles of fairness and prejudice

to the patent-holder.” Id. Here, the court reasonably

25a

Appendix A

held that consideration of the amended ANDA would be

inequitable and inappropriate. Rule 60(b) Order, 2023

U.S. Dist. LEXIS 86257, [WL] at *2. The court noted that

“[i]t is not a simple matter to determine whether an ANDA

applicant has successfully carved out language from a

label to turn infringement into non-infringement” and

that what Norwich sought in its Rule 60(b) motion “would

essentially be a second litigation” following final judgment.

Id. (noting also that, other than simply asserting that it

carved out the HE indication and providing the court with

the amended label, Norwich “ha[d] presented no evidence

in support of its assertion” that the amended ANDA would

no longer infringe the HE patents).

Norwich nevertheless argues that the amended

ANDA satisfies the judgment by not seeking approval for

the infringing use and that, in view of the amendment, it

is no longer equitable to apply the judgment prospectively.

But Rule 60(b) is permissive, holding only that the court

“may relieve a party or its legal representative from

a final judgment, order, or proceeding” under various

circumstances. That is—a district court has the discretion,

not the obligation, to modify a final judgment in view of

a post-judgment ANDA amendment. And as the district

court held, simply asserting that a patented indication

has been carved out of an ANDA application does not

necessarily satisfy the judgment or entitle the applicant

to direct entry to the market. See Rule 60(b) Order, 2023

U.S. Dist. LEXIS 86257, [WL] at *2. We see no abuse of

discretion in the district court reaching that conclusion

or in subsequently denying the motion.

26a

Appendix A

Norwich further argues that the district court erred

by not explicitly discussing Rule 60(b)(6), which provides

that a court may relieve a party from a final judgment

for “any other reason that justifies relief.” We disagree

that the district court so erred. The court’s Memorandum

Order thoroughly discussed the law, the equities, the

record, and the arguments before it. In so doing, the

court implicitly found no additional reason that justified

the relief that Norwich sought.

We therefore affirm the district court’s denial of the

motion to modify the final judgment.

Conclusion

We have considered both parties remaining arguments

and find them unpersuasive. For the foregoing reasons, we

affirm (1) the district court’s holding that claim 2 of the

’569 patent, claim 3 of the ’667 patent, claim 4 of the ’199

patent, and claim 36 of the ’206 patent would have been

invalid as obvious, (2) the district court’s order setting

the effective approval date of Norwich’s ANDA to be no

earlier than the date of expiration of the last to expire of

the HE patents, and (3) the district court’s denial of the

motion to modify the final judgment.

AFFIRMED

costs

No costs.

27a

Appendix A

Cunningham, Circuit Judge, dissenting in part.

I join most of the majority’s opinion, but I respectfully

dissent from the majority’s opinion concerning U.S. Patent

Nos. 8,309,569 and 10,765,667 (the “IBS-D patents”).

I would vacate the district court’s judgment that the

asserted claims of the IBS-D patents are obvious and

remand for further proceedings.

I

The district court found that “[t]he asserted IBS-D

claims describe a dosing regimen within the known range”

and that “[a] POSA would have been motivated to combine

the RFIB 2001 Protocol1 and Pimentel 2006 2 with a

reasonable expectation of success.” Salix Pharms., Ltd. v.

Norwich Pharms., Inc., No. 20-430-RGA, 2022 U.S. Dist.

LEXIS 142335, 2022 WL 3225381, at *17 (D. Del. Aug.

10, 2022) (“Decision”) (footnotes added). Based on these

findings of fact, the court concluded that “Pimentel 2006

in light of the RFIB 2001 Protocol renders the asserted

claims of the IBS-D patents obvious.” 2022 U.S. Dist.

1. Cl i n ica lT r ia ls.gov, Hi st o r y of Ch an ges fo r Stu dy:

NCT00269412, Randomized, Double Blind, Placebo-Controlled

Study to Assess the Efficacy and Safety of Three Different Doses

of Rifaximin Administered BID Either Two or Four Weeks in the

Treatment of Patients with Diarrhea-Associated Irritable Bowel

Syndrome (December 22, 2005); J.A. 7048-55.

2. M. Pimentel et al., The Effect of a Nonabsorbed Oral

Antibiotic (Rifaximin) on the Symptoms of the Irritable Bowel

Syndrome, 145 ANNALS INTERN. MED. 557 (2006); J.A. 4639-46.

The majority refers to this reference as Pimentel.

28a

Appendix A

LEXIS 142335, [WL] at *18. After reviewing the evidence

relied on by the district court, applying a clear error

standard, I am “left with the definite and firm conviction

that a mistake has been committed” regarding these

findings. Pfizer, Inc. v. Apotex, Inc., 480 F.3d 1348, 1359

(Fed. Cir. 2007) (quoting United States v. U.S. Gypsum

Co., 333 U.S. 364, 395, 68 S. Ct. 525, 92 L. Ed. 746 (1948)).

The evidence cited by the district court does not

support its finding that a skilled artisan would have a

reasonable expectation of success for the claimed dosage.

See Decision, 2022 U.S. Dist. LEXIS 142335, [WL] at *17,

*19. “The reasonable-expectation-of-success analysis must

be tied to the scope of the claimed invention”—here, the

claimed 1,650 mg/day (550 mg TID3) dosage for treating

IBS-D. Teva Pharms. USA, Inc. v. Corcept Therapeutics,

Inc., 18 F.4th 1377, 1381 (Fed. Cir. 2021). The district

court mainly relied on the results of the RFIB 2001 trial

disclosed in the RFIB 2001 Press Release4 in arriving at

this conclusion. Decision, 2022 U.S. Dist. LEXIS 142335,

[WL] at *19. However, there is no reason that a skilled

artisan “would have known about the successful RFIB

2001 Protocol results,” id., as to the claimed 1,650 mg/

day (550 mg TID) dosage because the RFIB 2001 Press

Release only discloses an improvement in the 550 mg

twice-a-day group. J.A. 7480; see Decision, 2022 U.S.

Dist. LEXIS 142335, [WL] at *19. In fact, evidence in

the record suggests the opposite—that a skilled artisan

3. TID stands for three times per day.

4. Salix Pharms., Ltd., Current Report (Form 8-K) (Sept. 5,

2007); J.A. 7477-82.

29a

Appendix A

might have understood the absence of discussions of the

1,100 mg twice-a-day group to imply that higher dosage

did not lead to similar successful results. See J.A. 3313-14.

Indeed, the 2,200 mg/day dosage “did not achieve more

responders compared to the placebo for adequate relief.”5

J.A. 3042. Thus, the court’s reliance on the RFIB 2001

Press Release to establish a reasonable expectation of

success was erroneous.6

The district court’s citations to other references do

not cure this error. Cuoco7 discloses a total dose of 1,200

mg/day for 14 days, and Barrett 8 similarly discloses 400

mg TID for a total dosage of 1,200 mg/day. Decision, 2022

U.S. Dist. LEXIS 142335, [WL] at *19; see also J.A. 4536;

5. Although the evidence that the 2,200 mg/day dosage did not

achieve adequate relief post-dates the priority date of the patent,

it clarifies what a skilled artisan would have understood from the

RFIB 2001 Press Release. See Syntex (U.S.A.) LLC v. Apotex, Inc.,

407 F.3d 1371, 1379 (Fed. Cir. 2005) (holding district court erred in

not considering a reference that post-dates the priority date when

it is relevant to what “was known in the art at the relevant time”).

6. Salix also challenges the district court’s finding that the

RFIB 2001 Press Release was prior art. Appellant’s Br. 30-39;

Decision, 2022 U.S. Dist. LEXIS 142335, [WL] at *20. I agree with

the majority that we do not need to reach this issue.

7. L. Cuoco & M. Salvagnini, Small intestine bacterial

overgrowth in irritable bowel syndrome: a retrospective study

with rifaximin, 52 Minerva Gastroenterol. Dietol. 89 (2006); J.A.

4533-39.

8. G. Barrett, Abstract, Benefits of the Antibiotic Rifaximin

as Empiric Therapy in Patients with Irritable Bowel Syndrome,

101 A m. J. Gastroenterol. S479 (2006); J.A. 4799-4800.

30a

Appendix A

J.A. 4800. The district court did not explain why these

references would give rise to a reasonable expectation

of success for a dosage that is almost 40% higher. The

reference by the district court to the “[w]idespread offlabel use” of rifaximin was also unaccompanied by any

discussion of dosages or citations to the record. Decision,

2022 U.S. Dist. LEXIS 142335, [WL] at *19. Likewise, it

discussed market research that shows many physicians

prescribe rifaximin for IBS without discussing their

prescribed dosages. Decision, 2022 U.S. Dist. LEXIS

142335, [WL] at *20 (citing J.A. 7186). The cited research

does not show that physicians prescribe at the 1,650 mg/

day (550 mg/TID) dosage. J.A. 7186.

Although “efficacy data is [not] always required for

a reasonable expectation of success,” OSI Pharms., LLC

v. Apotex Inc., 939 F.3d 1375, 1385 (Fed. Cir. 2019), the

analysis must still be tied to the scope of the claims—here,

the 1,650 mg/day dosage. See Teva, 18 F.4th at 1381; see

also In re Cyclobenzaprine Hydrochloride ExtendedRelease Capsule Pat. Litig., 676 F.3d 1063, 1070-72 (Fed.

Cir. 2012) (finding no reasonable expectation of success

when the court “cited no evidence specifically indicating

that a [drug with a pK profile disclosed in the prior art]

would be expected to yield the same therapeutic effect as [a

different pK profile as claimed]”); Ferring B.V. v. Watson

Lab’ys, Inc.-Fla., 764 F.3d 1401, 1407 (Fed. Cir. 2014)

(finding asserted claims not to be invalid for obviousness

when prior art references “disclose 500 mg [] formulations,

but no higher tablet strengths, and particularly not the

claimed 650 mg formulation”). Aside from its erroneous

reliance on the RFIB 2001 Press Release, the district

31a

Appendix A

court failed to tie its reasonable expectation of success

analysis to the claimed dosage. Therefore, I would find

that it clearly erred in its reasonable expectation of success

analysis.

In sum, the district court clearly erred in relying on

the RFIB 2001 Press Release and other references that

do not teach the claimed dosage. For these reasons, I

would have found the district court’s finding to be clearly

erroneous and would vacate the district court’s judgment

that the IBS-D claims were invalid as obvious.

II

In aff irming the district court’s judg ment of

obviousness, the majority relies on one additional sentence

in Pimentel 2006 regarding the reasonable expectation of

success analysis: “Recent data suggest that the optimal

dosage of rifaximin may, in fact, be higher than that used

in our study.” J.A. 4644; see Maj. Op. 8. But the lack of

discussion of any actual dosage that may be optimal, the

use of the word “may,” and the fact that the RFIB 2001

Protocol discloses a specific dosing regimen of 2,200 mg/

day rather than 1,650 mg/day all call into question the

majority’s finding. Indeed, the district court only relied

on this sentence in its motivation to combine analysis and

did not rely on this sentence in its reasonable expectation

of success analysis. See Decision, 2022 U.S. Dist. LEXIS

142335, [WL] at *18-20. The parties never made this

argument before us. Therefore, I disagree that this

additional sentence, when considered together with the

RFIB 2001 Protocol, would give rise to a reasonable

expectation of success for the claimed dosage.

32a

Appendix A

The majority also discusses references not relied

on by the district court in its reasonable expectation of

success analysis, including Lauritano9, Scarpellini10, and

Lin.11 Maj. Op. 9-10. But the district court did not make

any findings on what these references teach, other than

finding that the references were prior art. See Decision,

2022 U.S. Dist. LEXIS 142335, [WL] at *17-22. Nor are

the majority’s conclusions regarding these references

uncontested. For example, Salix argues that Scarpellini

and Lauritano are both directed to the treatment of

small intestinal bacterial overgrowth (SIBO), not to the

treatment of IBS or IBS-D, and therefore cannot establish

a reasonable expectation of success. Appellant’s Reply Br.

18. Although the majority may be right that Lauritano’s

and Scarpellini’s disclosures on treating SIBO also

support finding a reasonable expectation of success for

treating IBS-D, see Maj. Op. 9-10, the district court never

made this finding. See Golden Bridge Tech., Inc. v. Nokia,

Inc., 527 F.3d 1318, 1323 (Fed. Cir. 2008) (declining to find

what a prior art reference teaches in the first instance).

It merely found that “[t]he relationship between IBS and

SIBO was actively being explored,” and that certain prior

art references “do not teach away from using rifaximin

9. E.C. Lauritano et al., Rifaximin dose-finding study for the

treatment of small intestinal bacterial overgrowth, 22 A liment.

Pharmacol. Ther. 31 (2005); J.A. 7267-71.

10. E. Scarpellini et al., High dosage rifaximin for the

treatment of small intestinal bacterial overgrowth, 25 A liment.

Pharmacol. Ther. 781 (2007); J.A. 4663-67.

11. International Patent Application Publication No. WO

2006/102536; J.A. 4721-47.

33a

Appendix A

to treat IBS.” Decision, 2022 U.S. Dist. LEXIS 142335,

[WL] at *21. I would not make such fact-findings about

Scarpellini and Lauritano in the first instance.

In summary, I would vacate the district court’s

judgment that the asserted claims of the IBS-D patents

were obvious and remand for further proceedings. On

remand, I would order the district court to consider in

the first instance the teachings in the additional prior art

references. See ACS Hosp. Sys., Inc. v. Montefiore Hosp.,

732 F.2d 1572, 1578 (Fed. Cir. 1984) (“Where the trial

court fails to make findings, the judgment will normally be

vacated and the action remanded for appropriate findings

to be made.”). Accordingly, I respectfully dissent in part.

34a

B

APPENDIX B —Appendix

TRIAL OPINION

OF THE

UNITED STATES DISTRICT COURT FOR

THE DISTRICT OF DELAWARE,

FILED AUGUST 10, 2022

UNITED STATES DISTRICT COURT

FOR THE DISTRICT OF DELAWARE

Civil Action No. 20-430-RGA

SALIX PHARMACEUTICALS, LTD.; SALIX

PHARMACEUTICALS, INC.; BAUSCH HEALTH

IRELAND LTD.; ALFASIGMA S.P.A.,

Plaintiffs,

v.

NORWICH PHARMACEUTICALS, INC.,

Defendant.

August 10, 2022, Decided

August 10, 2022, Filed

Signed August 10, 2022

TRIAL OPINION

ANDREWS, U.S. DISTRICT JUDGE:

Salix sued Norwich for infringement of twenty-six

patents that cover Salix’s branded Xifaxan (rifaximin) 550

mg tablets. (D.I. 59 ¶¶ 12, 41). Before trial, Salix narrowed

35a

Appendix B

its case to U.S. Patent Nos. 7,612,199, 7,902,206 (“the

Polymorph Patents”), 8,642,573, 9,421,195, 10,335,397

(“the HE Patents”), 8,309,569, and 10,765,667 (“the IBS-D

Patents”). In March 2022, I held a four-day bench trial.

(D.I. 168-172, hereinafter “Tr.”).

I.

BACKGROUND

Norwich submitted an Abbreviated New Drug

Application (ANDA) to the Food and Drug Administration

(FDA) for approval to market a generic version of Xifaxan.

Salix alleges infringement under § 271(e)(2)(A) of the

Patent Act. 35 U.S.C. §271(e)(2)(A). Norwich counters that

the asserted patents are invalid.

In 2004, the FDA approved Xifaxan (rifaximin) 200

mg tablets to treat travelers’ diarrhea. (D.I. 155 ¶ 9). On

March 24, 2010, the FDA approved Xifaxan (rifaximin)

550 mg tablets to reduce the risk of overt hepatic

encephalopathy (“HE”) recurrence in adults. (Id. ¶10). On

May 27, 2015, the 550 mg tablets were approved to treat

irritable bowel syndrome with diarrhea (“IBS-D”) in

adults. (Id. ¶11). The asserted patents cover a polymorphic

form of rifaximin and methods of treating HE and IBS-D

in adults.

II. LEGAL STANDARD

A.

Infringement

A patent is directly infringed when a person “without

authority makes, uses, offers to sell, or sells any patented

36a

Appendix B

invention, within the United States . . . during the term of

the patent . . . .” 35 U.S.C. § 271(a). A two-step analysis is

employed in making an infringement determination. See

Markman v. Westview Instruments, Inc., 52 F.3d 967,

976 (Fed. Cir. 1995) (en banc), aff’d, 517 U.S. 370, 116 S.

Ct. 1384, 134 L. Ed. 2d 577 (1996). First, the court must

construe the asserted claims to ascertain their meaning

and scope. See id. The trier of fact must then compare the

properly construed claims with the accused infringing

product. See id. This second step is a question of fact.

See Bai v. L & L Wings, Inc., 160 F.3d 1350, 1353 (Fed.

Cir. 1998).

“Under § 271(b), whoever actively induces infringement

of a patent shall be liable as an infringer.” Warner-Lambert

Co. v. Apotex Corp., 316 F.3d 1348, 1363 (Fed. Cir. 2003).

To prevail on a theory of induced infringement, a plaintiff

must prove (1) direct infringement and (2) “that the

defendant possessed specific intent to encourage another’s

infringement and not merely that the defendant had

knowledge of the acts alleged to constitute infringement.”

Vanda Pharms. Inc. v. West-Ward Pharms. Int’l Ltd., 887

F.3d 1117, 1129 (Fed. Cir. 2019) (quoting DSU Med. Corp.

v. JMS Co., 471 F.3d 1293, 1306 (Fed. Cir. 2006)).

In a Hatch-Waxman case, a plaintiff “can satisfy

its burden to prove the predicate direct infringement

by showing that if the proposed ANDA product were

marketed, it would infringe the [asserted patent].” Vanda,

887 F.3d at 1130. For method-of-treatment patents, if

an ANDA applicant’s “proposed label instructs users to

perform the patented method . . . , the proposed label may

37a

Appendix B

provide evidence of [the ANDA applicant’s] affirmative

intent to induce infringement.” AstraZeneca LP v. Apotex,

Inc., 633 F.3d 1042, 1060 (Fed. Cir. 2010). “When proof

of specific intent depends on the label accompanying the

marketing of a drug inducing infringement by physicians,

the label must encourage, recommend, or promote

infringement” Vanda, 887 F.3d at 1129 (cleaned up).

B. Obviousness

A patent is invalid as obvious under 35 U.S.C. § 103 if

“the claimed invention as a whole would have been obvious

to a person of ordinary skill in the art at the time the

invention was made.” Kahn v. GMC, 135 F.3d 1472, 1479

(Fed. Cir. 1998). “Obviousness is a question of law based on

underlying factual findings: (1) the scope and content of the

prior art; (2) the differences between the claims and the

prior art; (3) the level of ordinary skill in the art; and (4)

objective considerations of nonobviousness.” In re Morsa,

713 F.3d 104, 109 (Fed. Cir. 2013) (citations omitted).

To show a patent is obvious, a party “must demonstrate

by clear and convincing evidence that a skilled artisan

would have been motivated to combine the teachings of

the prior art references to achieve the claimed invention,

and that the skilled artisan would have had a reasonable

expectation of success in doing so.” InTouch Techs., Inc. v.

VGo Communs., Inc., 751 F.3d 1327, 1347 (Fed. Cir. 2014)

(cleaned up). The overall inquiry into obviousness, though,

must be “expansive and flexible.” KSR Int’l Co. v. Teleflex

Inc., 550 U.S. 398, 415, 127 S. Ct. 1727, 167 L. Ed. 2d 705

(2007). In conducting the obviousness analysis, “a court

38a

Appendix B

can take account of the inferences and creative steps that

a of skill in the art would Id. at 418.

C.

Written Description

The written description “must clearly allow persons

of ordinary skill in the art to recognize that the inventor

invented what is claimed.” Ariad Pharms., Inc. v. Eli

Lilly & Co., 598 F.3d 1336, 1351 (Fed.Cir.2010) (en banc)

(cleaned up). The test is whether the disclosure “conveys to

those skilled in the art that the inventor had possession of

the claimed subject matter as of the filing date.” Id. This

requires an “objective inquiry into the four corners of the

specification from the perspective of a person of ordinary

skill in the art.” Id.

D.

Indefiniteness

35 U.S.C. § 112 requires that claims “particularly

point[] out and distinctly claim[] the subject matter.” The

claims, viewed in light of the specification and prosecution

history, must “inform those skilled in the art about

the scope of the invention with reasonable certainty.”

Nautilus, Inc. v. Biosig Instruments, Inc., 572 U.S. 898,

910, 134 S. Ct. 2120, 189 L. Ed. 2d 37 (2014). “While a

claim employing a term of degree may be definite where

it provides enough certainty to one of skill in the art when

read in the context of the invention, a term of degree that

is purely subjective and depends on the unpredictable

vagaries of any one person’s opinion is indefinite.” Intell.

Ventures I LLC v. T-Mobile USA Inc., 902 F.3d 1372, 1381

(Fed. Cir 2018) (cleaned up)

39a

Appendix B

III.

THE POLYMORPH PATENTS

The Polymorph Patents claim polymorphic forms of

rifaximin. Plaintiffs assert two such claims. Asserted

Claim 4 of the ’199 patent states:

4. Rifaximin in polymorphic form β, wherein

the rifaximin has x-ray powder diffraction

pattern peaks at about 5.4°; 9.0°; and 20.9° 20

and wherein the rifaximin has a water content

of greater than 5%.

Asserted Claim 36 of the ’206 patent depends on claim 34:

3 4. A solid phar maceutical composition

comprising rifaximin in polymorphic Form β

and a pharmaceutically acceptable excipient or

carrier, wherein the rifaximin Form β has x-ray

powder diffraction pattern peaks at about 5.4°;

9.0°; and 20.9° 2-0.

36. The pharmaceutical composition of claim

34, wherein the rifaximin Form β has a water

content of between about 4.5% to about 40%.

A.

Findings of Fact

1.

If approved, Norwich’s ANDA product will

infringe the asserted claims of the Polymorph

Patents.

40a

Appendix B

2.

The priority date of the asserted polymorph

claims is November 7, 2003.

3.

A person of skill in the art (a “POSA”) would have

had a B.S. in chemistry, chemical engineering,

or a related discipline with at least 3 years’

experience in the pharmaceutical industry

related to API manufacturing, crystallization,

characterization, or evaluation of solid state

forms. Or a POSA would have had an advanced

degree with less or no experience.

4.

The ’199 patent is a continuation of, and contains

substantially the same disclosures as, the ’206

patent.

5.

Rifaximin exists in polymorphic forms. Norwich’s

ANDA product comprises polymorphic form β.

6.

7.

X-ray powder diffraction (XRPD) peaks are an

inherent characteristic of a polymorph. Each

peak in an XRPD diffractogram is a structural

element of that form. XRPD was routine as of the

priority date.

A crystalline form of a known compound can be

characterized by a subset of XRPD peaks. The

subset of XRPD peaks at about 5.4°, 9.0°, and

20.9° 28 was sufficient as of the priority date to

distinguish rifaximin β from the other known

rifaximin polymorphs.

41a

Appendix B

8.

Water content is an inherent characteristic of a

crystal form that can be determined by routine

testing methods such as Karl Fischer (KF) or

thermogravimetric analysis (TGA).

9.

Cannata, Marchi, and the Normix Label are prior

art.

10. Cannata disclosed crystalline rifaximin, methods

of making it, and that it had antibacterial

properties.

11. The four post-filing references relied upon

by Defendant’s expert, Dr. Zaworotko, do not

show that any of the Cannata methods produces

rifaximin β every time.

12. Cannata does not inherently anticipate the

asserted polymorph claims.

13. Marchi disclosed methods of preparing crystalline

rifaximin, rifaximin’s antibacterial properties,

and that it could be used in pharmaceutical

compositions with conventional pharmaceutically

acceptable excipients or carriers.

14. The Normix Label describes the use of rifaximin

as a pharmaceutical.

15. Cannata in view of common knowledge discloses

each and every limitation of claim 4 of the ’199

patent.

42a

Appendix B

16. A POSA would have had a motivation to combine

Cannata with commonly known testing techniques

XRPD and KF or TGA because regulatory

bodies instructed applicants to characterize the

solubility, stability, and bioavailability of drug

candidates.

17. A POSA would have had a reasonable expectation

of success at characterizing the rifaximin β

polymorph and arriving at the claimed XRPD

peaks at about 5.4°, 9.0°, and 20.9° 20 and water

content of greater than 5%.

18. Marchi in view of Cannata and common knowledge

discloses each and every limitation of claim 36 of

the ’206 patent.

19. A POSA would have had a motivation to combine

Cannata w ith Marchi in light of common

knowledge.

20. A POSA would have had a reasonable expectation

of success at achieving a phar maceutical

composition comprising rifaximin β and a

pharmaceutically acceptable excipient or carrier.

21. All rifaximin β claim limitations are expressly

disclosed in the specifications of the Polymorph

Patents..

43a

Appendix B

B. Infringement

Norwich admits that its ANDA Product, if approved,

will infringe claim 4 of the ’199 patent and claim 36 of the

’206 patent. (DJ. 148, Ex. 1, ¶¶ 126, 127).

C.

Invalidity

1.

Inherent Anticipation

Each expert asserts that his validity analysis is not

impacted by which definition of a POSA I use. (Tr. 860:7861:8; Tr. 936:21-937:13). In view of Defendant’s burden to

prove invalidity by clear and convincing evidence, I will

adopt Plaintiffs’ definition of a POSA.

Norwich argues that U.S. Patent No. 4,557,866 (the

“Cannata” reference) (JTX-37) inherently anticipates

claim 4 of the ’199 patent because it discloses a process

that necessarily produces the claimed rifaximin β. (D.I.

176 at 32). “[A] prior art reference may anticipate without

disclosing a feature of the claimed invention if that

missing characteristic is necessarily present, or inherent,

in the single anticipating reference.” Schering Corp. v.

Geneva Pharms., Inc., 339 F.3d 1373, 1377 (Fed. Cir.

2003). A disclosed process may anticipate “if it discloses

in an enabling manner the production” of the claimed

polymorph. SmithKline Beecham Corp. v. Apotex Corp.,

403 F.3d 1331, 1344 (Fed. Cir. 2005).

Here, the issue is whether the process disclosed by

Cannata invariably produces rifaximin β Norwich has

presented the following evidence in support:

44a

Appendix B

• The “Viscomi Declaration,” a declaration to the PTO

stating that samples of batches produced according

to Cannata “are composed either of mixture of

polymorph (alpha and beta, and in some case alpha

and epsilon) or different polymorphs.” (JTX 80 ¶ 7).

• The “Viscomi 2008” article, which Norwich’s expert

Dr. Zaworotko testified shows that rifaximin β is a

necessary precursor to the formation of rifaximin

α, δ, and ϵ. (JTX 65; Tr. 880:20-881:1, 921:24-922:6).

• The “Braga 2012” article, which describes the

inherent properties of rifaximin β (JTX 105).

• The “Bacchi 2008” article, which described rifaximin

beta 4 (“RX4”), a substance the author concluded

was “the so-called beta rifaximin of the literature.”

(DTX 43; Tr. 882:14-24). The article describes slow

evaporation as the method of preparation. From

this article, Dr. Zaworotko concluded, “Examples 1

and 7, at the very least, of Cannata would have . . .

necessarily afforded rifaximin Beta because of the

solvent system used, the method used of controlled

crystallization, and the lack of drying or lack of

aggressive drying.” (Tr. 883:6-10).

According to this evidence, Norwich argues, “Cannata

inherently produced rifaximin β every time, either

directly or as a necessary precursor to the α, δ, and ϵ

forms and mixtures disclosed in the Viscomi Declaration.”

(D.I. 185 at 9).

45a

Appendix B

I do not think this evidence amounts to clear and

convincing evidence that Claim 4 is inherently anticipated

by Cannata. Norwich could have shown anticipation either

because (1) as a law of nature, rifaximin α, δ, and ϵ cannot

exist without having been derived from rifaximin β, or (2)

a method disclosed in Cannata produces rifaximin β each

and every time it is practiced. Dr. Zaworotko’s testimony

did not prove either.

Dr. Zaworotko’s opinion does not clearly support

the conclusion that, as a law of nature, rifaximin β is a

necessary precursor to rifaximin α, δ, and ϵ. For one thing,

had that been his opinion, he could have clearly stated that,

and I do not think he did. (See Tr. at 870-884). I think Dr.

Zaworotko’s opinion was relying upon the Viscomi 2008

article:

Q: Would rifaximin Beta form as a precursor to

any polymorph listed in the Viscomi declaration

listed at paragraph 7?

A: Yes, based upon the Viscomi 2008 article,

where the effect of moisture on rifaximin

crystal forms was studied and based upon the

diagram [derived from Viscomi 2008] it’s clear

that Beta has to be the precursor for any of the

other crystal forms with lower water content.

(Tr. 921:25-922:1). This opinion appears to be based

on Dr. Zaworotko’s reading of Viscomi 2008, and not a

conclusion that rifaximin α, δ, and ϵ cannot exist in the

world without having first been rifaximin β. I think Dr.

46a

Appendix B

Zaworotko stated his opinion the way he did because the

“diagram” to which Dr. Zawortko refers, which is based on

Figure 4 (“The relationship between the various crystal

forms of rifaximin”), was not the main point of the article.

The article’s purpose, consistent with its title (“Crystal

forms of rifaximin and their effect on pharmaceutical

properties”) was to report on a “study [] to identify the

presence of crystal forms of rifaximin and to assess

their impact on parameters such as solubility, intrinsic

dissolution and bioavailability.” (JTX-65 at 1074). The

paper concluded, “The unexpected outcome of this study is

that we have found that some crystal forms of rifaximin are

significantly absorbed, while it was previously considered

a non-absorbable drug. These finding[s] indicate the need

of putting appropriate manufacturing and analytical

procedures in place to consistently yield rifaximin of the

appropriate crystalline structure.” (Id. at 1080). Thus, to

the extent Dr. Zaworotko was offering an opinion that

Viscomi 2008 is conclusive proof that rifaximin α, δ, and

ϵ are necessarily derived from rifaximin β, I do not find

that conclusion to be well-supported. It is not clear and

convincing proof

Thus, to show that Cannata inherently anticipates

Claim 4, Norwich would need to show that every time

Cannata is performed, rifaximin β is produced. Norwich

has not done so.

The Viscomi Declaration does not help Norwich.

It stated that among “samples of batches” produced

according to Cannata, when retested in 2006, there

were four batches with no rifaximin β. The four batches

47a

Appendix B

consisted of (1) only the “delta polymorph,” (2) only of the

“epsilon form,” (3) a mixture of “the alpha and epsilon

form,” and (4) a mixture of the “alpha and delta forms,”

respectively. (JTX-80, ¶7; see Tr. 949:8-12).

Although Viscomi 2008 states that the “method of

production of rifaximin” was disclosed in European

Patent No. 161534, the counterpart to Cannata, Salix has

persuasively argued that Viscomi 2008 discloses steps that

are more specific than what Cannata describes. (See JTX

105 at 6404 n.3; JTX 65 at 1074 & 1074 n.29; Tr. 874:16-25).

In Viscomi 2008, the reaction step for preparing

wet rifaximin describes (1) heating the reaction mixture

to 50°C for 5 hours, then cooling it to 20°C; (2) adding

a mixture of 0.1 moles of ascorbic acid and 2.5 moles

of concentrated hydrochloric acid in 220 mL of 58%

ethyl alcohol in water over 30 minutes; and (3) adding

concentrated hydrochloric acid dropwise until pH 2.0 is

reached. (Tr. 951:8-13; JTX 65 at 1074). Cannata has none

of these details. (Tr. 951:13-17). The crystallization step

in Viscomi is also described with more precision than in

Cannata. (Tr. 951:18-952:2).

Similarly, Bacchi 2008 discloses a process that does

not precisely match Cannata’s examples 1 and 7. Bacchi

describes using a “slow evaporation” process while

Cannata does not mention evaporation. (DTX 43 at 1734;

Tr. 949:20-22). Furthermore, the Cannata examples

crystallize rifaximin from a 7:3 ethanol to water mixture,

whereas Bacchi does not disclose any ethanol to water

ratio. (Tr. 949:15-23; Tr. 953:2-954:3).

48a

Appendix B

Ultimately, it appears that Cannata left certain steps

up to the discretion of the chemist preparing the rifaximin.

To show that Cannata invariably produces rifaximin β,

Norwich would have needed to show that, no matter how

the chemist exercised his or her discretion, rifaximin β

would be produced. I do not think Norwich has done so.

“Experiments that do not follow the prior art procedure

alleged to inherently anticipate cannot show inherent

anticipation.” Merck & Cie v. Watson Lab’ys, Inc., 125

F. Supp. 3d 503, 513 (D. Del. 2015) (cleaned up), rev’d on

other grounds, 822 F.3d 1347 (Fed. Cir. 2016).

Thus, I find that Norwich has not shown by clear

and convincing evidence that claim 4 of the ’199 patent is

inherently anticipated by Cannata.

2.

Obviousness

Norwich contends that claim 4 of the ’199 patent is

obvious over Cannata in view of common knowledge. (DI

176 at 34-35). Norwich contends that claim 36 of the ’206

patent is obvious over Cannata in view of the Normix

Label and common knowledge or over Marchi in view of

Cannata and common knowledge. (Id. at 35).

A POSA would have understood from Cannata that

rifaximin exists in crystalline form and that rifaximin

has “outstanding antibacterial properties.” (JTX 37 at

3:10-16, 5:21-36). Norwich argues this knowledge would

motivate a POSA to “identify the characteristics of

the obtained rifaximin” using “routine methods.” (D.I.

176 at 35). Furthermore, Norwich argues that a POSA

49a

Appendix B

would recognize “that the crystallization solvent used

by Cannata included water, which could lead to hydrate

formation, and thus [the POSA] would have been motivated

to analyze the effect of water on the crystalline form

using conventional methods.” (Id.). A POSA could have

performed a “routine humidity experiment . . . in one day

and detected rifaximin β.” (Id.).

The Court of Appeals considered the obviousness of a

polymorph patent in Grunenthal GmbH v. Alkem Labs.

Ltd., 919 F.3d 1333, 1336 (Fed. Cir. 2019). The Grunenthal

patent claimed Form A of tapentadol hydrochloride

characterized by its XRPD peaks. Id. The Grunenthal

defendant, Alkem, argued that the claim was obvious in

light of prior art that disclosed a Form B of tapentadol

hydrochloride. Id. at 1337.

Alkem’s prior art references included (1) the prior

art patent that described a crystalline form of tapentadol

hydrochloride (later called “Form B”) and (2) an article

that “outlines a number of variables that may be adjusted

during the recrystallization process to determine whether

polymorphism occurs in a compound.” Id. at 1337, 1341.

The “polymorphism of tapentadol hydrochloride was

unknown at the time of filing the [asserted patent],” and

“Form B was the only crystal structure . . . known in the

art at the time.” Id. at 1341.

The Court of Appeals found that the article did not

provide “guidelines regarding which [variables] are

likely to result in polymorphs of particular compounds.”

Id. at 1342. Thus, the article did little more than tell a

50a

Appendix B

POSA to “vary all parameters or try each of numerous

possible choices until one possibly arrived at a successful

result,” which does not provide a reasonable expectation

of success. Id. (quoting Pfizer, Inc. v. Apotex, Inc., 480

F.3d 1348,1365 (Fed. Cir. 2007)).

Here, the prior art includes Cannata, which discloses

processes for preparing a crystalline form of rifaximin. As

in Grunenthal, rifaximin’s polymorphism was unknown

as of the priority date. In Grunenthal, however, the prior

art patent was known to produce a particular form—Form

B—of tapentadol hydrochloride. Here, by contrast, no

rifaximin had been publicly characterized as a particular

form as of the priority date.

I think the evidence is clear and convincing that a

POSA would have been motivated to characterize the

rifaximin produced by the Cannata processes. Cannata

disclosed that rifaximin had strong antibacterial

properties and low bioavailability, motivating a POSA

to evaluate the substance as a potential drug candidate.

(JTX 37 at 3:10-16; JTX 94 at 6-7; Tr. 869:16-870:4; Tr.

891:16-892:12). The FDA encouraged, if not required, that

the solid forms of a drug substance be well-characterized

during drug development, including as to the properties

of solubility, stability, and bioavailability. (DTX 315-35;

Tr. 892:13-894:7). XRPD profiling was the predominant

method for identifying crystalline materials. (DTX

315-38; Tr. 894:23-895:12). FDA guidance required

“appropriate manufacturing and control procedures”

when manufacturing and storing the drug substance could

result in a hydrated drug substance. (DTX 315-39; Tr.

51a

Appendix B

895:13-24). Because the Cannata process for preparing

rifaximin used water, a POSA would know about the

potential for a hydrate to form, and be motivated to

perform routine testing (e.g., KF or TGA) for water

content and hydration formation. (DTX 317-19; JTX 54

at 182; Tr. 888:3-890:5; DTX 315-39).

I think the evidence shows that a POSA would have

a reasonable expectation of success in characterizing the

polymorph β, as opposed to the other forms of rifaximin.

Although Norwich’s evidence failed to show that β was

produced each and every time rifaximin was prepared

according to Cannata, it did strongly suggest that

polymorph β is a commonly produced polymorph and the

most stable form of rifaximin.

The Viscomi Declaration stated that rifaximin

prepared according to Cannata yielded β along with other

polymorphs. (JTX 80 at ¶ 7). Dr. Zaworotko explained

that β is the most stable form. Tr. 877:17-18. (“[B]eta is

the winner in terms of stability under normal conditions

of temperature and humidity.”). Dr. Myerson’s critiques

of Dr. Zaworotko’s testimony do not have the same force

in the context of obviousness as they did in the context

of inherent anticipation. While Viscomi 2008’s increased

specificity in the method of preparation suffices to suggest

that Cannata may not produce rifaximin β each and every

time (as would be required for inherent anticipation), the

standard for obviousness is a reasonable expectation of

success. See Medichem, S.A. v. Rolabo, S.L., 437 F.3d 1157,

1165 (Fed. Cir. 2006) (“While the definition of ‘reasonable

expectation’ is somewhat vague, our case law makes clear

that it does not require a certainty of success.”).

52a

Appendix B

I reject Salix’s argument that a POSA would not have

been able to predict the precise peaks that characterize

rifaximin β, and accordingly a POSA would not have had

a reasonable expectation of success. The Federal Circuit

has held, “[A] rule of law equating unpredictability to

patentability, applied in this case, would mean that any

new salt . . . would be separately patentable, simply

because the formation and properties of each salt must

be verified through testing. This cannot be the proper

standard since the expectation of success need only be

reasonable, not absolute.” Pfizer, Inc. v. Apotex, Inc., 480

F.3d 1348, 1364 (Fed. Cir. 2007). I think the same is true

in this context. I credit the testimony of Dr. Zaworotko

that the XRPD peaks and water content are “inherent”

properties of a crystal form that can be tested using

routine methods. (Tr. 871:20-872:5; 884:2-13; 895:8-12).

Thus, a POSA would have a reasonable expectation of

success at characterizing the polymorph and arriving at

the claimed XRPD peaks and water contents.1

There is no evidence of secondary considerations of

nonobviousness for the Polymorph Patents. (See D.I. 174

at 15-18).

Thus, I find by clear and convincing evidence that

claim 4 of the ’199 patent is obvious in light of Cannata in

view of common knowledge.

1. Plaintiffs call to my attention Pharmacyclics LLC v. Alvogen

Pine Brook LLC, 556 F. Supp. 3d 377, 412 (D. Del. 2021), app.

filed, No. 21-2270 (Fed. Cir. Aug. 31, 2021). (D.I. 181 at 37). I have

considered that case but I do not agree with it on this point.

53a

Appendix B

Claim 36 of the ’206 patent claims a pharmaceutical

composition comprising (1) rifaximin β with the claimed

XRPD peaks and a water content between about 4.5% to

40% and (2) a pharmaceutically acceptable excipient or

carrier.

Norwich argues that rifaximin had previously been

formulated as a pharmaceutical composition comprising

pharmaceutically acceptable excipients or carriers. (D.I.

176 at 37). Marchi in 1982 and the Normix Label in 2001

each taught “pharmaceutical compositions” comprising

rifaximin. (Id.). Marchi disclosed that rifaximin can be

used as an “antibacterial agent[]” in pharmaceutical

compositions w ith conventional pharmaceutically

acceptable excipients or carriers. (JTX 48 at 4:27-33,

4:67-5:4, 5:14-40, 60-62, 6:6-31, Cls. 10-11; Tr. 865:10866:12, 868:20-869:3). The Normix Label disclosed that

rifaximin was an approved antibacterial drug in Italy in

1985 as a coated tablet comprising 200 mg of rifaximin

and pharmaceutically acceptable excipients. (JTX 94 at

5, 7-8; Tr. 867:13-17, 869:10-870:4, 903:3-9).

Norwich further argues that rifaximin’s antibacterial

properties were known. Cannata taught that rifaximin has

outstanding antibiotic properties and has poor absorption,

which indicates to a POSA that it could be used for

GI treatments. (Tr. 862:22-24; 863:14-18). Marchi also

disclosed “remarkable” antibacterial properties. (JTX 48

at 4:27-33, 4:67-5:4, 5:14-40, 5:60-62, 6:6-31, Cls. 10-11; Tr.

865:10-866:12, 868:20-869:3).

54a

Appendix B

Salix did not respond to these arguments. (See D.I.

181 at 37-39).

T he on ly d i f fe r enc e b et we en t he pr e v iou s

pharmaceutical compositions of rifaximin and claim 36

is that claim 36 characterizes rifaximin as polymorphic

form β Rifaximin β is obvious over Cannata in view of

common knowledge, for the same reasons as previously

stated in connection with asserted claim 4 of the ’199

patent. Accordingly, I find that a POSA would have had

the motivation to combine the prior art references of

Cannata, the Normix Label, or Marchi and Cannata, in

view of the commonly known testing techniques, with a

reasonable expectation of success in doing so. Salix offers

no evidence or arguments to the contrary. Thus, Norwich

has proved by clear and convincing evidence that claim 36

of the ’206 patent is invalid as obvious.

3. Written Description

The asserted claims describe rifaximin β as having

XRPD peaks “at about 5.4°, 9.0°, and 20.9° 20.”’199

Patent, Cl. 4, ’206 Patent, Cl. 36. The specification states

that rifaximin β is “characterized . . . by a powder X-ray

diffractogram (reported in FIG. 2) which shows peaks

at the values of the diffraction angles 20 of 5.4°; 6.4°;

7.0°; 7.8°; 9.0°; 10.4°; 13.1°; 14.4°; 17.1°; 17.90°; 18.30°;

20.9°.”’199 Patent 5:64-6:3. Norwich argues that the

polymorph patents improperly claim a genus, whereas

the specification recites only a species. (D.I. 176 at 37-38).

Salix responds that (1) the claims, on their face, are

limited to the specific polymorphic form rifaximin β,

55a

Appendix B

rendering Norwich’s genus characterization inaccurate,

and (2) even if Norwich is right, the claims identify

structural features common to the genus as required by

the caselaw. (D.I. 181 at 39-42). I agree with Salix on the

first point, and accordingly will not address Salix’s second

argument.

The evidence shows that a subset of XRPD peaks

can identify the polymorph. The “normal practice at the

USPTO” is to claim a polymorphic form using “at least

three powder diffraction pattern peaks.” (Tr. 965:11-17;

JTX 28 at XIFAX_NOR_0002208). Dr. Zaworotko’s own

patent explains, “For XRPD data herein, each composition

of the present invention[, a new crystalline form of a known

compound,] may be characterized by any one, any two, any

three, any four, any five, any six, any seven, or any eight

or more the 20 angle peaks.” (Tr. 916:17-917:18, PTX 707

at 15:36-39). I do not think the asserted claims claim a

genus. They claim only rifaximin β, a polymorphic form

which can be identified using the three peaks recited in

the claims.

Thus, I reject Norwich’s written description challenge.

IV. THE METHOD PATENTS

A.

Inducement

1.

1.

Findings of Fact

At least some physicians will review Norwich’s

label.

56a

Appendix B

2.

Physicians will instruct patients to take rifaximin

according to the instructions on the label.

2.

Infringement

Before tu r n i ng t o a l i m it at ion-by-l i m it at ion

infringement analysis for the method patents, I will address

an underlying dispute regarding induced infringement

when the patient is the one performing the patented

method. Inducement requires direct infringement. Salix

argues that either (1) the patients, in taking rifaximin, will

directly infringe “because patients will read and follow

the instructions in Norwich’s Label (with or without the

help of their physician),” or (2) physicians and patients will

jointly infringe based on the label. (D.I. 174 at 4). I do not

think there is joint infringement. I find that Plaintiffs have

not shown that doctors condition the patient’s receipt of a

rifaximin prescription on the performance of particular

steps in the way contemplated by Akamai. See Akamai

Techs., Inc. v. Limelight Networks, Inc., 797 F.3d 1020,

1023 (Fed. Cir. 2015) (en banc). Rather, the patients

directly infringe.

According to Norwich, “Because patients will not

take rifaximin correctly without physician instruction,

the Norwich Label does not induce patients and cannot

be the basis for finding specific intent.” (D.I. 183 at 3-4

(citation omitted)). Essentially, because there is another

party involved in the inducement (physicians), the “chain

of events leading to infringement is . . . too attenuated

to prove specific intent.” (D.I. 183 at 6-7). I disagree.

The Court of Appeals has long held, “the sale of a

57a

Appendix B

product specifically labeled for use in a patented method

constitutes inducement to infringe that patent[.]” Eli Lilly

& Co. v. Actavis Elizabeth LLC, 435 F. App’x 917, 926 (Fed.

Cir. 2011). In the context of a prescription medication,

physicians have a particularly important role in conveying

essential information to patients. The evidence in this

case bears this out. (See Tr. 66:22-69:20; Tr. 119:5120:16 (describing the process of prescribing rifaximin

to patients)). Other areas of law, such as the learned

intermediary doctrine, recognize the physician’s essential

role in communicating information about a medication to

the patient. See Reyes v. Wyeth Laboratories, 498 F.2d

1264, 1276 (5th Cir. 1974). A pharmaceutical company,

such as Norwich, is well aware of how doctors prescribe

medications to patients. Thus, if there will be direct

infringement, then Norwich will have the specific intent

to induce patients’ direct infringement.

B. The HE Patents

HE is a liver disease that affects the brain. (Tr.

41:15-21; 48:10-16). For patients with HE, the liver does

not properly filter toxins from the blood. These toxins

can cause changes to the patient’s mental state. (Id.)

Physicians grade HE severity using the Conn score, which

ranges from 0 to 4. (Tr. 45:14-47:4). Conn scores of 0 or

1 reflect a normal or near-normal mental state. A Conn

score of 2 or higher reflects more serious symptoms, from

obvious personality changes to stupor or even coma. (Tr.

46:6-11, 14-15). Conn scores of 0 and 1 cannot be detected in

a routine physical exam. (Tr. 45:20-21; 46:4-5). Physicians

also assess HE severity using an asterixis score. (Tr.

58a

Appendix B

346:5-8). Asterixis occurs when a patient cycles between

lower and higher levels of consciousness and can be

measured by tremors in a patient’s outstretched hand. (Tr.

46:16-47:4).+++ HE can be either episodic or persistent.

(Tr. 44:13-25). Persistent HE is characterized by a Conn

score that remains at 2 or above. (Tr. 44:24-25). Patients

with episodic HE have periods of remission punctuated

by episodes of breakthrough overt HE. (Tr. 44:13-25;

45:14-46:15). An episode of “breakthrough overt HE” is an

increase in the patient’s Conn score to grade 2 or higher

(e.g., going from 0 or 1 to 2 or more), or an increase in the

patient’s Conn and asterixis scores of one grade each with

a baseline Conn Score of 0. (D.I. 149, Ex. 1 ¶ 81). Patients

with a history of overt HE who are not currently having

an overt HE episode are in “remission of HE.” (Id. ¶ 81;

Tr. 48:2-6). Thus, patients with a Conn score of 0 or 1 and

no asterixis are in remission. (Tr. 48:2-6). After a first

overt HE episode, only about half of patients will live one

year. (Tr. 50:6-19).

Plaintiff asserts four method claims in connection

with the HE patents.

Asserted Claim 6 of the ’195 patent is a dependent

claim with three elements: (1) reducing the risk of HE

recurrence, (2) by orally administering about 550 mg of

rifaximin twice daily (BID) to the adult subject, (3) for a

period of 12 months or longer.

Asserted Claim 8 of the ’573 patent is a dependent

claim with three elements: (1) maintaining remission of

HE, wherein remission is defined as a Conn score of 0 or

59a

Appendix B

1, (2) by administering 550 mg of rifaximin to the subject

BID, (3) for a period of 12 months or longer.

Asserted Claim 11 of the ’397 patent is a dependent

claim with four elements: (1) reducing a subject’s risk of

experiencing a breakthrough overt HE episode, (2) by

orally administering to the subject 550 mg of rifaximin

BID, (3) for a period of about 12 months or longer, (4) to a

subject with a Conn score of 0 or 1.

Asserted Claim 12 of the ’397 patent is a dependent

claim with five elements: (1) reducing a subject’s risk of

experiencing a breakthrough overt HE episode, (2) by

orally administering to the subject between about 1000 mg

to about 1200 mg of rifaximin daily, (3) for a period of about

12 months or longer, (4) to a subject with a Conn score of

0 or 1, (5) “further comprising administering lactulose.”

1.

Findings of Fact

1.

Norwich has knowledge of the HE patents.

2.

Norwich’s label will encourage administration of

rifaximin for 12 months or longer.

3.

Norwich’s label will encourage administration

of rifaximin for the “reduction in risk of overt

hepatic encephalopathy (HE) recurrence in

adults.”

4.

Norwich’s label will encourage administration in

patients having a Conn score of 0 or 1.

60a

Appendix B

5.

Norwich’s label will encourage at least some

physicians to co-administer rifaximin and

lactulose.

6.

Patients will take rifaximin according to the

instructions on the label and will directly infringe

the asserted HE claims.

7.

Norwich’s label will induce infringement of the

asserted HE claims.

8.

The priority date of the asserted claims is

October 2, 2008.

9.

A POSA would have had a Ph.D. in pharmacology,

biology, biomedical sciences, microbiology

and/or an M.D. with board certification in

gastroenterology. He or she would have had

training in or experience with liver and GI

disorder research. If needed, a POSA would have

collaborated with others having ordinary skill

in areas relevant to the claimed subject matter,

including infectious diseases and microbiology.

10. The Salix Presentation was not publicly accessible

as of the priority date and is not prior art.

11. Leevy 2007 does not disclose a method of

administering rifaximin to maintain remission.

12. As of the priority date, a 12-month duration for

the administration of rifaximin was not within

the common knowledge of a POSA.

61a

Appendix B

13. The claimed method met a long-felt need

of reducing the risk of HE recurrence and

maintaining remission.

14. There was skepticism in the industry regarding

the long-term use of antibiotics to maintain

remission in HE patients.

15. The HE patents are not invalid as obvious.

16. The specification describes using rifaximin with

or without lactulose.

17. A POSA would recognize that the inventors had

possession of the claimed method.

2.

Infringement

i.

Administering for 12 Months or

Longer (All Claims)

It is more likely than not that Norwich’s Label will

encourage administration of the ANDA product for 12

months or longer in at least some patients, and that

Norwich knows and specifically intends for this period

of administration. Norwich’s product is indicated for

reducing overt HE recurrence. (JTX 73 § 1.2). HE is

chronic. It must be managed until the patient gets a liver

transplant or dies. I credit the testimony of Drs. Mahl and

Brown that they have had HE patients maintain remission

of HE for 12 months while on rifaximin 550 mg BID. (Tr.

120:21-24; Tr. 55:3-11). The label has no recommendation

62a

Appendix B

as to duration of administration. The label further

describes a study in which some patients used the product

for 12 months or longer. Taken together, this evidence

demonstrates by a preponderance of the evidence that

Norwich’s label would encourage administering rifaximin

for at least 12 months.

ii.

Maintaining Remission (’573 patent,

Claim 8)

I find that Salix has proved by a preponderance of the

evidence that Norwich’s label instructs as to “maintaining

remission of HE” as required by the asserted claims.

Norwich’s label is indicated for the “reduction in risk of

overt hepatic encephalopathy (HE) recurrence in adults.”

(JTX 73 § 1.2). The experts described “reducing the risk

of overt HE recurrence” and “maintaining remission of

HE” as “basically synonymous” or a “continuum of the

same thing.” (Tr. 249:23-250:18, 252:9-18; Tr. 51:21-52:19).

Remission is binary—either a patient is in remission or

the patient is not. An overt HE recurrence ends remission.

Thus, to maintain remission, a patient must avoid overt

HE recurrence.

iii. Conn Score of 0 or 1 (’397 patent,

Claims 11 and 12)

Norwich’s label will more likely than not induce use

of rifaximin in patients with a Conn score of 0 or 1. The

label encourages use to prevent an overt HE recurrence,

which as I have found, means maintaining remission. The

evidence shows that patients in remission of HE have a

63a

Appendix B

Conn score of 0 or 1. Thus, the label will encourage the

use of rifaximin in patients who have a Conn score of 0

or 1. This conclusion is bolstered by the Clinical Studies

section, which describes a clinical study in which the

patients were “defined as being in remission (Conn score

of 0 or 1) from hepatic encephalopathy.” (JTX 73 § 14.2).

Norwich argues that (1) doctors do not calculate a

Conn score for their patients before prescribing rifaximin,

and (2) the Indications section does not reference the

Clinical Studies section and thus it “merely describe[es] a

parameter of the study, rather than actually encouraging,

recommending, or promoting” the infringing use. (D.I. 183

at 10). I find these arguments unpersuasive.

The expert testimony shows that at least some

physicians use Conn scores in clinical practice. (Tr. 154:222; 264:6-7). Defendant’s expert, Dr. Mahl, testified that

he does not calculate Conn scores but does record the

“elements that might go into a Conn score.” (Tr. 114:1620). The patents do not require the calculation of a Conn

score. Rather, they require use in patients with a Conn

score of 0 or 1, which can be present regardless of whether

it has been calculated. On this testimony, it seems likely

that Norwich’s ANDA product will be used in at least

some patients who have a calculated Conn score of 0 or 1

as well as patients whose Conn scores would be a 0 or 1,

if calculated, based on the symptoms observed by their

physicians.

Regarding the Clinical Studies section, the law does

not require the indication section of a label to specifically

64a

Appendix B

direct the reader to look at other sections in order for those

other sections to be considered. The Court of Appeals has

held, “The jury was entitled to credit expert testimony

regarding the label’s instructions on who should take what

drug, when, why, and how, and to reject the argument

that certain portions of the label were disjointed from

others.” GlaxoSmithKline LLC v. Teva Pharms. USA

Inc., 7 F.4th 1320, 1329 (Fed. Cir. 2021), petition for cert.

filed, No. 22-37 (July 11, 2022). I credit the testimony of Dr.

Brown that physicians commonly read the Clinical Studies

section. (Tr. 67:24-68:8). The “Hepatic Encephalopathy”

subsection starts with the sentence: “The efficacy of

rifaximin tablets 550 mg taken orally two times a day

was evaluated in a randomized, placebo-controlled,

double-blind, multi-center 6-month trial of adult subjects

from the U.S., Canada, and Russia who were defined as

being in remission (Conn score of 0 or 1) from hepatic

encephalopathy (HE).” (JTX 73 § 14.2). Accordingly, I

find that the label will induce use in patients with a Conn

score of 0 or 1.

iv.

Administration with Lactulose (’397

patent, Claim 12)

Norwich’s label will encourage co-administration

with lactulose. In the Indications and the Clinical Studies

section, the label notes that 91% of patients took rifaximin

and lactulose concomitantly, and that lactulose did not alter

the treatment effect of rifaximin. (JTX 73 §§ 1.2, 14.2).

This strongly suggests that taking lactulose concomitantly

is safe and effective, and it will likely encourage some

physicians to administer rifaximin in conjunction with

65a

Appendix B

lactulose as required by the claims. I reject Norwich’s

comparison to Shire LLC v. Amneal Pharmaceuticals,

which held that label indicating that a drug could be taken

“with or without” food was “indifferent” as to which option

was select and thus not an instruction to infringe. 2014

U.S. Dist. LEXIS 85369, 2014 WL 2861430, at *5 (D.N.J.

June 23, 2014), aff’d in part, rev’d on other grounds, 802

F.3d 1301 (Fed. Cir. 2015). The high percentage of patients

who took lactulose concomitantly, and the fact that this

information was included in the Indications section,

encourages physicians to prescribe the two concomitantly.

I credit the testimony of Dr. Brown, who stated that

the label, by citing the 91 percent figure, “makes clear

that you can — you can and probably should use Lactulose

in the majority of your subjects.” (Tr. 76: 5-7). I further

credit Dr. Brown’s testimony, “Whenever possible, I use

the combination of Lactulose and rifaximin because that’s

where the bulk of the data is.” (Tr. at 76:12-13). I find that

a physician reading the Norwich label and considering

a study in which 91% of the patients were administered

lactulose concomitantly will be inclined to do so likewise

“because that’s where the bulk of the data” showing the

efficacy of rifaximin is.

v.

Substantial Noninfringing Use (All

Claims)

Norwich argues that its ANDA product has substantial

noninfringing uses, which is relevant to intent to induce.

(D.I. 183 at 11-12). Most HE patients live less than

12 months after their first overt HE episode. Thus, a

66a

Appendix B

substantial number of patients taking Norwich’s ANDA

as directed will not take rifaximin for 12 months or more,

and these uses will not meet the 12-month-or-more claim

limitation. Norwich points to Warner-Lambert Co. v.

Apotex Corp., 316 F.3d 1348, 1363-66 (Fed. Cir. 2003) in

support of this argument.

The Federal Circuit has distinguished WarnerLambert, where the infringing use would be off-label use

of the defendant’s ANDA product and encompass only a

small number of sales, and cases where “the proposed

label itself recommends infringing acts.” Vanda Pharms.

Inc. v. West-Ward Pharms. Int’l Ltd., 887 F.3d 1117, 113233 (Fed. Cir. 2018). Here, since I find that the label itself

recommends infringement, the potential for substantial

non-infringing uses does not negate Norwich’s intent to

induce infringement.

3.

Invalidity

The parties agree that the definition of a POSA is

not outcome determinative. (D.I. 176 at 2; D.I. 181 at 1). I

adopt Plaintiffs’ definition of a POSA.

Norwich argues that as of 2008, it was widely known

that rifaximin was safe and effective for treating HE. (D.I.

176 at 3). Rifaximin was indicated abroad for HE in 2000.

(JTX 94 at 5, 9). In 2004, the FDA approved Salix’s Xifaxan

for traveler’s diarrhea. From that time, there is evidence

of widespread off-label use of Xifaxan by physicians to

treat patients with HE. Market research conducted by

Salix shows that, by January 2007, 77% of physicians

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Appendix B

who treated HE patients had prescribed Xifaxan for HE.

(DTX 349-16).

The prior art described the use of rifaximin in HE

patients. For instance, a 1993 article (“Festi”) described one

open study and two randomized, controlled, comparative

studies. The three studies “confirm[ed] the usefulness of

rifaximin in the management of cirrhotic patients with

mild HE.” (JTX 42 at 607; Tr. 165:11-166:5). A 2000 article

(“Williams 2000”) described a study confirming that

1200 and 2400 mg doses of rifaximin showed significant

improvement “in reducing objective parameters of HE

in cirrhotic patients,” and “treatment with rifaximin

1200 mg/day may be considered as an adjuvant or an

alternative” to lactulose, with no adverse effects. (JTX

66 at 203-4, 207). Lactulose was the “mainstay” for HE

therapy at the time. (See Tr. 203:17-204:5). In 2004, doctors

at a Salix-hosted conference on hepatology reported

being “very happy with [rifaximin’s] results” and that

rifaximin had “excellent” tolerability with “no significant

side effects.” (Tr. 172:10-18; 174:8-22; DTX 584-1, 3). A

2007 retrospective chart review (“Leevy 2007”) showed

better treatment outcomes for patients on rifaximin than

on lactulose. (DTX 390-3; Tr. 204:6-16).

Norwich also points to retrospective chart reviews

published after the priority date that show use of rifaximin

for HE before the priority date. (See D.I. 176 at 9-10

(citing JTX 111, JTX 109)). I do not think these uses

are in the prior art because there is no evidence that a

POSA would have known about them. They do provide

evidence of a POSA’s state of mind, since the physicians

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Appendix B

prescribing Xifaxan off-label meet both parties’ definition

of a POSA. (See D.I. 182 ¶ 121; D.I. 177 ¶ 1). See In Re:

Copaxone Consol. Cases, 906 F.3d 1013, 1025 (Fed. Cir.

2018) (holding, “The district court . . . properly relied on

[a reference] not as statutory prior art, but for the fact

that [POSAs] were interested in pursuing less frequent

dosing regimens.”).

i.

Prior Art Combinations

Norwich presents two obviousness combinations for

the asserted HE claims: the Bausch HE Study in light of

the Salix Presentation, and Leevy 2007 in light of common

knowledge. I will consider each in turn.

The Bausch HE Study is the protocol for the clinical

trial that ultimately led to the approval of rifaximin

for HE. It disclosed the method, dosage, lactulose, and

Conn score limitations of the asserted claims. The Salix

Presentation was a presentation given by Dr. Leevy at a

Salix shareholder’s meeting in which Dr. Leevy described

using rifaximin to treat HE. (DTX 52-4). Dr. Leevy

described the duration limitation. Between the two, all

claim limitations are disclosed.

Salix argues that the Salix Presentation was not in

the prior art because it was not accessible. (D.I. 181 at 4).

Salix tried to exclude the evidence before trial. (D.I. 150).

I denied Salix’s motion without prejudice to evaluating its

prior art status based on a complete understanding of the

record. (D.I. 161 at 28:9-18). Norwich’s response to the

motion in limine relied on evidence that Norwich did not

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Appendix B

present at trial. (See D.I. 150 at 9 of 18 (describing a Salix

press release announcing the conference)). Accordingly,

I will reconsider the question in light of the evidence

presented at trial.

At trial, Defendant offered the transcript of the

Salix Presentation and expert testimony regarding the

presentation. (DTX 660; Tr. 175:20-176:22). Defendant’s

expert, Dr. Berg, testified that the Salix presentation

was publicly available online at the SEC and that a POSA

would be motivated to find it because Salix was the only

company selling rifaximin in the United States at the

time. (Tr. 175:22-24; 176:15-22). Salix responds that this

testimony is unsupported by explanation or evidence.

(D.I. 181 at 4-5). While I credit Dr. Berg’s assertions

regarding a POSA’s motivation to look for and methods

of finding such a document, I do not credit his testimony

regarding the availability of the Salix Presentation online

before the priority date. I do not think a medical doctor’s

expertise is a basis for opining on what the SEC had

available online more than a decade ago. Dr. Berg’s opinion

is not supported by independent evidence. “At this critical

point in the determination of obviousness, there must

be factual support for an expert’s conclusory opinion.”

Upjohn Co. v. Mova Pharm. Corp., 225 F.3d 1306, 1311

(Fed. Cir. 2000). Without evidence of online accessibility,

and without evidence that the meeting was attended by

interested POSAs (or even directed to POSAs, rather

than investors), I find that Defendant has not shown by

clear and convincing evidence that the Salix Presentation

is prior art.

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Appendix B

Norwich’s second prior art combination is Leevy 2007

and common knowledge. Norwich argues, “Leevy 2007

disclosed the method, dosage, and Conn score limitations.”

(D.I. 176 at 8). Norwich argues that common knowledge

supplies the missing limitations of duration (of 12 months

or more) and lactulose. (Id. at 9).

Upon review of the evidence, I find that Leevy 2007

does not describe the method limitation. Independently,

common knowledge cannot supply the duration limitation.

I will address each in turn.

The claims are directed to maintaining remission or

reducing the risk of breakthrough overt HE. Leevy 2007

concluded that HE hospitalizations were less frequent

and shorter for patients on rifaximin than for patients

on lactulose. Norwich argues that these hospitalizations

are a metric for breakthrough overt HE and therefore

Leevy 2007 discloses the method limitation. (D.I. 176

at 8). But Norwich’s argument is not supported by the

record. Norwich’s expert, Dr. Berg, testified as to Leevy

2007’s disclosure of rifaximin’s ability “to treat HE” or as

“therapy for HE.” (E.g., Tr. 181:9-18; 206:2-10). He did not

characterize it as disclosing prevention or the like. I see

no testimony linking Leevy’s reduction in hospitalizations

with the claimed method of preventing breakthrough

overt HE.

Furthermore, Leevy 2007 did not track Conn scores

throughout the study. As Salix argues, “a POSA would not

have been able to determine whether subjects who had a

Conn score of 1 at the beginning of the rifaximin phase

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Appendix B

maintained that Conn score throughout the 6 months.”

(D.I. 181 at 5). I credit Dr. Brown’s testimony, “You

cannot interpret the natural course of these patients’ HE

through the six-month period based on the data provided.”

(Tr. 393:4 6). Leevy 2007 does not teach the maintaining

remission limitation.

Thus, Leevy 2007 cannot supply the limitations

required for the asserted claims, whether it is maintaining

remission of HE or reducing the risk for breakthrough

overt HE. On that basis alone, Defendant fails to prove

obviousness.

There is a second, independent basis to reject the prior

art combination of Leevy 2007 and common knowledge.

I do not think that a POSA would have a reasoned basis

to resort to the “common sense” that rifaximin could be

used for 12 months or longer. Common sense can supply

a limitation missing from the prior art if a “searching”

review of the prior art provides a “reasoned basis for

resort to common sense.” Arendi S.A.R.L. v. Apple Inc.,

832 F.3d 1355, 1363 (Fed. Cir. 2016).

Many of the sources Norwich relies upon to show

long-term administration are not prior art. (See D.I. 176

at 9-10 (citing retrospectives published after the priority

date and the Salix Presentation)). They were not, at that

point, in the common knowledge of the field.

Administration of rifaximin for 12 months or more

suggests prevention (i.e., maintaining remission or

reducing the risk of overt HE recurrence), not mere

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Appendix B

treatment. Norwich argues, “[T]he record is replete with

prior art disclosing the use of rifaximin in patients in

remission from HE (i.e., having a Conn score of 0 or 1).”

(D.I. 185 at 5-6). It is true that some of the studies included

patients with Conn scores of 0 or 1. (JTX 66 at 205; JTX

42 at 607.) Many of these patients would have been in

remission, but the sources discuss HE “treatment,” not

prevention or maintenance of remission. The Bausch HE

study was the first prior art source to clearly articulate

a desire to prevent hepatic encephalopathy. (DTX 52-4).

As of the priority date, the Bausch Study did not have

any results. Accordingly, I do not think that a 12-month

treatment period was within the common knowledge as

of the priority date.

Furthermore, Salix has presented evidence that a

POSA would have known that long-term administration

of rifaximin, an antibiotic, was risky. Not only could longterm use of antibiotics lead to a superinfection, which could

kill the patient, but, “A POSA would have been concerned

that if an HE patient developed clinical resistance to

rifaximin, [the POSA] would not be able to administer

rifaximin the next time the patient experienced an HE

episode.” (D.I. 181 at 11; Tr. 388:3-9). The parties’ experts

disagreed about the level of risk associated with longterm administration of rifaximin and how a POSA would

consider that risk. I credit Dr. DuPont’s testimony that

without further studies, a POSA would have been reluctant

to administer rifaximin long-term. (Tr. 467:7-12). Thus,

I think that the prior art does not provide enough of a

reasoned basis for supplying the duration limitation.

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Appendix B

Finally, Salix has presented evidence of secondary

considerations of nonobviousness that weigh in favor of

finding the HE patents nonobvious. The claimed HE

methods met a long-felt need for maintaining remission

and reducing the risk of breakthrough overt HE episodes.

Salix argues, “As of October 2008, no drug had been

approved for HE in over 30 years, and no drug had ever

been approved to prevent HE recurrence.” (D.I. 174 at

17). Norwich’s expert responded that there was no need

because physicians were already using a combination of

rifaximin and lactulose to treat HE. (Tr. 222:7-20). As

Salix points out, however, “Short-term, off-label use of

rifaximin to treat HE did not meet a long-felt need for

long-term prevention of HE recurrence.” (D.I. 186 at 10).

There was also some skepticism in the industry. Salix

points to comments from the FDA advisory committee

expressing the concern “that indefinite use of rifaximin

could change the gut flora and cause antibiotic resistance.”

(D.I. 174 at 17). Norwich argues that the FDA statements

lack a nexus to the asserted claims. I disagree. “Where

the offered secondary consideration actually results from

something other than what is both claimed and novel in

the claim, there is no nexus to the merits of the claimed

invention.” Novartis AG v. Torrent Pharms. Ltd., 853 F.3d

1316, 1330 (Fed. Cir. 2017) (citation omitted). But here, the

potential antibiotic resistance would have resulted from

the claimed method of treatment. Accordingly, I give some

weight to the FDA comments as evidence of skepticism.

Ultimately, I find that Norwich has not shown by clear

and convincing evidence that the asserted HE claims are

invalid as obvious.

74a

Appendix B

ii.

Written Description

Norwich argues, “Claim 8 of the ’573 patent, claim 6 of

the ’195 patent, and claim 11 of the ’397 patent are invalid

for lack of written description because the specifications

of the patents fail to show that the administration of

rifaximin alone (i.e., in the absence of concomitant

administration of lactulose) achieves the claimed effects.”

(D.I. 181 at 16). Norwich’s argument seems to be that

the specifications lack data supporting the efficacy of

rifaximin alone. (See id.). This is not the standard for

written description. The specifications all describe using

rifaximin with or without lactulose. (JTX 19 at 16:6217:3 (“This method includes: administering rifaximin to

a subject daily that is being treated with lactulose, and

tapering lactulose consumption.... In one embodiment, the

baseline use of lactulose is no use.”); JTX 11 at 16:62-17:3;

JTX 22 at 10:49-57). I therefore find that Norwich has not

shown a lack of adequate written description by clear and

convincing evidence.

C.

THE IBS-D PATENTS

Irritable bowel syndrome (“IBS”) is characterized by

symptoms including abdominal pain, bloating, frequency,

urgency, gas, and changed bowel habits, such as diarrhea,

constipation, or alternating diarrhea and constipation.

(E.g., Tr. 618:23-620:2). Subtypes of IBS include IBS

with diarrhea (IBS-D), IBS with constipation (IBS-C), or

IBS with alternating diarrhea and constipation (IBS-A).

(Tr. 622:9-623:1). The IBS-D subtype comprises about

one-third of IBS patients. (Tr. 622:21-623:1). IBS may

75a

Appendix B

be caused, for example, by abnormal motility, abnormal

muscular coordination, changes in the microbiome in the

colon or small intestine, intolerance to certain foods, or

psychological factors. (Tr. 618:23-620:2).

Plaintiffs assert two claims in connection with the

IBS-D patents.

Asserted Claim 3 of the ’667 patent is a dependent

claim that has three elements: (1) administering 550 mg

of rifaximin three times a day (TID) for 14 days; (2) to

treat one or more symptoms of IBS-D; (3) in a subject 65

years of age or older.

Asserted Claim 2 of the ’569 patent is a dependent

claim with two elements: (1) administering 550 mg of

rifaximin TID for 14 days; and (2) after stopping rifaximin,

achieving a durability of response that comprises about

12 weeks of adequate relief of symptoms.

1.

Findings of Fact

1.

Norwich is aware of the IBS-D patents.

2.

Norwich’s label will encourage administering

rifaximin to adults aged 65 years or older with

IBS-D.

3.

Norwich’s label will encourage administration of

“one 550 mg tablet taken orally three times a day

for 14 days” for the treatment of IBS-D, which

inevitably will result in at least some patients

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Appendix B

having a durability of response comprising

about 12 weeks of adequate relief after stopping

rifaximin.

4.

Patients will take rifaximin according to the label

and will directly infringe the asserted IBS-D

claims.

5.

Norwich’s label will induce infringement of the

asserted IBS-D claims.

6.

The priority date for the IBS-D claims is

February 26, 2008.

7.

A person of skill in the art would have had a

medical degree with training in gastroenterology

or have been a practicing physician, such as an

internist, with experience in treating IBS.

8.

The prior art includes the ’608 patent (JTX

132), the Pimentel Book (PTX 752), Yang (DTX

892), the RFIB 2001 Press Release (DTX 657),

Pimentel 2006 (JTX 53), the RFIB 2001 Protocol

(DTX 340), Cuoco (JTX 38), Barrett (JTX 71),

Viscomi 2005 (JTX 64), Lin 2006 (JTX 69),

Lauritano (DTX 384), and Scarpellini (JTX 60).

9.

The RFIB 2001 Protocol and Pimentel 2006

disclose all limitations of the IBS-D claims.

10. A POSA would have been motivated to combine

the RFIB 2001 Protocol and Pimentel 2006 with

a reasonable expectation of success.

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Appendix B

11. As of the priority date, the prior art disclosed

positive results in using rifaximin to treat IBS-D

for a range of doses. The asserted IBS-D claims

describe a dosing regimen within the known

range.

12. A POSA would have had motivation to treat

IBS-D patients 65 years of age or older with

rifaximin. A POSA would have had a reasonable

expectation of success in treating this patient

group with rifaximin.

13. The prior art did not teach away from using

rifaximin to treat IBS-D according to the claimed

methods.

14. There was some skepticism in the literature.

15. The asserted IBS-D claims are invalid as obvious.

16. The specification describes “durability of

response” as including adequate relief from

symptoms for 12 weeks.

17. A POSA would recognize that the inventor

possessed the claimed durability of response.

18. A POSA would have reasonable certainty

regarding the meaning of “adequate relief” and

“durability of response.”

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Appendix B

2.

Infringement

i.

Age 65 and Over (’667 patent,

Claim 3)

Claim 3 of the ’667 patent requires administration of

rifaximin to patients who are 65 years and older. I find

that Norwich’s label will induce administration to this

patient population. Norwich’s ANDA product is indicated

for “adults.” (JTX 73 § 1.3). “Adults” include people

who are 65 years and older. The label’s “Use in Special

Populations” section describes “Geriatric Use.” (JTX 73

§ 8.5). The label states, “No overall differences in safety or

effectiveness were observed between these subjects [aged

65 and over] and younger subjects for either indication.”

(Id.) Accordingly, Norwich knows and specifically intends

that its ANDA product will be used to treat IBS-D in

patients who are 65 and older.

ii.

12 Week Durability of Response

(’569 patent, Claim 2)

Claim 2 of the ’569 patent requires a “durability of

response [that] comprises about 12 weeks of adequate

relief.” I find that Norwich’s label will induce such a

response in at least some patients. Salix argues, “By

following [the dosing] instructions [on the label], some

patients will inevitably have a durability of response

comprising about 12 weeks of adequate relief.” (D.I. 174 at

14). Salix’s expert testified to this, and Norwich’s expert

admitted as much. (Tr. 537:12-540:4, 581:16-22 (agreeing

that at least some patients “will experience adequate

79a

Appendix B

relief of their IBS-D symptoms for 12 weeks after taking

rifaximin 550 milligrams three times a day for 14 days”)).

“[A]n accused product that sometimes, but not always,

embodies a claimed method nonetheless infringes.” Bell

Communications Research v. Vitalink Communications

Corp., 55 F.3d 615, 622-23 (Fed. Cir. 1995).

Norwich’s label supports a finding of inducement. The

product is indicated “for the treatment of irritable bowel

syndrome with diarrhea.” (JTX 73 § 1.3). The Clinical

Studies section states, “The efficacy of rifaximin tablets for

the treatment of IBS-D was established in 3 randomized,

multi-center, double-blind, placebo-controlled trials in

adult patients.” (JTX 73 § 14.3). The third study, TARGET

3, tracked long-term response to treatment. In it, “382

[patients] experienced a period of symptom inactivity or

decrease that did not require repeat treatment by the

time they discontinued, including patients who completed

the 22 weeks after initial treatment with rifaximin.” (Id.).

Norwich argues that TARGET 3 only measured two

symptoms of IBS-D, rather than the claimed “adequate

relief” of IBS-D symptoms, and that it reported “time

to recurrence” rather than the claimed “durability of

response.” (D.I. 183 at 14). Even when a proposed label

does not exactly track the claim language, a package

insert containing directives that will “inevitably lead

some consumers to practice the claimed method” provides

sufficient evidence for a finding of specific intent. See

AstraZeneca LP v. Apotex, Inc., 633 F.3d 1042, 1060 (Fed.

Cir. 2010). Accordingly, I find that Norwich’s label will

induce some patients to experience a 12-week durability

of response as required by the patents and that Norwich

will have the specific intent to induce infringement.

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Appendix B

3.

Obviousness

Salix asserts that the definition of a POSA is not

outcome determinative. (D.I. 181 at 16). Noriwch has

proposed that a POSA would have had a medical degree

with training in gastroenterology or have been a practicing

physician, such as an internist, with experience in treating

IBS. (D.I. 181 at 17). I adopt Norwich’s definition of a

POSA.

Norwich argues that, as of the priority date, rifaximin

was known to be safe and effective in treating IBS-D.

Prior to February 2008, there was widespread off-label

use of Xifaxan to treat IBS in the United States. As

of January 2008, 74% of gastroenterologists polled by

Salix had prescribed Xifaxan for IBS. (DTX 349-130).

Prescription data showed that 27.7% of Xifaxan 200 mg

tablet uses in November 2007 had been for IBS. (DTX

349-89; Tr. 832:2-833:23).

The prior art also discussed using rifaximin to treat

IBS. In 1999, Dr. Pimentel applied for patents on the use

of rifaximin to treat IBS. (JTX 132; JTX 133; Tr. 617:121). The ’608 patent claims a method of “treating a subject

suffering from [IBS], comprising administering rifaximin

to the subject. . .” (JTX 132 at cl. 1; Tr. 620:3-621:9). 2 At a

2005 conference hosted by Salix, Dr. Pimentel disclosed

that his practice group had used rifaximin to treat about

900 patients. (Tr. 627:7-628:5; DTX 582-4, 5). In 2006, Dr.

2. The ’608 patent issued in 2010 but the parties agree that it

was publicly accessible before the priority date. (D.I. 149, Ex. 1 ¶ 136).

81a

Appendix B

Pimentel published a book titled A New IBS Solution,

Bacteria - the Missing Link in Treating Irritable Bowel

Syndrome, which recommended the use of rifaximin as

a safe and effective way to treat IBS-D. (PTX 752; Tr.

623:25-624:21).

In 2006, three studies were published on the use

of rifaximin to treat IBS. A randomized, double-blind,

placebo-controlled study found rifaximin to be more

effective than placebo in improving IBS. (“Pimentel 2006,”

JTX 53). A retrospective chart review of IBS patients

who had tested positive for small intestine bacterial

overgrowth (“SIBO”) reported a significant reduction in

the number of patients having IBS symptoms 4-5 months

after treatment, and that 12 of 23 patients had “complete

resolution of IBS symptoms.” (“Cuoco,” JTX 38 at 94).

Another retrospective chart review of 8 patients disclosed,

“rifaximin use resulted in complete resolution of clinical

symptoms in 4 patients, with no IBS relapse (follow-up,

1 to 6 months),” and “partial symptom improvement was

observed in 4 patients, 3 of whom were treated for an

additional 2 months with rifaximin 400 mg three times

daily cycle therapy (2 weeks on / 1 week off []) which

resulted in a 50% to 70% improvement from baseline.”

(“Barrett,” JTX 71; Tr. 639:9-640:5).

Norwich proposes three prior art combinations

involving three pieces of prior art. Because I agree that

Pimentel 2006 in light of the RFIB 2001 Protocol renders

the asserted claims of the IBS-D patents obvious, I will

not address the other two combinations.

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Appendix B

Pimentel 2006 administered rifaximin, 400 mg TID for

10 days, to treat IBS patients aged 18-65. Pimentel 2006

taught, “rifaximin resulted in statistically greater global

improvement in IBS than placebo,” and “[i]mprovements

were sustained through 10 weeks of follow-up” after 10

days of treatment. (JTX 53 at 562).

The “RFIB 2001 Protocol” (DTX 340) was a Phase

II trial designed to administer rifaximin to patients aged

18 and over, 550-2,220 mg per day for 14 days for the

treatment of IBS-D. The protocol included the outcome

measures of providing adequate relief of symptoms

and evaluating a durability of response over a 12-week

post-treatment period. Salix announced the successful

completion of this study on Se

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