Case Information
*3 Before NEWMAN , FRIEDMAN , ∗ AND LOURIE , Circuit Judges . N EWMAN , Circuit Judge .
This case arises on the filing by each of the defendants of an Abbreviated New Drug Application (ANDA), accompa- nied by a Hatch-Waxman Act “Paragraph IV certification” challenging the validity and enforceability and asserting non-infringement of United States Patent No. 5,658,590 (the ’590 patent) owned by Eli Lilly and Company. The ’590 patent is directed to the use of the drug atomoxetine to treat attention-deficit/hyperactivity disorder (ADHD). Lilly obtained federal regulatory approval from the Food and Drug Administration (FDA), and markets the product for ∗ Circuit Judge Friedman heard oral argument in this appeal, but died on July 6, 2011 and did not participate in the final decision. The case was decided by the remaining judges of the panel, in accordance with Fed. Cir. Rule 47.11. this use, with the brand name Strattera®. The defendants seek to sell generic counterparts of this drug before the expiration date of the ’590 patent.
The United States District Court for the District of New Jersey sustained the ’590 patent against the defendants’ challenges on the grounds of inequitable conduct, anticipa- tion, obviousness, and non-enablement. However, the court held the claims invalid for lack of utility, which the court called “enablement/utility.” The court also held that if the claims were valid the defendants would be liable for in- ducement to infringe, but that they would not be liable for contributory infringement. The ruling of invalidity for lack of utility, and the ruling that contributory infringement does not also apply, are reversed. The district court’s other rulings are affirmed. [1]
I
T HE P ATENTED I NVENTION
The ’590 patent is directed to the use of the compound tomoxetine, [2] having the chemical name (R)-(–)-N-methyl-3- (2-methylphenoxy)-3-phenylpropylamine, for treatment of ADHD. Claim 1 is as follows:
1. A method of treating attention- deficit/hyperactivity disorder comprising adminis- tering to a patient in need of such treatment an ef- fective amount of tomoxetine.
Claim 1 was treated by the parties and the district court as dispositive of the issues. At the time the ’590 patent appli- cation was filed, tomoxetine was a known compound, de- scribed and claimed in Lilly’s U.S. Patent No. 4,314,081, issued February 2, 1982. Tomoxetine was studied through Phase II clinical trials for the treatment of urinary inconti- nence, and through Phase III clinical trials for treatment of depression. See 21 C.F.R. §312.21 (explaining Phase I, Phase II, and Phase III clinical trial criteria). Although the clinical trials showed that tomoxetine was safe for human use, the product did not provide the medicinal benefits for which it was being evaluated.
In 1993 Lilly scientists Dr. John Heiligenstein and Dr.
Gary Tollefson suggested that tomoxetine might be effective
for treatment of ADHD. ADHD is a complex neurobiological
disorder characterized by developmentally inappropriate
levels of inattention, hyperactivity, and impulsiveness. The
district court explained that the occurrence of ADHD is
wide, the cause is unknown, and the mechanism of drug
treatment is unclear.
Eli Lilly
,
At the time of this invention, all of the products that were being used to treat ADHD exhibited deficiencies. The ’590 patent explains that the stimulants that were being used require multiple doses per day, produce a rebound effect between doses, and cause undesirable side effects; and the tricyclic antidepressants that were being used also produce undesirable side effects, and require careful super- vision and dosage titration. The record states that the suggestion of Drs. Heiligenstein and Tollefson that tomoxet- ine might be an effective treatment for ADHD was met with skepticism. However, arrangements were made to conduct clinical tests at Massachusetts General Hospital, and on December 1, 1994 the investigators submitted to the FDA an Investigational New Drug (IND) application for treat- ment of ADHD with tomoxetine. On January 3, 1995 the FDA authorized the investigation. The ’590 patent applica- tion was filed on January 11, 1995, and the clinical investi- gation commenced. By May 1995 initial positive results were obtained, and in October 1995 the investigators re- ported their preliminary results at a meeting of the Ameri- can Association of Child and Adolescent Psychiatry.
Clinical investigation continued over the next seven years, including treatment of patients of various ages and ADHD severity, determination of possible side effects and of the cumulative effect of treatment, the development and evaluation of formulations, schedules, and dosages, and other studies relevant to determination of efficacy and safety. On November 26, 2002 the FDA approved the use of tomoxetine for treatment of ADHD in adults, children, and adolescents, at dosages of 10, 18, 25, 40, and 60 mg/day of oral administration; on February 14, 2005 the FDA also approved dosages of 80 and 100 mg/day. The record states that the product has achieved wide use.
II
O BVIOUSNESS The defendants challenged patent validity on the ground
of obviousness, arguing that atomoxetine was a known
norepinephrine inhibitor and thus that it would have been
obvious to test this product for treatment of ADHD. The
defendants argued that the inventors simply “substituted
one potent selective norepinephrine reuptake inhibitor
(atomoxetine) for another (desipramine) known to be effec-
tive in treating ADHD.”
Eli Lilly
,
The district court, discussing this argument, referred to
the reports of sudden death of children taking desipramine,
and found that these “negative reports concerning desip-
ramine. . . . must weigh to some extent away from using
atomoxetine as a potential ADHD treatment” although
“desipramine was functionally a similar compound to ato-
moxetine.”
Id.
at 365. The court found that “while the prior
art demonstrated that norepinephrine reuptake inhibition
was relevant to ADHD treatment, the literature does not
appear to indicate that it was alone sufficient.”
Id.
at 362.
The court stated that “it is impermissible to pick and choose
from any one reference only so much of it as will support a
given position, to the exclusion of other parts necessary to
the full appreciation of what such reference fairly suggests
to one of ordinary skill in the art.”
Id.
at 365-66 (quoting
In
re Weslau
,
The district court observed that the entirety of the prior art must be considered in determining obviousness. There was no evidence that the advantageous and effective proper- ties of atomoxetine to treat ADHD, devoid of the negative effects of known and similar products, would have been obvious from the prior art. The district court found that treatment of ADHD with atomoxetine would not have been predicted by skilled artisans with a reasonable degree of certainty, and concluded that there was not clear and con- vincing evidence that the effective use of atomoxetine to treat ADHD would have been obvious to a person of ordi- nary skill in the field of the invention.
The defendants argue that, at the very least, it would have been “obvious to try” atomoxetine for this use. How- ever, applying the guidance of KSR International Co. v. Teleflex Inc. , 550 U.S. 398 (2007), there was no evidence that use of atomoxetine had been identified as a possible solution to the problems of treating ADHD, nor that the exercise of common sense would have led a person of ordi- nary skill to test atomoxetine for treatment of ADHD. See id. at 420-21. The evidence was contrary to the likelihood that atomoxetine would be effective to treat ADHD, for atomoxetine was known not to be an effective antidepres- sant, and the known norepinephrine inhibitor despiramine was associated with sudden death in children. The experts for both sides were in agreement that they would not have expected that atomoxetine would be a successful treatment of ADHD.
We discern no error in the district court’s ruling that the claims had not been proved invalid on the ground of obvi- ousness.
III E NABLEMENT /S COPE The defendants argue that the ’590 specification does not enable the full scope of claim 1, pointing out that the claim’s words “administering to the patient an effective amount” are not limited to the formulations that are specifi- cally exemplified in the specification. The defendants argue that the patent enables only the immediate release products and dosages in the specific examples, and that claim 1 is invalid because it is not so limited. The defendants’ expert witness testified that formulations and dosages for treat- ment of ADHD are not routine, and thus that undue ex- perimentation would be required to determine the specific formulation and effective amount to be administered to a specific patient.
The ’590 patent describes the formulation and admini- stration of tomoxetine as follows:
Since tomoxetine is readily orally absorbed and requires only once/day administration, there is little or no reason to administer it in any other way than orally. It may be produced in the form of a clean, stable crystal, and thus is easily formulated in the usual oral pharmaceutical forms, such as tablets, capsules, suspensions, and the like. The usual methods of pharmaceutical scientists are applicable. It may be usefully administered, if there is any rea- son to do so in a particular circumstance, in other pharmaceutical forms, such as injectable solutions, depot injections, suppositories and the like, which are well known to and understood by pharmaceuti- cal scientists. It will substantially always be pre- ferred, however, to administer tomoxetine as a tablet or capsule and such pharmaceutical forms are recommended.
’590 patent, col. 2 ll.20-33. The patent’s description of dosages for treatment of ADHD with tomoxetine includes:
The effective dose of tomoxetine for ADHD is in the range from about 5 mg/day to about 100 mg/day. The preferred adult dose is in the range from about 10 to about 80 mg/day, and a more highly preferred adult dose is from about 20 to about 60 mg/day. The children’s dose of course is smaller, in the range from about 5 to about 70 mg/day, more preferably from about 10 to about 50 mg/day. The optimum dose for each patient, as always, must be set by the physician in charge of the case, talking into account the patient’s size, other medications which the pa- tient requires, severity of the disorder and all of the other circumstances of the patient.
Id. at col. 2 ll.7-19.
The district court found that “the various conceivable formulations are standard—and they were not part of the basis for the invention’s patentability.” Eli Lilly , 731 F. Supp. 2d at 375. The court observed that the particular dosage form is not the invention, and is routinely deter- mined:
a dosage formulator as defined by the parties—a scientist with at least a bachelor’s degree in phar- macy or some closely related field, at least three to five years of work experience in developing a par- ticular pharmaceutical dosage form, and the ability to consult with others skilled in other particular disciplines (e.g., physicians, analytical chemists, and biopharmaceutical scientists)—would be able to do so without undue experimentation.
Id.
at 376. In
In re Wands
,
(1) the quantity of experimentation necessary, (2) the amount of direction or guidance presented, (3) the presence or absence of working examples, (4) the nature of the invention, (5) the state of the prior art, (6) the relative skill of those in the art, (7) the pre- dictability or unpredictability of the art, and (8) the breadth of the claims.
The defendants cite
ALZA Corp. v. Andrx Pharmaceuti-
cals LLC
,
Enablement is not negated if a reasonable amount of
experimentation is required to establish dosages and formu-
lation of an active ingredient.
See Enzo Biochem, Inc. v.
Calgene Inc.
,
IV
E NABLEMENT /U TILITY
The district court held all of the ’590 patent claims inva- lid for lack of “enablement/utility.” The court held that utility was not established because experimental data showing the results of treatment of ADHD were not in- cluded in the specification. The court held that “the court cannot conclude that a person of skill in the art would have recognized the method of treatment’s utility in view of the specification and prior art.” Eli Lilly , 731 F. Supp.2d at 389.
The patent statute requires that the specification “dis-
close as a matter of fact a practical utility for the invention.”
In re Ziegler
,
The method of the present invention is effective in the treatment of patients who are children, adoles- cents or adults, and there is no significant difference in the symptoms or the details of the manner of treatment among patients or different ages.
Col.4 ll.14-18. No criticism of the correctness of these statements has been offered. The defendants do not dispute that the ’590 patent describes the utility of tomoxetine for treatment of ADHD, and that the utility is correctly de- scribed. Lilly agrees that human test data were not avail- able at the time the patent application was filed, because human tests were prohibited without FDA authorization.
Dr. Heiligenstein, one of the inventors, testified about his uncertainty whether this treatment of ADHD would be effective, when he and Dr. Tollefson suggested experimental testing for this purpose:
Q: At the time of this filing, did you have a reason- able expectation that tomoxetine would work to treat ADHD?
A: It was a hypothesis.
Q: Did you have a reasonable expectation? A: Reasonable? Can you define reasonable? Q: Did you believe it was going to work for ADHD? A: No, I wasn’t sure at all that it would work.
Heiligenstein Dep. 127:4-12, August 7, 2008. It was not
disputed that persons experienced in this field would re-
quire actual human tests to verify the effectiveness of this
use. As the Court discussed in
Daubert v. Merrell Dow
Pharmaceuticals, Inc.
,
Although it was recognized that Dr. Heiligenstein’s hy- pothesis required testing, Lilly points out that support for the testing was provided, patent procedures were initiated, and the FDA authorized proceeding with human clinical trials. The Manual of Patent Examining Procedure in- structs examiners to give presumptive weight to the utility for which human trials have been initiated:
MPEP §2107.03 (8th ed. 2008). IV. . . . Before a
drug can
enter
human clinical trials, the sponsor, of-
ten the applicant, must provide a convincing ration-
ale to those
especially
skilled in the art (e.g., the
Food and Drug Administration) that the investiga-
tion may be successful. Such a rationale would pro-
vide a basis for the sponsor’s expectation that the
investigation may be successful. In order to deter-
mine a protocol for phase I testing, the first phase of
clinical investigation, some credible rationale of how
the drug might be effective or could be effective
would be necessary.
Thus, as a general rule, if an
applicant has initiated human clinical trials for a
therapeutic product or process, Office personnel
should presume that the applicant has established
that the subject matter of that trial is reasonably
predictive of having the asserted therapeutic utility
.
(Emphases in original.) During examination of the ’590
application, the patent examiner did not require the sub-
mission of data showing treatment of ADHD with atomoxet-
ine, although it is not disputed that such data were obtained
shortly after the patent application was filed. The utility of
this product to treat ADHD is not so incredible as to war-
rant the special procedures that are authorized for use when
the examiner doubts the described utility, as in
In re
Swartz
,
In this case, evidence of the described utility of tomoxet- ine was not requested by the patent examiner, although experimental verification was obtained soon after the filing of the patent application. The examination of the ’590 patent was in accordance with the rules, as the court has explained:
[A] specification which contains a disclosure of util- ity which corresponds in scope to the subject matter sought to be patented must be taken as sufficient to satisfy the utility requirement of §101 for the entire claimed subject matter unless there is reason for one skilled in the art to question the objective truth of the statement of utility or its scope.
In re Langer
,
A specification disclosure which contains a teaching of the manner and process of making and using the invention in terms which correspond to those used in describing and defining the subject matter sought to be patented must be taken as in compliance with the enabling requirement of the first paragraph of §112 unless there is reason to doubt the objective truth of the statements contained therein which must be relied on for enabling support.
The district court’s statement that “there was no credi-
ble disclosure of utility to begin with,”
Eli Lilly
, 731 F.
Supp. 2d at 386 n.18, does not comport with the specifica-
tion’s extensive disclosure of utility. The district court
appears to have accepted the defendants’ argument that in
view of the absence of experimental data in the specifica-
tion, the disclosed utility must be deemed incredible. The
district court apparently also accepted the defendants’
position that such data were required to be included in the
specification. However, the purported authority cited by the
defendants concerned quite different issues, where, for
various reasons, it was appropriate to offer experimental
evidence. For example, the district court relied on patent
“interference” cases, as in
Rasmusson v. SmithKline
Beecham Corp.
,
When priority is not at issue, generally the applicant
may provide data obtained either before or after the patent
application was filed. With reference to demonstration of
utility, in
Brana
,
The only relevant concern of the Patent Office under these circumstances should be over the truth of any such assertion. The first paragraph of §112 requires nothing more than objective enablement. How such a teaching is set forth, either by the use of illustra- tive examples or by broad terminology, is of no im- portance.
The defendants rely on
Janssen Pharmaceutica N.V. v.
Teva Pharmaceuticals USA, Inc.
,
On the entirety of the evidence, invalidity for lack of en- ablement/utility was not shown by clear and convincing evidence. The district court’s holding of invalidity on this ground is reversed.
V I NFRINGEMENT The district court held that the defendants would be li- able for inducement to infringe the ’590 patent by providing atomoxetine bearing the FDA-approved label authorizing use to treat ADHD. The defendants argue that “the mere distribution of generic atomoxetine products cannot estab- lish inducement liability, even though the labeling includes the legally required statement of FDA-approved use.” Lilly responds that the label use to treat ADHD is the only le- gally approved use, and the only use for which the defen- dants are authorized to provide the product.
The defendants rely on
Warner-Lambert Co. v. Apotex
Corp.
,
[T]he request to make and sell a drug labeled with a permissible (non-infringing) use cannot reasonably be interpreted as an act of infringement (induced or otherwise) with respect to a patent on an unap- proved use, as the ANDA does not induce anyone to perform the unapproved acts required to infringe.
The defendants also argue that there are off-label uses
of atomoxetine, stated by the defendants to be as high as
29% of the total, and conceded by Lilly as possibly as high as
8% of the total. However, the product sold by the defen-
dants is labeled solely for the patented use to treat ADHD.
We have long held that the sale of a product specifically
labeled for use in a patented method constitutes inducement
to infringe that patent, and usually is also contributory
infringement.
See Astrazeneca LP v. Apotex, Inc.
, 633 F.3d
1042, 1060 (Fed. Cir. 2010) (finding intent to induce in-
fringement based on the product label authorizing the
patented use, which “would inevitably lead some consumers
to practice the claimed method”);
see also DSU Med. Corp. v.
JMS Co. Ltd.
,
No clear error has been shown in the district court’s findings and conclusion regarding inducement. We affirm the judgment that the provision of atomoxetine labeled solely for use to treat ADHD constitutes inducement to infringe the ’590 patent.
As for contributory infringement, the district court held that liability is avoided if the product has any “frequent” non-infringing use. Lilly argues that atomoxetine is not a “staple article of commerce suitable for substantial non- infringing use,” the words of 35 U.S.C. §271(c), for the only authorized use of atomoxetine is the patented use to treat ADHD. The defendants are restricted from selling a feder- ally regulated drug for unapproved uses. See 21 C.F.R. §202.1(e)(4). The defendants respond that physicians may nonetheless prescribe atomoxetine for unauthorized use. Such unauthorized activity does not avoid infringement by a product that is authorized to be sold solely for the infringing use.
We conclude that the district court erred in its applica- tion of the law of contributory infringement. That aspect of the district court’s decision is reversed.
S UMMARY
The judgment that the ’590 patent claims are invalid for lack of “enablement/utility” is reversed. The district court’s rulings of validity on other grounds, and the judgment of infringement, are affirmed. We remand for further proceed- ings.
AFFIRMED-IN-PART, REVERSED-IN-PART, and
REMANDED
Notes
[1] Eli Lilly & Co. v. Actavis Elizabeth LLC , 676 F. Supp. 2d 352 (D.N.J. 2009); 731 F. Supp. 2d 348 (D.N.J. 2010).
[2] The common names “atomoxetine” and “tomoxetine” are both used in the record, and are used herein as they appear in the record.