United States District Court, District of Columbia
RANDOLPH D. MOSS UNITED STATES DISTRICT JUDGE.
Federal Food, Drag, and Cosmetic Act ("FDCA"), as
amended by the Drag Price Competition and Patent Restoration
Act of 1984 ("Hatch-Waxman Act") and the Medicare
Prescription Drag Improvement and Modernization Act of 2003
("Medicare Modernization Act"), grants 180 days of
market exclusivity to the first generic manufacturer to file
an abbreviated new drag application ("ANDA") that
challenges a patent covering the brand-name version of the
drag. But that right is not absolute and is subject to
various statutorily defined "forfeiture events." As
relevant here, an applicant who fails "to obtain
tentative approval of [its AND A] within 30 months after the
date on which the [AND A] is filed" forfeits its right
to the 180 days of market exclusivity, "unless th[at]
failure is caused by a change in or a review of the
requirements for approval of the application imposed after
the date on which the application is filed." 21 U.S.C.
plaintiff in this case, Amneal Pharmaceuticals LLC
("Amneal"), was the first manufacturer to file an
ANDA to market a generic version of Namenda XR (memantine
hydrochloride extended release capsules), and its ANDA
challenged a patent held by the manufacturer of the
brand-name version of the drug. Amneal did not, however,
obtain tentative approval for its ANDA within the 30-month
window. As a result, Amneal's eligibility for the 180
days of generic market exclusivity turns on whether its
failure to obtain timely approval was "caused by a
change in or a review of the requirements for approval of
the" ANDA. In proceedings before the Food and Drug
Administration ("FDA"), Amneal argued (1) that the
delay was caused by the FDA's demand for data from a
commercial-scale batch of the drug and (2) that this demand
constituted a change in a requirement for approval of the
ANDA. The FDA disagreed on both counts. Amneal, in response,
brought the present action pursuant to the Administrative
Procedure Act ("APA"), 5 U.S.C. § 701 et
seq., challenging the FDA's decision.
case is now before the Court on Amneal's motions for
summary judgment, Dkt. 25, and for a preliminary injunction
or, in the alternative, a temporary restraining order, Dkt.
62, and the cross-motions for summary judgment filed by the
FDA, Dkt. 34, and intervenor-defendant Lupin Pharmaceuticals
("Lupin"), Dkt. 30. Although Amneal raises a host
of other issues, the heart of the dispute is whether the
FDA's request that Amneal supplement its ANDA with data
from a commercial-scale batch, as opposed to data from the
pilot-scale batches that Amneal originally submitted,
constituted a "change in . . . the requirements for
approval of Amneal's ANDA-or, more precisely, whether the
FDA's decision that the request did not was contrary to
law or otherwise unreasonable. As explained below, the Court
concludes that the FDA acted within its authority and
reasonably in rejecting Amneal's claim to market
exclusivity. The Court will, accordingly, deny Amneal's
motion for summary judgment, Dkt. 25, and will grant the
FDA's and Lupin's cross-motions for summary judgment,
Dkt. 30; Dkt. 34. Moreover, having resolved the case on the
merits, the Court will deny Amneal's motion for a
preliminary injunction or, the alternative, a temporary
restraining order, Dkt. 62, as moot.
Statutory and Regulatory Background
obtain approval to market a new drug, the
innovator-manufacturer must submit a new drug application
("NDA") to the FDA that contains extensive
information and data, including "full reports of
investigations which have been made to show" that the
new drug is safe and effective, "a full statement of the
composition" of the new drug, "a full description
of the methods used in, and the facilities and controls used
for, the manufacture, processing, and packaging" of the
new drug, and proposed labeling for the new drug. 21 U.S.C.
§ 355(b)(1). In addition, the NDA must include "the
patent number and the expiration date of any patent which
claims the drug for which the applicant submitted the [NDA]
or which claims a method of using [the new] drug and with
respect to which a claim of patent infringement could
reasonably be asserted if a person not licensed by the owner
engaged in the manufacture, use, or sale of the drug."
Id. The FDA then lists this patent information in
the "Orange Book: Approved Drug Products with
Therapeutic Equivalence Evaluations" or, as it is
commonly known, simply the "Orange
Book." See also Mylan Labs. Ltd. v. FDA,
910 F.Supp.2d 299, 301 (D.D.C. 2012).
1984, Congress enacted the Drug Price Competition and Patent
Term Restoration Act, Pub. L. No. 98-417, 98 Stat. 1585
(1984), popularly known as the "Hatch-Waxman Act."
The Act sought, among other things, to encourage the
development of generic drugs to increase market competition
and to lower prices for consumers. See Mead Johnson
Pharm. Grp., Mead Johnson & Co. v. Bowen,
838 F.2d 1332, 1333 (D.C. Cir. 1988). To that end, the
Hatch-Waxman Act streamlined the process for bringing new
generic drugs to market by creating the abbreviated new drug
application-or "ANDA"-process, under which a
manufacturer can "piggyback on the original
manufacturer's evidence of safety and efficacy."
Teva Pharm., USA, Inc. v. Leavitt, 548 F.3d 103, 104
(D.C. Cir. 2008). To obtain FDA approval for a generic drug,
the AND A ate (1) that it is "bioequivalent" to the
brand-name drug (also referred to as the "listed
drug"); (2) that the prescribed conditions of use have
been approved for the listed drug, 21 U.S.C §
355(j)(2)(A); (3) that the generic drug satisfies certain
chemistry and labeling requirements; (4) and that the
proposed manufacturing and packaging processes and controls
are adequate to "preserve its identity, strength,
quality, and purity, " id. § 355(j)(4)(A).
the Hatch-Waxman Act streamlined the process for bringing
generic drugs to market, obtaining FDA approval for an ANDA
remains a prolonged task. The process begins with the
submission of an application, which must comply with FDA
requirements for receipt. If an application is not
"substantially complete, " 21 C.F.R. §
314.101(b)(1), the FDA will issue a "refuse-to-receive
decision" in which it rejects the ANDA without
evaluating the substance of the application, id.
§ 314.101(b)(3). In response, an applicant may resubmit
the ANDA with the required data or may withdraw the ANDA.
Id. Only after the FDA has determined that the ANDA
meets the receipt requirements does the agency begin to
evaluate whether the applicant's product is
bioequivalent, manufactured in an appropriate manner, and
properly labeled. During this substantive review, there is
"inevitably and invariably back and forth" between
the agency and the applicant, see Dkt. 69 at 8 (Tr.
8:7), in which the agency generally requests additional data
or information to determine whether the AND A meets the
requirements for approval, see 21 C.F.R. §
314.127. This process can take years to complete.
must also include one of four certifications with respect to
each of the Orange Book patents that claims the listed drug.
21 U.S.C. § 355(j)(2)(A)(vii)(I)-(IV). The four
certifications are identified by the paragraph in which they
appear: A "paragraph I" certification attests that,
to the best of the applicant's knowledge, no such patent
information has been filed. Id. §
355(j)(2)(A)(vii)(I). A "paragraph II"
certification attests that any such patent has expired.
Id. § 355(j)(2)(A)(vii)(II). A "paragraph
III" certification identifies the date on which any such
patent will expire. Id. §
355(j)(2)(A)(vii)(III). And, most importantly for present
purposes, a "paragraph IV" certification asserts
that any such patent is invalid or will not be infringed by
the generic drug. Id. § 355(j)(2)(A)(vii)(IV).
"If an ANDA applicant makes one of the first two
certifications, [the] FDA may approve the ANDA immediately,
" and, if the "applicant makes a paragraph III
certification, [the] FDA may grant tentative approval of the
ANDA, to be made effective on the date the patent
expires." Mylan Labs., 910 F.Supp.2d at 301.
The consequences of making a paragraph IV certification,
however, are different in kind. Most significantly, a
paragraph IV certification is treated as an act of patent
infringement. 35 U.S.C. § 271(e)(2)(A). If the patent
holder brings an infringement action within 45 days of
receiving notice of the certification, moreover, the
FDA's approval of the ANDA will not take effect for a
period of 30 months, unless otherwise ordered by the district
court in which the patent litigation is pending. Id.
generic drug manufacturers thus risk costly patent
infringement litigation if they seek FDA approval before the
brand-name drug's patent has expired or is invalidated-a
risk that Congress feared would discourage market competition
and delay bringing lower-priced generic drags to market.
See leva Pharm. USA, Inc. v. Sebelius, 595 F.3d
1303, 1305 (D.C. Cir. 2010). To "compensate [generic]
manufacturers for research and development costs as well as
the risk of litigation from patent holders, " Teva
Pharm., 548 F.3d at 104, Congress enacted an incentive
for generic drag manufacturers to submit AND As and, if
necessary, to engage in patent litigation: the "first
applicant" to file an ANDA containing a paragraph IV
certification is eligible for 180 days of market exclusivity,
"during which the FDA may not approve for sale any
competing generic version of the drug at issue."
Teva Pharm., 595 F.3d at 1305; see also 21
U.S.C. 355O')(5)(B)(iv); Mylan Labs., 910
F.Supp.2d at 302.
first-filer's entitlement to the exclusivity period is
not absolute, however, and may be forfeited under certain
conditions. As relevant here, the exclusivity period is
forfeited if the "first applicant fails to obtain
tentative approval of [its ANDA] within 30 months after the
date on which the [ANDA] is filed." 21 U.S.C. §
355(j)(5)(D)(i)(rV). Congress added this forfeiture rule to
the statute as part of the Medicare Modernization Act of
2003, Pub. L. No. 108-173, 117 Stat. 2066 (2003), to
"ensure that the 180-day exclusivity period enjoyed by
the first generic to challenge a patent [could not] be used
as a bottleneck to prevent additional generic
competition." Hi-Tech Pharmacol Co. v. U.S. Food
& Drug Admin., 587 F.Supp.2d 1, 4 (D.D.C. 2008)
(quoting 149 Cong. Rec. SI5746 (daily ed. Nov. 24, 2003)
(statement of Sen. Schumer)).
created one exception to the 30-month forfeiture rale: the
180-day market exclusivity is not forfeited if the
applicant's failure to obtain tentative approval within
30 months was "caused by a change in or a review of the
requirements for approval of the application imposed after
the date on which the application is filed." 21 U.S.C.
§ 355(j)(5)(D)(i)(IV). This exception was included to
ensure that ANDA applicants are not penalized "for
delays in tentative approval caused by changes in approval
requirements beyond [the] ANDA applicant's control."
Mylan, 910 F.Supp.2d at 311. If an applicant fails
to obtain tentative approval within 30 months and the failure
is not excused under the exception, however, the FDA may
approve other AND As for the same generic drug product.
10, 2013, Amneal submitted an AND A seeking approval to
market a generic version of Namenda XR-a medication intended
to treat moderate to severe dementia of the Alzheimer's
type. AR 153, 160. Namenda XR is a memantine hydrochloride
capsule designed to facilitate an "extended
release" of the drug. AR 1059. The FDA had previously
approved an NDA submitted by Forest Laboratories LLC
("Forest") to market Namenda XR in four dosage
levels: 7 mg, 14 mg, 21 mg, and 28 mg. AR 160. Amneal's
ANDA included all four dosage levels; it was the first filed;
and it included a paragraph IV certification for at least one
of the patents listed in the Orange Book. AR 1041, 1043-44.
ANDA proposed to achieve Namenda XR's extended-release
effect by manufacturing capsules containing tiny
"beads" of the active ingredient that would
dissolve into the body at different rates. AR 182. Unlike the
brand-name version of Namenda XR, which includes a single
type of bead, Dkt. 33 at 13 & n.5, each capsule of
Amneal's proposed product would contain both immediate
release beads ("IRs") and extended release beads
("ERs") __, AR 185. Consistent with the FDA's
Guidance on ANDA Submissions-Refuse-to-Receive Standards, AR
240, 252, Amneal submitted data from three "pilot
batches" of 150, 000 capsules for each of the four
dosage strengths in its ANDA, AR 198- 99. These pilot batches
produced the capsules by combining __ to create the extended
release effect. AR 437. For purposes of commercial sales,
however, Amneal proposed to produce much larger batches of 1,
000, 000 capsules and, in doing so, to blend up to six
different lots of ER beads with two different lots of IR
beads. AR 199, 437.
November 5, 2013, the FDA sent Amneal a letter refusing to
receive Amneal's AND A because it was "not
sufficiently complete to merit a critical technical
review." AR 63. Specifically, the FDA explained that
Amneal had "failed to produce accelerated stability data
which encompasses at least 84 days in the accelerated
stability chamber for the 30 and 500 counts for all
strengths." Id. Amneal responded a month later
by clarifying that the required data had, in fact, been
included-it only appeared insufficient because a
"typographical error" indicated the wrong date on
which the stability testing began. AR 67. After confirming
that the date in the ANDA was indeed a typographical error,
the FDA rescinded its "Refuse to Receive" letter
and treated the date of Amneal's original submission as
the date of the application. AR 109. Although the record does
not reflect when other generic manufacturers filed their AND
As, there is no dispute that, using Amneal's original
date of submission, Amneal qualified as the "first
applicant" to submit an ANDA for Namenda XR containing a
paragraph IV certification, making it eligible for 180 days
of generic exclusivity if approved within 30 months,
i.e., by December 10, 2015. AR 1016.
September 10, 2014, the FDA sent Amneal a letter identifying
a number of substantive deficiencies with Amneal's ANDA.
See AR 230-39. As relevant here, the FDA wrote:
proposed combination of multiple ER and IR lots for
commercial production, combined with the deficiencies
observed in the information submitted for the exhibit lots,
requires the review of the resulting data from the
manufacture of a commercial size lot before application
approval. In this regard, please submit all the required
[chemistry, manufacturing, and controls] information for the
production of a 7 mg and 28 mg Memantine HC1 lot of the size
intended for commercial distribution.
As the FDA further explained in its chemistry review, this
deficiency was based on several factors. In particular: (1)
Amneal's product required a specific ratio of IR beads to
ER beads in each capsule __ to ensure the desired rate of
release, AR 189, 222-23; (2) the pilot batches used in the
AND A involved mixing __of IR beads, while Amneal proposed to
market a product produced in commercial batches made by
mixing "six different ER batches with two IR lots,
" AR 199; (3) Amneal's pilot batches had
deficiencies such as overfilled capsules, AR 224; and (4) the
"in-process controls" that Amneal proposed to use
for the commercial manufacture of the drug were "regular
controls used for simpler encapsulated drugs[, ] which
[might] not be sufficient to .. . monitor the quality of a
product made by combining "different types of... beads,
" AR 203. Overall, the FDA reviewers concluded that,
"[d]ue to the complexity of the proposed process,
combined with the deficiencies noted in the review, "
and because "mixing multiple lots of ER and IR beads
could induce additional deviations not observed during the
manufacture of the [pilot] lots that may require additional
control, " Amneal "should submit a scale up batch
before approval." AR 199; see also AR 233
(requesting that Amneal "please submit all the required
. . . information for" commercial lot sizes).
with the FDA's request required considerable time and
effort on Amneal's part. Amneal needed to "acquire
commercial-scale quantities of source materials, ramp up
production to manufacture commercial-size lots, conduct
comprehensive analytical testing on the finished product,
evaluate the resulting data, and resubmit its AND A"-a
process that took eight months to complete. AR 654. But, upon
review of the additional data, the FDA noted several issues.
Most problematically, Amneal's proposed IR-to-ER bead
ratio "was not followed in the newly submitted
batches" and, while "some latitude in this ratio
[was] required[, ] ... the deviation . .. was not
justified." AR 460.
submitted a lengthy response to the FDA's review, which,
among other things, highlighted the differences in processes
used in producing the pilot-scale and commercial-scale
batches. AR 437-44. As Amneal explained, "[i]n the ANDA
exhibit batches, __were used to manufacture the intermediate
blend; whereas for manufacturing of future commercial scale
batches, multiple batches of IR pellets and ER pellets will
be used." AR 437. Acknowledging that combining multiple
lots of IR and ER beads introduced additional
"complexity" into the production process, which
"may result in calculation errors, " Amneal
proposed an "additional control... to ensure [that the]
accurate dose of the drug product is administered to the
patients." AR 444. The FDA, however, concluded that the
additional control was "not acceptable, " and it,
accordingly, "recommend[ed]" that Amneal
"scale down the proposed commercial batch size to a
size with a constant, reproducible capsule filling weight as
well as a constant bead type composition." AR 483.
Amneal accepted the FDA's recommendation to scale down
the proposed commercial-scale batches-from 1, 000, 000
capsules to 150, 000 capsules-thus resolving the issue and
clearing the way for approval of its ANDA. AR 488-89.
meantime, however, Amneal experienced a further delay: an
"Import Alert" was issued on October 15, 2015, to
the supplier of Amneal's active pharmaceutical ingredient
("API"). AR 486, 490, 527. As the FDA has
explained, an Import Alert signals that an "imported
product will be detained because it appears to be in
violation of the FDCA or its implementing regulations."
Dkt. 34 at 16 n.10. In light of this development, Amneal
sought approval to use a different API supplier, AR 486, 490,
527, and sought to amend its ANDA to substitute the new
supplier in place of the one that was previously identified,
AR 495. Amneal's troubles continued, however, and, on
December 7, 2015, the FDA notified Amneal that its proposal
to change its source of API was "not acceptable"
because Amneal had yet to demonstrate bioequivalence. AR 740.
Amneal provided the missing data demonstrating bioequivalence
using the new source of API on February 25, 2016, but FDA
chemistry reviewers raised additional deficiencies in
Amneal's product, which were not addressed until August
11, 2016 and September 15, 2016. AR 1037. Finally, on
September 28, 2016, the FDA tentatively approved Amneal's
ANDA. Id. By that time, however, the 30-month period
for approval had run.
December 2, 2015, Amneal requested that the FDA "confirm
... that Amneal's Memantine XR ANDA will remain eligible
for 180-day generic marketing exclusivity regardless of
whether the [a]gency grants tentative approval... or final
approval to that ANDA on or before December 10, 2015."
AR 640. In support of that request, Amneal raised a variety
of arguments, but only one is relevant for present purposes.
That argument posited, as Amneal argues in this proceeding,
that its failure to obtain approval within 30 months of June
10, 2013- the date that the FDA treated as the date of
filing-was caused by the FDA's "post-filing review
of and change in the requirements for approval." AR 651.
Amneal asserted that, prior to the date on which it filed its
ANDA, the FDA "long . .. permitted applicants to submit
AND As ... based on the production of, and presentation of
date regarding, pilot-size test batches." Id.
It was only after the ANDA was filed, Amneal argued, that the
FDA changed "the pertinent approval requirements"
and required "that [it] scale up and complete 'the
production of a 7 mg and 28 mg Memantine HC1 lot of the size
intended for commercial distribution' and then
'submit all the required ... information' in order to
enable FDA 'review of the resulting data from the
manufacture of a commercial size lot before application
approval.'" Id. (emphasis omitted).
Finally, Amneal asserted that it was unaware "of any
other ANDA for which the [a]gency ha[d] ever required the
production and analysis of. .. data from a commercial-size
lot as a condition of approval, " and, indeed, despite
having obtained 95 ANDA approvals, it had "never
previously been required to produce" such data in
support of an ANDA. AR 652 (emphasis omitted).
September 28, 2016, the same day the FDA tentatively approved
Amneal's ANDA, the agency issued a 17-page letter
decision concluding that Amneal had forfeited the 180-day
period of exclusivity. AR 1041-57. In that letter, the FDA
explained that its request that Amneal provide
commercial-scale data was not a "change" in
"requirements for approval" that would trigger the
exception. AR 1055. The "approval requirement" at
issue was not, according to the FDA, the submission of
commercial-scale data; rather, the relevant requirement was
that the applicant "demonstrate that the methods used
in, or the facilities and controls used for, the manufacture,
processing, and packing of the drug are adequate to assure
and preserve its identity, strength, quality, and
purity." Id. The FDA wrote: "That
statutory requirement has not changed, nor has [the]
FDA's specific requirements for certain complex products
like Amneal's proposed memantine hydrochloride ER
capsules to meet it." Id.
FDA's letter decision further explained that its request
for commercial-scale data was nothing new. To the contrary,
although limited in its ability to disclose proprietary
information regarding other applications, AR 1055 n.43, the
FDA represented that it has, "[s]ince at least 2010,
" requested commercial-scale data for "certain
complex drug products and/or a complex manufacturing
process." AR 1055. The decision whether that information
is "necessary, " however, is case-specific
"and is made during the substantive review of the ANDA
by the chemistry reviewers." Id. "Merely
having a complex process, " the FDA continued, "is
not, by itself, typically sufficient to warrant a request for
the manufacture of commercial batches pre-approval, "
[I]f the applicant does not demonstrate a good understanding
of its product and manufacturing process and have appropriate
in-process controls, [the] FDA will have concerns about the
ability of the applicant to successfully produce scaled-up
commercial lots of the drug product upon approval. In that
situation, [the] FDA typically would request that an
applicant manufacture a commercial scale batch and submit
information on that batch to the Agency for review prior to
approving the ANDA. If, as is the case here, the applicant
then revises its proposed commercial, batch size to match the
size of its exhibit batches, this would address the
[a]gency's concern, as the applicant would no longer be
seeking to produce a scaled-up commercial batch.
Id. Accordingly, the FDA reasoned, because neither
statutory requirements nor agency policy had changed, the
exception to the 30-month rule did not apply. AR 1056.
alternative basis for its decision, the FDA also concluded
that the FDA's request for data from a commercial-scale
batch, even if a change in a requirement for approval, did
not cause Amneal to miss the 30-month mark. AR
1054-55. It premised that conclusion on two points: First,
the FDA's request for commercial scale data was resolved
before the forfeiture date and, therefore, could not have
"preclude[d] tentative approval or approval at that
time." AR 1055. Second, Amneal did not
"demonstrate that the [FDA's] request" that
Amneal provide the commercial-scale data "caused it to
fail to obtain tentative approval or approval by [the
relevant date]." Id.