Amicus Curiae Brief — Merck KGaA v. Integra Lifesciences I, Ltd.

O,

No. 03-1237

IN THE

Supreme Court of the United States

MERCK KGAA,

Petitioner,

Vv.

INTEGRA LIFESCIENCES I, LTD. AND

THE BURNHAM INSTITUTE,

Respondents.

On Writ of Certiorari

to the United States Court of Appeals

for the Federal Circuit

BRIEF OF AMICI CURIAE GENENTECH, INC. AND

BIOGEN IDEC, INC. INSUPPORT OF PETITIONER

SEAN JOHNSTON CARTER G. PHILLIPS

GARY H. LOEB VIRGINIA A. SEITZ*

GENENTECH, INC. JEFFREY P. KUSHAN

| DNA WAY ‘= DAVID L. FITZGERALD

SOUTH SAN FRANCISO, CA SIDLEY AUSTIN BROWN &

94080 WocbD LLP

(650) 225-1000 1501 K STREET, N.W.

WASHINGTON, D.C. 20005

RAYMOND G. ARNER (202) 736-8000

JAMES D. DARNLEY, JR.

BIOGEN IDEC, INC.

14 CAMBRIDGE COURT

CAMBRIDGE, MA 02142

(617) 914-5967

Counsel for Amici Curiae

February 22, 2005 * Counsel of Record

Gn )

WILSON-EPES PRINTING CO., INC. — (202) 789-0096 -— WASHINGTON, D. C. 20001

TABLE OF CONTENTS

Page

pF | __ ill

SPUD Eee © CU ARGICE CURIA cncccccoccescosecccosccccscosccsooses |

SUMMARY OF ARGUMENT ..........ccccccsccssssscssessossesenees 3

Tn on TE EO 5

ie ean UIT titcstrierrevensennssntnsinieensnnsseonesecsssceveness 5

Il. BIOLOGICS DIFFER FROM CHEMICALLY-

- io SYNTHESIZED DRUGS IN WAYS THAT

MAKE APPLICATION OF THE FDA EX-

EMPTION EVEN MORE CRITICAL TO THEIR

DEVELOPMENT AND DEPLOYMENT.............. 8

A. Biologics Differ From Chemically-Synthe-

sized Drugs In Ways That Significantly Affect

The Regulatory Approval Process And Its

SED ccinsirconsusnnenmepnmnnenicininsnisenninseesseotenes 8

B. Because The FDA Requires Manufacturers Of

Pioneer Drugs, Including Biologics, To Submit

Substantial Preclinical Research In An IND

Application, The “Use” Of “Patented Inven-

tion|s]” In Such Research Is Protected By The

? i ales 10

Re Se eI ennsaiintcssncnsnmacutatinsinienenencith 1!

ie RF PID cccccncntensncerencctenintesnsecnenes a

C. Interpreting The FDA Exemption Narrowly

Due to Congress’s Focus On The FDA’s

Approval Of Generic Drugs Is Particularly

Harmful To The Discovery And Development

Ber GUID cnccinnuescsiipenmimantsnnsentitmenstansmnntiontins 16

(i)

ii

TABLE OF CONTENTS -— continued

Ill. CONGRESS'S CHOICE OF THE REASON-

ABLE-RELATIONSHIP TEST MANDATES A

RATIONAL-BASIS INTERPRETATION OF

THE FDA EXEMPTION .......c0cccccssscscssesscososesssssess

A. Congress’s Decision To Employ The Reason-

able-Relationship Test Is Significant.............000+

B. The Question Of The Application (If Any) Of

The FDA Exemption To Research Tools Is

|

CONCLUSION .......cccccccossccscssccesssesssesssoeesssssssseessnennanenne

Page

TABLE OF AUTHORITIES

CASES Page

Block v. Rutherford, 468 U.S. 576 (1984)... 21

Chevron U.SA., Inc. vy. National Res. Def.

Council, Inc., 467 U.S. 837 (1984) ...cccccceeceeeees 22

City of Monterey v. Del Monte Dunes at

Monterey, Ltd., 526 U.S. 687 (1999) ..........ccccceee 20

Complete Auto Transit, Inc. v. Brady, 430 U.S.

A 20

Eli Lilly & Co. v. Medtronic, Inc., 496 U.S. 661

nT eiadliatiebnrtetersteeecicentecneneancceensssessctccceecee 7, 16

Hodel v. Virginia Surface Mining & Reclamation

FEE i Ge ies BO CEB E Peccccccccccccesccccccsccsccsccece 20

Hazelwood Sch. Dist. v. Kuhlmeier, 484 U.S. 260

TIT ielaeeceediadiidescnentenenetenscncnecsccsssccesenescoesnsnecses 20

Massachusetts v. United States, 435 U.S. 444

rn sisiiiieileeshctheeieeebecnemeenenisinencsemmenscsesccsccseestecesee 20

New Jersey v. T.L.O., 469 U.S. 325 (1985)............. 20

Roche Prods., Inc. v. Bolar Pharm. Co., 733 F.2d

858 (Fed. Cir. 1984), overruled/superseded by

a 5

United Steelworkers of Am. v. Sadlowski, 457

SIT cereiceerecictecennscansncennsencnseeneneesee 20

Terry V. Ohio, 392 U.S. 1 (1968) .....cccccseseeeseseseeeees 20

Turner v. Safley, 482 U.S. 78 (1987) .........cccccece00 20, 21

STATUTES AND REGULATIONS

ee 3

| 10, 11, 18

Eee 3, 5, 12

| 3, 11, 12, 13

Be OP IPOD GOT, cncccceccccscescnceceseceencsescessecss 11

IIT diietireipeeteeeensnenennenenesncsesneeseenane 11

| an 12, 13

a 13

iv

TABLE OF AUTHORITIES — continued

Page

rife) EO} 13

Public Information, 39 Fed. Reg. 44602 (Dec. 24,

DP ED nccssesssersssssesnssesnesnensmanensmenenmmnnennennmmsnetts 10

Abbreviated New Drug Application Regulations,

57 Fed. Reg. 17950 (Apr. 28, 1992) .......ccccceseeees 17

LEGISLATIVE HISTORY

H.R. Rep. No. 98-857, pt. 1 (1984) .......cccccceceeeeeeeees 7

SCHOLARLY AUTHORITIES

Joy A. Cavagnaro, Preclinical Safety Assessment

of Biological Products, in Biologics Develop-

ment: A Regulatory Overview (M. Mathieu ed.,

rE , ee 14

Jeanne M. Novak et al., The Biological IND, in

Biologics Development: A Regulatory Over-

view (M. Mathieu ed., 2d ed. 1997)............. 12, 14, 15

Suzanne M. Sensabaugh, A Primer on CBER’s

Regulatory Review Structure And Process, 32

Drug Info. J. LOT) (1998) .......cecceeeeeeereeeeeenesens 12

OTHER AUTHORITIES

Biotechnology Indus. Org., Biotechnology

Industry Facts (2005), at http://www.bio.org/

speeches/pubs/er/StatistiCS.aSp ..........ccccseeeeeeeeeees l

FDA, Guidance Concerning Demonstration of

Comparability of Human Biological Products

Including Therapeutic Biotechnology-derived

Products (Apr. 1996), available at http://www.

fda.gov/cder/guidance/compare.htm............+0++ 8,9, 18

v

TABLE OF AUTHORITIES - continued

FDA, Guidance for Industry: Content and Format

of Investigational New Drug Applications

(INDs) for Phase I Studies of Drugs, Including

Well Characterized, Therapeutic, Biotech-

nology-derived Products (Nov. 1995) ..........0000++

PhRMA, 2004 Survey: Medicines in Develop-

ment, Biotechnology (Oct. 2004) ..........ccccceeceeeeeee

S. Usdin, CBER’s Abbreviated Route, BioCen-

GU, FRR. Ty Tie ccsesecencnsermnnmnsreninmesemianatians

Page

INTEREST OF AMICI CURIAE'

Founded in 1976, Amicus Genentech, Inc. was the first bio-

technology company, and today is a leading manufacturer of

biotechnology-derived products (“biologics”). Genentech’s

growth is mirrored by that of the biotechnology sector of the

pharmaceutical industry. In 1989 biologics represented only

5% of the market share for drugs. Today, more than three

hundred and fifty biotechnology medicines are in

development. See PhRMA, 2004 Survey: Medicines in

Development, Biotechnology, | (Oct. 2004); Biotechnology

Indus. Org., Biotechnology Industry Facts (2005), at

http://www.bio.org/speeches/pub/er/statistics.asp. Continuing

innovation, product development, and cost containment in

biotechnology are critically important both to the

pharmaceutical industry and to the American public; and they

are at stake in this case.

In order to develop safe, innovative, and effective products,

Genentech necessarily undertakes significant commercial

risks, involving substantial investments of time, resources,

energy and scientific expertise. Specifically, in the pasi 28

years, Genentech has invested more than $6.4 billion in the

research and development of biologics, and has discovered

and introduced more than a dozen significant therapies for

serious and life-threatening diseases, including cancer, heart

disease, stroke and pulmonary disease.

In 1985, for example, Genentech received approval to

market the synthetic human growth hormone Protropin®, one

of the first biologics manufactured and marketed in the

United States. This was followed by approval of Activase®, a

human tissue plasminogen activator for use in dissolving

' Letters of consent have been filed with the Clerk. Pursuant to Rule

37.6, Amicus states that no counsel for a party authored any part of this

brief, and no person or entity other than amicus and its counsel made a

monetary contribution to the preparation or submission of this brief.

2

blood clots in patients suffering from acute myocardial

infarction. Since then, Genentech has developed or co-

developed and received approval for numerous breakthrough

drugs, including Pulmozyme®, the first new therapy for

management of cystic fibrosis in 30 years; Herceptin® for

treatment of a certain form of metastatic breast cancer;

Xolair® for treatment of asthma; and Avastin® for use in

treatment of metastatic colorectal cancer. In addition,

Genentech has discovered new indications for drugs already

approved by the FDA, such as Activase® used in treating

acute ischemic stroke.

Amicus Biogen Idec, Inc. was created by the 2003 merger

of Biogen, founded in 1978, and IDEC Pharmaceuticals,

founded-in 1985. In the past 26 years, Biogen Idec has

invested more than $3.9 billion in the research and

development of biologics, and has discovered more than 7

significant therapies for serious and life-threatening diseases,

including multiple sclerosis, cancer, hepatitis B and psoriasis.

In 1986, for example, a Biogen developed product, Intron®

A (recombinant interferon alpha-2b), received marketing

approval for treatment of hairy cell leukemia. This was

followed by the 1989 launch by Biogen’s licensee of its

hepatitis B vaccine, Engerix®-B. Since then, Biogen Idec has

developed or co-developed and received approval for several

breakthrough drugs, including Avonex® for treatment of

relapsing forms of multiple sclerosis; Rituxan® for treatment

of certain forms of B-cell non-Hodgkin’s lymphoma (which

was co-developed and is co-marketed by Genentech), and

Tysabri” for treatment of relapsing forms of multiple

sclerosis.

Today, Genentech and Biogen Idec (collectively, “Amici’’)

manufacture the majority of the world’s protein-based

biologics. Because the development and commercial

production of each biologic involves an extensive effort to

invent, develop, test, and gain federal approval, Amici

aggressively pursue patents on inventions they make during

3

this process of discovery and development. Amici believe the

patent system, including appropriate enforcement of patent

rights, is crucial to the continuing development of innovative,

life-saving drugs. Yet Amici also strongly support a generous

and practical reading of the statutory exemption from patent-

liability for the testing and evaluation of new drugs as being

equally necessary to encourage innovation. Amici plainly

have a substantial and critical interest in the issue presented

here. As leading developers and manufacturers of biologics,

Amici invest billions of dollars in both preclinical and clinical

research — viz., in investigating and testing innovative

candidate biologics and translating this work into therapeutic

medical interventions.

SUMMARY OF ARGUMENT

The issue presented in this case is scope of section

202(e)(1) of the Drug Price Competition and Patent Term

Restoration Act of 1984 (“the Hatch-Waxman Act”), 35

U.S.C. § 271(e)(1). This provision, also known as the FDA

exemption, exempts from infringement the use of a patented

invention “solely for uses reasonably related to the

development and submission of information under a Federal

law” regulating the manufacture, use, or sale of “drugs.” /d.

A biologic is a “drug” within the meaning of the FDA

exemption.’ In the decision below, the Federal Circuit

seemingly limited the FDA exemption to the formal process

of clinical research and testing of drugs for FDA approval

that takes place under an Investigational New Drug (“IND”)

application. It thus improperly excluded from the scope of the

* Section 201 of the Federal Food Drug and Cosmetics Act (“FDCA”),

21 U.S.C. § 321(g)(1), defines a “drug” as a product “intended for use in

the diagnosis, cure, mitigation, treatment, or prevention of disease in

man”; and a “biologic” is similarly defined by the Public Health Services

Act (“PHSA”) as a live cellular product “applicable to the prevention,

treatment, or cure of a disease or condition of human beings.” 42 U.S.C.

§ 262(i).

4

FDA exemption the preclinical research that must be

performed during the investigation or development of

candidate drugs to generate information to support an IND

application.

Preclinical testing of a new drug or biologic generates

information that is essential to the FDA approval process.

The Federal Circuit’s limiting construction of the FDA

exemption, however, exposes this preclinical research to

patent infringement liability. Such liability risks would

impinge on the very preclinical testing which the FDA

exemption was designed to induce.

The Federal Circuit’s position — that the FDA exemption

should be narrowly interpreted because it was intended

primarily to support FDA approval of generic drugs, an

abbreviated process which does not require preclinical

research supporting an IND application — has a uniquely

harsh impact on the biotechnology sector of the

pharmaceutical industry for two reasons. First, for reasons set

forth below, there is no such thing as a generic biologic, and

no abbreviated approval process for biologics; each and every

biologic is a new or “pioneer” drug that must be supported by

the full panoply of preclinical and clinical investigation.

Further, again as explained below, unlike manufacturers of

traditional chemically-synthesized drugs, manufacturers of

biologics must demonstrate to the FDA that not only the

product, but also the manufacturing process is safe and

effective. This requires significant additional preclinical

‘research and the use of a broader array of technology in order

to provide the FDA with the more exiensive information it

requires.

Issues that go beyond the question of the scope of the FDA

exemption are not raised by the present case. In particular,

the question of whether the use of patented “research tools” in

the discovery of new drug candidates should be exempted

from patent infringement other than in situations governed by

the FDA exemption is not presented. The present case does

-_— -

5

not concern activities done for reasons other than to generate

information needed for the FDA drug approval process, and

petitioner is not seeking to shield its acts under the uncodified

experimental use defense. Accordingly, Amici urge the Court

to limit its holding to the scope of the FDA exemption.

ARGUMENT

I. INTRODUCTION,

Under the Patent Act, “whoever without authority makes,

uses, Offers to sell, or sells any patented invention . . . during

the term of the patent therefor, infringes the patent.” 35

U.S.C. § 271(a). In 1984, however, Congress enacted the

Drug Price Competition and Patent Term Restoration Act

(“the Hatch-Waxman Act”), which carved out an exemption

from that rule:

It shall not be an act of infringement to make, use, offer

to sell, or sell . . . a patented invention . . . solely for uses

reasonably related to the development and submission of

information under a Federal law which regulates the

manufacture, use, or sale of drugs. [/d. § 271(e)(1)

(“FDA exemption”).}°

Here, the issue presented is what uses of a patented

invention are “reasonably related to the development and

‘The FDA exemption was created, in part, to respond to the Federal

Circuit's determination, in Roche Products, Inc. v. Bolar Pharmaceutical

Co., 733 F.2d 858 (Fed. Cir. 1984), that testing done by a generic

manufacturer to generate information to support approval of its copy of a

new drug was not shielded by the common law “experimental use

defense” to patent infringement. /d. at 862-63. As the Federal Circuit

held:

[djespite Bolar’s argument that its tests are ‘true scientific inquiries’

to which a literal interpretation of the experimental use exception

logically should extend, we hold the experimental use exception to be

truly narrow, and we will not expand it under the present

circumstances. Bolar's argument that the experimental use rule

deserves a broad construction is not justified. [/d. at 863.]

6

submission of information” under a Federal 'aw regulating

drugs. A divided panel of the Federal Circuit held that the

FDA exemption is “correctly confined... to activity that

‘would contribute (relatively directly)’ to information the

FDA considers in approving a drug.” Pet. App. 13a (quoting

Intermedics, Inc. v. Ventritex Inc., 775 F. Supp. 1269, 1280

(N.D. Cal. 1991), affd, 991 F.2d 808 (Fed. Cir. 1993)

(table)). The panel observed that the FDA “does not require

information about drugs other than the compound featured in

an Investigational New Drug application,” and concluded that

the FDA “has no interest in the hunt for drugs that may or

may not later undergo clinical testing for FDA approval.” Id.

at 12a (emphases supplied). The court thus seemingly limited

the FDA exemption to the human clinical research that occurs

under an IND application, and denied the exemption to all

preclinical research. In so doing, the panel relied heavily on

legislative history indicating that “the express objective of the

{Hatch-Waxman Act] was to facilitate the immediate entry of

safe, effective generic drugs.” Jd. (emphasis supplied). Al-

though the court subsequently clarified that the “scope of the

safe harbor is not limited to generic drug approval,” the court

nonetheless found that the legislative history of the Hatch-

Waxman Act “inform[ed] the breadth of the statutory text.”

Id. at 36a. See also id. at 13a (finding in the “context of this

safe harbor” a focus on “facilitating expedited approval of”

generic versions of patented drugs “already on the market”).

Amici endorse petitioner’s and the United States’ position

that the Federal Circuit’s decision erroneously limits the FDA

exemption and would complicate the development of

innovative drugs in contravention of congressional command

* Judge Newman dissented from the liability determination on the

ground that all of the experiments at issue were exempt under either the

FDA exemption or the common law experimental use exemption. Pet.

App. 35a. As petitioner and the United States have recognized, the

common law experimental use exception is not implicated in this case, and

is not before this Court.

7

and intent. The text of the exemption is phrased in broad

terms, embracing the “development” of information; and both

the legislative history and the purposes of the Hatch-Waxman

Act support a generous construction. See Pet. Br. 36-37; U.S.

Br. 14-15. Using these traditional tools of statutory

construction, the exemption is best interpreted to extend to all

research intended to generate information that the FDA would

require or consider in connection with an IND application.

Logically, it also must include the same research performed

by the developer of a candidate drug or biologic who elects

not to pursue an IND application for that candidate drug or

biologic (e.g., because the candidate did not exhibit results in

testing that could justify preclinicai investigations). As the

House Report describing the FDA exemption explained, “[a]

party which develops such information but decides not to

submit an application for approval, is protected as long as the

development was done to determine whether or not an

application for approval would be sought.” H.R. Rep. No.

98-857, pt. 1, at 45 (1984).

Consistent with the text, structure, and the purposes of the

Hatch-Waxman Act, this Court has already made clear that

the FDA exemption should be generously interpreted. In Eli

Lilly & Co. v. Medtronic, Inc., 496 U.S. 661 (1990), the Court

addressed the meaning of the phrase “‘a Federal law which

regulates the manufacture, use, or sale of drugs.”” Jd. at 665.

Eli Lilly argued that this phrase should be limited to “those

individual provisions of federal law that regulate drugs,”

denying the exemption to medical devices, while Medtronics

asserted that the exemption referred to “the entirety of any

federal Act . . . at least some of whose provisions regulate

drugs,” an interpretation that would extend the exemption

beyond drugs to medical devices. /d. at 665-66. The Court

concluded that the FDA exemption broadly exempts from

infringement the use of patented inventions to develop and

submit information to the FDA under any provision of a

Federal law regulating drugs. A similarly broad construction

8

of the reasonable-relationship test incorporated into the FDA

exemption is warranted.

Amici write separately to make two points: First, for

several reasons, limiting the FDA exemption to human

clinical research conducted under an IND application has a

particularly harmful impact on the biologics component of the

pharmaceutical industry. Second, Congress’s considered

decision to employ the familiar reasonable-relationship test

reflects its intent to accord a generous sweep to ihe FDA

exemption; that test, as applied in numerous areas of law

noted infra, requires only that the use of the patented

invention be reasonably intended to produce information that

would be required or considered by the FDA.

il. BIOLOGICS DIFFER FROM CHEMICALLY-

SYNTHESIZED DRUGS IN WAYS THAT MAKE

APPLICATION OF THE FDA EXEMPTION EVEN

MORE CRITICAL TO THEIR DEVELOPMENT

AND DEPLOYMENT.

A. Biologics Differ From Chemically-Synthesized

Drugs In Ways That Significantly Affect The

Regulatory Approval Process And Its Require-

ments.

Biologics are fundamentally different from traditional

chemically-synthesized drugs, sometimes known as “smal!

molecule drugs.” The active ingredient of a biologic usually

is a large, complex molecule derived from a living organism;

a biologic, typically a protein, can be a chain of hundreds of

amino acids with a complex three-dimensional structure. As

the FDA has explained, biologics are “complex mixtures of

molecular species that [are] difficult to characterize as

individual entities. In some cases, the specific active moiety

could not be identified, or the active moiety existed in a

milieu of other components that had the potential to affect

many of its characteristics.” FDA, Guidance Concerning

Demonstration of Comparability of Human Biological

9

Products Including Therapeutic Biotechnolugy-derived

Products (Apr. 1996) (“Comparability Guidance’), available

at http://www.fda.gov/cder/guidance/compare.htm. Thus, un-

like chemically-synthes' sed drugs — the functional character-

istics of which generally do not vary significantly — the safety

or effectiveness of a biologic cannot be evaluated simply by

identifying the physical structure of the active ingredient.

In addition, unlike a chemically-synthesized drug,

conclusions about the safety or effectiveness of a biologic

cannot be separated from the specific process used to

manufacture each biologic. The manufacturing process for a

chemically-synthesized drug involves discrete, linear steps

that progress predictably. The manufacturing processes for

biologics, in contrast, generally use living cells as hosts or

miniature factories that create the desired product. The

capabilities of these hosts are inherently variable. Biologics

inckde, for example, products such as recombinant DNA-

derived therapeutic proteins which are created by inserting a

DNA sequence into a living organism that synthesizes the

desired protein. As the FDA has stated:

[bjecause of the limited” ability to characterize the

identity and structure and measure the activity of the

clinically-active component(s), a biological product was

often defined by its manufacturing process.... FDA

recognized that changes in the manufacturing process,

equipment or facilities could result in changes in the

biological product itself.... [FDA, Comparability

Guidance (emphasis supplied).]

Simply put, each biologic manufacturing process will result

in a unique product. Minor differences in a biologic’s

manufacturing process can have a significant impact on the

biologic’s clinical attributes, including both its effectiveness

and its safety; and manufacturers employ extensively

validated manufacturing controls. Thus, even if the physical,

chemical, and biological properties of the process and the

resulting product are carefully defined or characterized, that

10

does not ensure clinical or therapeutic equivalence of two

biologics produced in different conditions of manufacture.

“There is no such thing as a ‘me-too’ biologic.” See Public

Information, 39 Fed. Reg. 44602, 44641 (Dec. 24, 1974)

(“[A]ll biological products are required to undergo clinical

testing in order to demonstrate safety, purity, potency, and

effectiveness prior to licensing, regardless whether other

versions of the same product are already marketed or

standards for the product have been adopted by rule

making. .... This is required because all biological products

are to some extent different and thus each must be separately

proved safe, pure, potent, and effective.”).

It is also instructive that to date, no legal regulatory

framework is in place in Japan, Europe or the United States

that would permit a so-called “generic biologic” to gain

regulatory and market approval. While the responsible

regulatory agencies in these countries have been wrestling

with these issues for some time and have promised that

guidelines would be forthcoming, none is persuaded that

chemical and _ biological similarity between innovator

products and “biogeneric” copies thereof can effectively be

shown. The FDA’s regulation of biologics and the

application of the FDA exemption to the investigation and

development of biologics can only be understood with the

unique characteristics of biologics in mind.

B. Because The FDA Requires Manufacturers Of

Pioneer Drugs, Including Biologics, To Submit

Substantial Preclinical Research In An IND

Application, The “Use” Of “Patented Inven-

tion{s]” In Such Research Is Protected By The

FDA Exemption.

Federal law — specifically, the FDCA and the PHSA -

forbids the introduction into commerce of any drug,

chemically-synthesized or biologic, unless the Secretary of

Health and Human Services has determined the drug is both

safe and effective. See 21 U.S.C. § 355(a) & (d) (all drugs),

42 U.S.C. §262(a2)A) (biologics). To permit the

investigation of products not yet found to be safe and

effective, Congress exempted from the statutory requirements

of safety and effectiveness “drugs intended solely for

investigational use by experts qualified by scientific training

and experience to investigate the safety and effectiveness of

drugs.” 21 U.S.C. § 355(i)(1) (all drugs). In addition,

Congress authorized the Secretary to promulgate regulations

“conditioning such exemption upon . .. the submission to the

Secretary ... of preclinical tests (including tests on animals)

of such drug adequate to justify the proposed clinical testing.”

Id. § 355i IMA). See also 42 U.S.C. § 262(a)(3) (“[T]he

Secretary shall prescribe requirements under which a

biological product undergoing investigation shall be exempt”

from the safety, purity and potency requirements of

§ 262(a)( 1) & (2)).

1. The FDCA Process.

Pursuant to the FDCA’s authorization of investigational

uses of unapproved drugs, the Secretary has _ issued

regulations establishing the IND application process. See 21

C.F.R. § 312.20 et seg. Those regulations do not require

particular studies, but they clearly and expressly anticipate the

submission of results from preclinical research. Specifically,

they require “[{a] summary of the pharmacological and

toxicological effects of the drug in animals,” “[a}dequate

information about pharmacological and toxicological studies

of the drug involving laboratory animals or in vitro,” and

provision of the “rationale for the drug or the research study.”

See id. § 312.23(a)(3iv), (Si) & (8). It is preclinical

studies that generally provide the data and hence the support

for these showings. Thus, it is preclinical work that allows

the manufacturer to demonstrate that the drug warrants

clinical trials, i.e., that the drug does not “represent{] an

unreasonable risk to the safety of the persons who are the

subjects of the clinical investigation.” 21) USC.

§ 355113) Bi); see also id. § 355(i( 1A). Only if the IND

12

application is granted can the drug manufacturer proceed to

the clinical testing necessary to submit a new drug application

(“NDA”). Once the NDA is approved, the drug may be

marketed.

What is critical here is that data from preclinical research

are routinely submitted to the FDA in IND applications, and

are considered by the FDA in its review of an IND

application. Thus, the generation of data from preclinical

testing of patented inventions is “reasonably related to the

development and submission of information under a Federal

law which regulates” drugs. 35 U.S.C. § 271(e)(1).

2. The PHSA Process.

In contrast to drugs, biologics are subject to the regulatory

processes of the PHSA. The PHSA requires the Secretary to

establish by regulation requirements for the licensing of

biologics. 42 U.S.C. § 262(a2) & (3). To obtain approval

of a biological license application (“BLA”), the manufacturer

must demonstrate that the biologic is safe, pure, and potent.

See id. § 262(a2C); 21 C.F.R. § 601.2. The regulatory

process for biologics is administered by the FDA Center for

Biologics Evaluation and Research (“CBER”). CBER

reviews and approves biologics through a process akin to that

for chemically-synthesized drugs. See Jeanne M. Novak et

al.. The Biological IND, in Biologics Development: A

Regulatory Overview 49-81 (M. Mathieu ed., 2d ed. 1997);

see also Suzanne M. Sensabaugh, A Primer on CBER’s

Regulatory Review Structure And Process, 32 Drug Info. J.,

1011, 1017-18 (1998).

There is some overlap in the regulation of biologics and

drugs; however, the biologics regulatory pathway is more

“At the outset of the biotechnology industry, a small number of

biologics were evaluated and approved as drugs under the FDCA process.

Since that trme, nearly every biologic has been evaluated and approved

under the PHSA.

13

extensive and requires more information.” For example, a

biologics manufacturer seeking approval to begin clinical

testing of a new biologic must fulfill all the requirements

placed on the manufacturers of new chemically-synthesized

drugs; in addition, a biologics manufacturer seeking a BLA

must further establish that the facility in which a biologic is

manufactured, processed, packed or held meets standards that

ensure that the product remains safe, pure, and potent. 21

C.F.R. § 601.2(a); see also id. § 601.20(c).

As is the case with chemically-synthesized drugs, a new

candidate biologic must be investigated through preclinical

development and research before the FDA will approve an

IND application which grants the sponsor the legal authori-

zation to evaluate the biologic in clinical investigations.

Under the FDA regulations implementing the PHSA, the

biologic manufacturer “shall submit data derived from

nonclinical laboratory and clinical studies whiv) .lemonstrate

that the manufactured product meets prescribed requirements

of safety, purity, and potency.” /d. § 601.2(a). With regard to

“products under development,” the regulations expressly

incorporate sections 505(i) and 520(g) of the FDCA, invoking

the Secretary’s authority to authorize investigational uses of

biologics and to establish the IND application process. /d.

§ 601.21.

As a practical matter, there can be no doubt that a wide

range of preclinical research forms an essential part of the

FDA's decision to approve an IND application for a biologic.

One author explained that “[p]re-clinical development [of a

biologic] should include pharmacology and toxicology studies

in appropriate animal models” in order to “permit the FDA to

assess whether the product is reasonably safe for initial

“The PHSA provides that the FDCA “applies to a biological product

subject to regulation under {the PHSA)}, except.that a product for which a

license has been approved under [PHSA § 351] shall not be required to

have an approved application under section [SOS of the FDCA].” See 42

U.S.C. § 262()).

14

testing in humans.” Novak, supra, at 53. Another author

further highlighted the importance and essential “[p]urpose[s]

of [p}re-clinical [sJafety [e]valuation” for biologics:

A primary goal in conducting preclinical studies is to

obtain data necessary to initiate clinical trials. The data

derived from preclinical studies provide the scientific

basis for the development of clinical monitoring

parameters and the rational selection of an initial safe

starting dose, a dose-escalation scheme, a duration of

use, a route of administration, and potential target organs

tor toxicity.

Preclinical studies should be designed to answer specific

questions. These answers should provide an under-

standing of the dose/activity relationship, the relation-

ship of route and scheduling to activity/toxicity, the

dose/toxicity relationship, and the risks for toxicity.

Often additional studies are designed to help discern a

product's mechanism of action, to facilitate future

clinical development (i.c., to help ensure that clinical

trials are not needlessly interrupted), and to satisfy

liability and/or labeling issues. [Joy A. Covagnaro,

Preclinical Safety Assessment of Biological Products in

Biologics Development: A Regulatory Overview 21, 25-

26 (M. Mathieu ed., 2d ed. 1977) (emphasis supplied). }

The ideal, this author concluded, is “a dialogue between FDA

and industry scientists [that] will take place early m product

development.” /d. at 27.

In addition, because the manufacturing process determines

the safety and efficacy of a biologic, the biologics

manufacturer must also provide sufficient information “so

that CBER can assess the validity and safety of manufacture.”

Novak, supra, at 53. The regulation of the process as well as

the product dramatically increases the amount of preclinical

investigation that must be done prior to the submission of an

IND application. And the breadth of the preclinical work

15

necessary means that a broader array of technology — viz.,

patented inventions are implicated.

This explains why an IND application submitted to CBER

requires a summary of preclinical data, see id. at 59-62

(describing investigator’s brochure and clinical protocol).

And, as noted, the application must also include “adequate

information about the pharmacological and toxicological

studies performed in animal models or in vitro to establish

that the investigational product is reasonably safe for the

initiation of clinical studies.” /d. at 59-66 (citing 21 C.F.R.

§ 312.23(a)(8)). Guidance for this section was issued by the

FDA in November 1995, see FDA, Guidance for Industry:

Content and Format of Investigational New Drug

Applications (INDs) for Phase I Studies of Drugs, Including

Well Characterized, Therapeutic, Biotechnology-derived

Products (Nov. 1995). That Guidance spells out in detail the

extensive preclinical support that the FDA expects to receive

and will consider in connection with their evaluation of an

IND application for a biologic. See, e.g., id. at 10 (explaining

that one section of an IND application should contain “a

description of the pharmacologic effects and mechanism(s) of

actions of the drugs in animals”): id. (“[p}Jresent regulations

require an integrated summary of the toxicologic effects of

the drug in animals and in vitro”); id. at 11-13 (describing

information required in summary of toxicologic findings of

animal studies and in data tabulation, and requiring records to

be made available for inspection).

In sum, both legally and practically, manufacturers of

biologics conduct substantial preclinical research to satisfy

the FDA’s requirements for an IND application. Equally to

the point, in developing a biologic, a manufacturer will

conduct substantial preclinical research not only on the safety

or effectiveness of a new biologic, but also on how the

biologic can be produced and purified. Information from

such research — whether conducted before the IND applica-

tion is submitted or after the BLA has been approved — must

16

be retained and made available to the FDA at its request,

regardless of whether the steps used to produce or purify the

biologic in the preclinical stage ultimately are those used to

produce the biologic on a commercial scale. The use of

patented inventions in such research should be shielded by the

FDA exemption; protection from infringement litigation

cannot turn on the success or failure of the research being

conducted without having the practical effect of discouraging

the research itself. This is why the text does and should

protect all uses “reasonably related” to the approval process.

Although it may come to pass that some data that is generated

by use of a patented invention is not submitted to the FDA

with the IND application, or is only submitted later in

response to a CBER inquiry, the “use” was nonetheless

“reasonably related to the development and submission of

information” to the FDA under the FDCA and the PHSA.

C. Interpreting The FDA Exemption Narrowly Due

to Congress’s Focus On The FDA’s Approval Of

Generic Drugs Is Particularly Harmful To The

Discovery And Development Of Biologics.

As noted above, the Federal Circuit was intent on

narrowing the interpretation of the text of the FDA exemption

because, in its view, the exemption had to be construed to

reflect at least in part Congress’s “express objective... to

facilitate ... generic drugs.” Pet. App. 12a. In so doing, the

Federal Circuit resisted the necessary implications of this

Court's decision in Medtronic, which expressly rejected the

notion, that the FDA exemption is restricted to generic drugs

and heid that even medical devices are covered. See 496 U.S.

at 665-67, 669 & n.2. Critically, for Amici, a narrow focus on

generic drugs is uniquely damaging to the biologics sector.

The primary approval route for generic versions of

chemically-synthesized drugs is section 505(j) of the FDCA,

which authorizes review and approval of abbreviated new

drug applications (“ANDAs”) based on a demonstration that

the generic drug is the “same as” an approved pioneer drug.

17

If a generic contains the same active ingredient, the same

route of administration, the same dosage form, the same

strength, and the same bioavailability as an approved drug,

the generic may be approved based on the clinical safety and

effectiveness data included in that approved drug’s NDA.

As explained above, ‘there is no such thing as a ‘me-too’

[generic] biologic.” See supra at 10 (quoting 39 Fed. Reg. at

44641). The FDA has never applied an abbreviated approval

process to a biologic. Indeed, in 1984, the Agency expressly

recognized that the new abbreviated mechanism did not

extend to biologics. See Abbreviated New Drug Application

Regulations, 57 Fed. Reg. 17950, 17951 (Apr. 28, 1992) ‘the

ANDA process is “inapplicable to... biological drug

products licensed under [the PHSA]”).’ While chemically-

synthesized drugs generally have simple chemical structures

that can be easily identified and replicated to achieve

therapeutic equivalence, this is not true of biologics. Under

current scientific testing methods, biologics cannot be shown

to be identical to approved drugs due to their complexity and

inherent variability. See, e.g., S. Usdin, CBER’s Abbreviated

Route, BioCentury, Apr. 15, 2002, at A6-7 (FDA official

concludes that because of safety issues, even the best-

characterized biologics require clinical data, and are not

suited to an abbreviated approval process). Put in terms of

the statutory language, because the ANDA process may be

used only when manufacturers show that the new drug is the

“same as” — i.e., the bioequivalent of — an approved drug, see

” As noted supra, for reasons largely of history, a small number of

drugs which fulfill the definition of “biological product” under the PHSA

(e.g., insulin and human growth hormone) have been approved instead

under § 505 of the FDCA. But, the FDA has never treated these products

differently from other biologics — that is, the FDA has never used the

abbreviated approval process in connection with such a drug.

18

21 U.S.C. § 355(j( 2 Ai), the ANDA process cannot be

utilized in order to seek FDA approval of a biologic.”

Accordingly, limiting the scope of the FDA exemption to

activities in connection with the abbreviated or generic Jrug

approval process would have a disproportionately harsh

impact on the biologics sector of the pharmaceutical industry.

Under the strictest interpretation of the exemption (an

interpretation, we submit, that should have been effectively

foreclosed by Medtronics), no use of patented inventions in

preclinical and clinical biologics research and development

would ever be exempted because a biologic can never be

approved through an abbreviated or “generic” application

process.

Under the Federal Circuit’s somewhat less constrained

interpretation of the exemption, uses of a patented invention

in connection with clinical trials conducted under an IND

application would be protected but uses in connection with

preclinical research would not. Such clinical trials may never

occur, however, if biologics manufacturers were confronted

with claims of patent infringement during the preclinical

investigations of a new candidate biologic that the FCA

expects to occur. This is because, for the reason set forth

supra, the developer of a new biologic must employ a diverse

and broad range cf investigative technologies in conducting

such research, some or all of which may be subject to patents.

In some instances, it simply will not be economically feasible

for a biologics manufacturer to continue the preclinical

"The FDA has authorized certain changes in the manufacturing process

ic be made by a biologic’s experienced manufacturer in an abbreviated

application process. See FDA, Comparability Guidance. Changes to an

approved manufacturing process by a manufacturer with complete

knowledge of that process and significant historical and experience

making and validating the biologic are not remotely analogous, of course,

to approving a different manufacturer’s biologic — which uses different

Starting materials and a different process — as safe and effective without

product-specific testing.

19

investigation needed of a candidate biologic if doing so

creates substantial licensing costs or other liability.

To this end, the FDA exemption should be interpreted to

encourage complete analysis and study of a new drug or

biologic in order to generate as much information as possible

regarding that product’s safety and effectiveness. Indeed, an

interpretation that exposes these preclinical investigations of a

new drug or biologic to patent liability would run precisely

counter to the legislative design of the FDA exemption. The

Federal Circuit’s constrained view of the scope of the FDA

exemption thus contravenes to the reason for its incorporation

into the patent statute; namely, to encourage the types of

testing that both manufactures and the FDA believe should be

done on a new candidate biologic or drug before it is first

administered to a human in a clinical setting.

III. CONGRESS’S CHOICE OF THE REASONABLE-

RELATIONSHIP TEST MANDATES A

RATIONAL-BASIS INTERPRETATION OF THE

FDA EXEMPTION.

A. Congress’s Decision To Employ The Reasonable-

Relationship Test Is Significant.

In law, the reasonable-relationship test is a familiar one, a

formulation with connotations of deference to decision

makers, whether they are lawmakers or administrators.

Congress’s use of this typical formulation indicates its intent

that the FDA exemption be expansively interpreted.

As petitioner and the United States have already explained,

the text, the legislative history, the purposes of the FDA

exemption, and this Court’s decision in Medtronics all

support a broad interpretation of the FDA exemption, not only

for research actually recited in an application to the FDA, but

also for research that was reasonably calculated to result in an

application ultimately not submitted. Amici will not burden

the Court with a repetition of that analysis here. Instead,

Amici show that this Court’s broad construction of the FDA

20

exemption is amply justified by the congressional decision to

employ a reasonable-relationship test — a test with a familiar

and generally accepted meaning across the legal spectrum that

mandates this result.

The question whether an act or decision is reasonably

related to a particular goal frequently recurs in this Court’s

jurisprudence. The test for whether a search is lawful is

whether it is “reasonably related in scope to the circumstances

which justified [the stop].” Terry v. Ohio, 392 U.S. 1, 20

(1968) (Terry stop search); see also New Jersey v. T.L.O., 469

U.S. 325, 341 (1985) (school search). The test for the

lawfulness of restrictions on prisoners’ First Amendment

rights is whether those restrictions are “reasonably related to

legitimate penological interests,” see Turner v. Safley, 482

U.S. 78, 89 (1987); while the test for analogous restrictions

on students’ rights is whether they are “reasonable related to

legitimate pedogogical concerns.” See Hazelwood Sch. Dist.

v. Kuhimeier, 484 U.S. 260, 273 (1988). The test for whether

a tax On interstate commerce is lawful is whether that tax is

“reasonably related” to the taxpayer’s presence or activities in

the state. See Complete Auto Transit, Inc. v. Brady, 430 U.S.

274, 286-87 (1978). And, the test for whether conditions

imposed in Spending Clause legislation are constitutional is

whether they are “reasonably related” to the purposes of the

spending. See Massachusetts v. United States, 435 U.S. 444,

461-62 (1978) (plurality opinion). There are many further

examples. See, e.g., Hodel v. Virginia Surface Mining &

Reclamation Ass'n, 452 U.S. 264, 283 (1987) (legislation

does not violate the Equal Protection Clause if the means

employed are “reasonably related” to the goals Congress

sought to achieve); City of Monterey v. Del Monte Dunes at

Monterey Lid., 526 U.S. 687, 703-07 (1999) (property

regulation is lawful if “reasonably related” to legitimate

public interests); United Steelworkers of America v.

Sadlowski, 457 U.S. 102, 111-12 (1982) (question is whether

a union rule that interferes with a member’s statutorily

21

protected interest is “reasonably related to the protection of

the organization”).

In all these settings, the reasonable-relationship test has a

well accepted meaning. It inquires whether there is a “valid,

rational connection” between one act or decision and another.

Block v. Rutherford, 468 U.S. 576, 586 (1984). A connection

fails the reasonable-relationship test only if it is “arbitrary or

irrational.” Turner, 482 U.S. at 89-90. The question whether

the use of a patented invention is “reasonably related” to the

“development and submission” of information to the FDA is

thus akin to this Court’s rational-basis test — that is, a

deferential and lenient test that asks only whether the drug

manufacturer had a rational basis for believing that the “use”

at issue would produce information that would be useful to

the FDA in assessing an IND application, an NDA or a BLA.

B. The Question Of The Application (If Any) Of

The FDA Exemption To Research Tools Is

Premature.

Contrary to the decision of the Federal Circuit, this case

does not raise the question whether the FDA exemption

covers “research tools.” Pet. App. I4a. As _ petitioner

explains, respondent has never asserted that the patented

inventions at issue are research tools. Pet. Br. 41-42. The

issue simply is not presented here.

Amici submit that the sole inquiry necessary for the Court is

whether the acts done by petitioner are shielded under the

FDA exemption because they were “solely for uses

reasonably related to the development and submission of

information under a Federal law which regulates the

manufacture, use, or sale of drugs or veterinary biological

products.” To the extent that use of a patented invention —

whether or not it can be labeled a “research tool” — is to

* There also is no established definition or understanding of the term

“research tool”; and the FDA, the expert agency that administers and

implements the FDCA and the PHSA, has never attempted to develop a

22

generate such information, such use is shielded by the FDA

exemption.

Amici also submit that the concerns expressed by the

Federal Circuit in its decision are both unwarranted and

premature. We note that even if the exemption were

interpreted to cover “research tools,” it would shield only

those acts done with the “research tool” to generate

information reasonably related to the FDA review of a new

drug or biologic; the “research tool” patent holder would be

able to enforce its patent in all other contexts. Moreover, as

Judge Newman observed in dissent below, there are obvious

and accepted differences between the use of a substance or

device as a tool to study other substances or devices, and the

study of the substance or device itself. See Pet. App. 35a.

Researchers often pay licensing fees for the former, but

generally not for the latter.”

In light of the breadth and flexibility of the statutory

language and the highly specialized and technical nature of

the inquiry, it is likely that any FDA determinations about the

meaning of the term “research tool” and the application of the

FDA exemption to the use of such tools would receive

substantial deference from the courts. See Chevron U.S.A.,

Inc. v. National Res. Def. Council, Inc., 467 U.S. 837, 859-66

(1984). And, although the brief of the United States in

response to the Court’s invitation strongly supports a

generous interpretation of the scope of the FDA exemption, it

does not provide the United States’ view on whether the FDA

exemption applies to research tools, instead stating (correctly)

regulatory definition. Nor has the FDA ever considered the application of

the FDA exemption to research tools or whether or to what extent the use

of a research tool is “reasonably related” to the development and

submission of information to the FDA.

"Indeed, Amici are not simply “users” of patented research tools.

Instead, both Amici have invented, developed, patented and licensed a

variety of basic and platform technologies that are properly considered to

be “research tools.”

23

that research tools are not implicated here. Indeed, the FDA

would likely seek input from all its constituents before

making a final judgment on this issue.

For all these reasons, Amici respectfully submit that the

Court should not prematurely address the application of the

FDA exemption to research tools.

CONCLUSION

The decision below should be reversed.

Respectfully submitted,

SEAN JOHNSTON CARTER G. PHILLIPS

GARY H. LOEB VIRGINIA A. SEITZ*

GENENTECH, INC. JEFFREY P. KUSHAN

| DNA WAY DAVID L. FITZGERAL®

~ SOUTH SAN FRANCISO, CA SIDLEY AUSTIN BROWN &

94080 WOOD LLP

(650) 225-1000 1501 K STREET, N.W.

WASHINGTON, D.C. 20005

RAYMOND G. ARNER (202) 736-8000

JAMES D. DARNLEY, JR.

BIOGEN IDEC, INC.

14 CAMBRIDGE COURT

CAMBRIDGE, MA 02142

_ (617) 914-5967

Counsel for Amici Curiae

February 22, 2005 * Counsel of Record