Friday, June 24, 2005

Some aspects of Merck v. Integra at the Supreme Court

I. The case cited by the Supreme Court

In Merck v. Integra, 2005 U.S. LEXIS 4840; 73 U.S.L.W. 4468, the Supreme Court cited the underlying Federal Circuit decision as Integra Lifesciences I, Ltd. v. Merck KGaA, 331 F.3d 860, 2003 U.S. App. LEXIS 11335 (Fed. Cir. 2003), rather than the amended decision of the Federal Circuit.

II. Common law exception not at issue

The earlier decision that activities before 1995 were covered by the common law research exemption was not at issue. The Supreme Court was deciding whether activities after 1995 fell within the scope of 35 USC 271(e)(1).

Thus, the activities at issue arose after Dr. Cheresh of Scripps submitted a detailed proposal for expanded collaboration between Scripps and petitioner Merck KGaA on February 1, 1995. This proposal set forth a 3-year timetable in which to develop "integrin antagonists as angiogenesis inhibitors," beginning with in vitro and in vivo testing of RGD peptides at Scripps in year one and culminating with the
submission of an IND to the FDA in year three. Merck agreed to the material terms of the proposal on February 20, 1995, and on April 13, 1995, pledged $ 6 million over three years to fund research at Scripps. Pursuant to the agreement, Dr. Cheresh directed in vitro and in vivo experiments on RGD peptides provided by petitioner from 1995 to 1998. These experiments focused on EMD 66203 and two closely related derivatives, EMD 85189 and EMD 121974, and were designed to evaluate the suitability of each of the peptides as potential drug candidates. Accordingly,
the tests measured the efficacy, specificity, and toxicity of the particular
peptides as angiogenesis inhibitors, and evaluated their mechanism of action and
pharmacokinetics in animals. Based on the test results, Scripps
decided in 1997 that EMD 121974 was the most promising candidate for testing in

On July 18, 1996, after licensing negotiations broke down, Integra filed a patent-infringement suit against petitioner, Scripps, and Dr. Cheresh in the District Court for the Southern District of California.

With the consent of the parties, the District Court gave the following instruction regarding the § 271(e)(1) exemption:

"To prevail on this defense, [petitioner-Merck] must prove by a
preponderance of the evidence
that it would be objectively reasonable for a party in [petitioner 's] and Scripps' situation to believe that there was a decent prospect that the accused activities would contribute, relatively directly, to the
generation of the kinds of information that are likely to be relevant in the
processes by which the FDA would decide whether to approve the product in

"Each of the accused activities must be evaluated separately to
determine whether the exemption applies.

"[Petitioner] does not need to show that the information gathered
from a particular activity was actually submitted to the FDA."

III. Supreme Court's handling of "preclinical" boundary of CAFC

The Supreme Court made short work of the CAFC's discussion of preclinical work.

As an initial matter, we think it apparent from the statutory text
that § 271(e)(1)'s exemption from infringement extends to all uses of patented
inventions that are reasonably related to the development and
submission of any information under the FDCA. Cf. Eli Lilly, 496 U.S., at 665-669, 110 L. Ed. 2d 605, 110 S. Ct. 2683 (declining to limit § 271(e)(1)'s exemption from
infringement to submissions under particular statutory provisions that
regulate drugs). This necessarily includes preclinical studies of patented
compounds that are appropriate for submission to the FDA in the regulatory process.
There is simply no room in the statute for excluding certain information
from the exemption on the basis of the phase of research in which it is
developed or the particular submission in which it could be included. n6

Note 6 -->

n6 Although the Court of Appeals' opinion suggests in places that §
271(e)(1)'s exemption from infringement is limited to research conducted in
clinical trials, see 331 F.3d at 866, we do not understand it to have adopted
that position.
The Court of Appeals recognized that information included in
an IND would come within § 271(e)(1)'s safe harbor. Ibid. Because an IND must
be filed before clinical trials may begin, such information would necessarily be
developed in preclinical studies.

IV. Supreme Court's handling of CAFC's policy arguments

The Supreme Court noted:

The Court of Appeals' conclusion that § 271(e)(1) did not protect
petitioner 's provision of the patented RGD peptides for research at Scripps
appeared to rest on two somewhat related propositions.

First, the court credited the fact that the "Scripps-Merck experiments did not supply information for submission to the [FDA], but instead identified the best drug candidate to subject to future clinical testing under the FDA processes." 331 F.3d at 865; see also id., at 866 (similar). The court explained:

"The FDA has no interest in the hunt for drugs that may or may not
later undergo clinical testing for FDA approval. For instance, the FDA
does not require information about drugs other than the compound featured in an
[IND] application. Thus, the Scripps work sponsored by [petitioner] was not
'solely for uses reasonably related to' clinical testing for FDA." Ibid.

Second, the court concluded that the exemption "does not globally
embrace all experimental activity that at some point, however attenuated, may lead
to an FDA approval process." Id., at 867. n7

We do not quibble with the latter statement. Basic scientific
research on a particular compound, performed without the intent to develop a
particular drug or a reasonable belief that the compound will cause the sort of
physiological effect the researcher intends to induce, is surely not "reasonably
related to the development and submission of information" to the FDA. It does not
follow from this, however, that § 271(e)(1)'s exemption from infringement
categorically excludes either (1) experimentation on drugs that are not ultimately the subject of an FDA submission or (2) use of patented compounds in experiments that are not ultimately submitted to the FDA. Under certain conditions, we think the exemption is sufficiently broad to protect the use of patented compounds in both situations.

As to the first proposition, it disregards the reality that, even at
late stages in the development of a new drug, scientific testing is a
process of trial and error. In the vast majority of cases, neither the drugmaker
nor its scientists have any way of knowing whether an initially promising
candidate will prove successful over a battery of experiments. That is the reason they conduct the experiments. Thus, to construe § 271(e)(1), as the Court of
Appeals did, not to protect research conducted on patented compounds for which
an IND is not ultimately filed is effectively to limit assurance of exemption to
the activities necessary to seek approval of a generic drug [LBE note: no!]: One can know at the outset that a particular compound will be the subject of an eventual
application to the FDA only if the active ingredient in the drug being tested is
identical to that in a drug that has already been approved.

[As to the second proposition] For similar reasons, the use of a patented compound in experiments that are not themselves included in a "submission of information" to the FDA does not, standing alone, render the use infringing. The relationship of the use of a patented compound in a particular experiment to the "development and
submission of information" to the FDA does not become more attenuated (or less
reasonable) simply because the data from that experiment are left out of the
submission that is ultimately passed along to the FDA. Moreover, many of the
uncertainties that exist with respect to the selection of a specific [*26] drug exist as well with respect to the decision of what research to include in an IND or NDA. As a District Court has observed, "It will not always be clear to parties
setting out to seek FDA approval for their new product exactly which kinds of
information, and in what quantities, it will take to win that agency's approval."
Intermedics, Inc. v. Ventritex, Inc., 775 F. Supp. 1269, 1280 (ND Cal.
1991), aff'd, 991 F.2d 808 (CA Fed. 1993). This is especially true at the
preclinical stage of drug approval. FDA regulations provide only that "the amount
of information on a particular drug that must be submitted in an IND . . .
depends upon such factors as the novelty of the drug, the extent to which it
has been studied previously, the known or suspected risks, and the developmental
phase of the drug." 21 CFR § 312.22(b). We thus agree with the Government that
the use of patented compounds in preclinical studies is protected under §
271(e)(1) as long as there is a reasonable basis for believing that the experiments will produce "the types of information that are relevant to an IND or NDA." Brief of
United States as Amicus Curiae 23.

V. Merck will probably lose on remand

The Supreme Court said:

Thus, the evidence presented at trial has yet to be reviewed under
the standards set forth in the jury instruction, which we believe to be
consistent with, if less detailed than, the construction of § 271(e)(1) that we
adopt today.

Footnote 8:
The relevant jury instruction provided only that there must be a
"decent prospect that the accused activities would contribute, relatively
directly, to the generation of the kinds of information that are likely to be
relevant in the processes by which the FDA would decide whether to approve the product in question." App. 57a. It did not say that, to fall within § 271(e)(1)'s
exemption from infringement, the patented compound used in experimentation must
be the subject of an eventual application to the FDA. And it expressly
rejected the notion that the exemption only included experiments that produced
information included in an IND or NDA. Ibid.

[LBE note: meaning that the jury instruction did not include things that the Supreme Court rejected. That is, nothing in the jury instruction is incompatible with the Supreme Court's ruling.]

VI. Issues with "research tool" patents used in drug research were NOT addressed

Footnote 7:

The Court of Appeals also suggested that a limited construction
of § 271(e)(1) is necessary to avoid depriving so-called "research tools" of
the complete value of their patents. Respondents have never argued the RGD
peptides were used at Scripps as research tools, and it is apparent from the
record that they were not. See 331 F.3d at 878 (Newman, J., dissenting) ("Use of an
existing tool in one's research is quite different from study of the tool
itself"). We therefore need not -- and do not -- express a view about whether, or to what extent, § 271(e)(1) exempts from infringement the use of "research
tools" in the development of information for the regulatory process.


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