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

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## Record

- **Collection:** Supreme Court brief
- **Document type:** Amicus Curiae Brief
- **Published:** January 1, 2005
- **Citation:** 545 U.S. 193

## Text

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

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Counsel for Amici Curiae

February 22, 2005 * Counsel of Record

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Source: Frix Law Library, https://www.frixlaw.com/law-library/documents/brief%3Amicro_IA40385014_0744%3A23. Public record. Not legal advice.