An Orange Book Landscape: Drugs, Patents, and

Generic Competition

JONATHAN J. DARROW* & DANIEL T.C. MAI†

ABSTRACT
Patents are widely considered to be a critical incentive for drug development
because they allow manufacturers to recoup investments in research and development
activities. However, patents are also criticized for preventing competition and
contributing to higher prices. To better understand the patent landscape for approved
drug products and the relationship between patents, other exclusivities, and generic
competition, we examined all prescription drug products listed in the Orange Book as
of February 2021. Surprisingly, only 31% to 39% of drug products had any remaining
patent protection as of this date, meaning the majority of approved drug products are
unencumbered by patents. This finding remained true even when regulatory
exclusivities were considered. We also found that generic drug approval occurred
despite the presence of patent protection in 28% of cases, and that patent expiration
was not followed by generic drug approval in 32% of cases. These findings suggest
that even valid patents do not necessarily block competition, as is commonly believed,
and that dramatic price decreases often cannot be expected when patents expire. As
scholars and policymakers craft policies aimed at controlling drug prices, they should
seek to better understand how factors other than patents and regulatory exclusivities
affect generic competition and patient health.

I. INTRODUCTION
Since the signing of the Constitution, the United States has embraced a philosophy
of granting exclusive rights to inventors to promote technological advance, including
in the field of medicine.1 Patents are intended to achieve this goal by giving inventors
the ability to temporarily exclude direct competition and last for twenty years from the

* Assistant Professor of Medicine, Harvard Medical School; Associate Professor of Law, Bentley
University; Associate Scientist, Brigham & Women’s Hospital, at time of acceptance for publication.
Darrow has received research support from Arnold Ventures, the Commonwealth Fund, the Greenwall
Foundation, the Harvard–MIT Center for Regulatory Science, Health Action International’s ACCISS
program, the Kaiser Permanente Institute for Health Policy, West Health, and under a Novo Nordisk
Foundation grant for a scientifically independent Collaborative Research Programme (grant
NNF17SA0027784). The funders had no role in the conception, drafting, editing, or submission of this
manuscript. The authors thank Jerry Avorn and fellow members of the Program on Regulation,
Therapeutics, and Law at Brigham & Women’s Hospital and Harvard Medical School for offering feedback
that helped improve the manuscript.
† Yale University School of Management.
1 U.S. CONST. Art. I, § 8, cl. 8. For an example of an early medicine patent, see U.S. Pat. No. 4848
(Nov. 12, 1846) (patent on ether as an anesthetic).

51
52 FOOD AND DRUG LAW JOURNAL VOL. 77

date of patent application filing.2 This, in turn, allows prices to rise so that the inventors
may receive a return on up-front investments. The patent system has emerged as a
foundational aspect of the pharmaceutical industry, in particular, due to the expensive
and high-risk nature of drug development.3 From 1986 to 2014, only twenty-six drugs
came to market with no remaining patent protection at the time of drug approval.4
Congress enacted the Hatch–Waxman Act in 1984, which required FDA to publish
a list of patents covering brand-name drugs and their expiration dates, helping to
promote transparency and facilitating potential patent challenges.5 The increased
transparency, however, has directed excessive attention to the role of patents and their
expiration, contributing to overgeneralizations about their effect on price. For
example, academic literature and lay media commonly state that competing
manufacturers enter the market when patents expire and create competition that
substantially reduces prices.6 Although such reductions in price have sometimes

2 35 U.S.C. § 154(a)(2).
3 Henry Grabowski, Patents, Innovation and Access to New Pharmaceuticals, 5 J INT’L ECON. L.
849, 850 (2002) (“The importance of patents to pharmaceutical innovation has been demonstrated in several
studies by economists.”); Edwin Mansfield, Patents and Innovation: An Empirical Study, 32 MGMT. SCI.
173, 174 (1986) (“Taylor and Silberston (1973), using data from 27 firms, found that about 60 percent of
pharmaceutical R and D . . . [was] dependent on patent protection. Mansfield, Schwartz, and Wagner
(1981), using data for 48 product innovations, found that about 90 percent of the pharmaceutical
innovations . . . would not have been introduced without patents.”).
4 Maxwell R. Morgan, Owen G. Roberts & Aled M. Edwards, Ideation and Implementation of an
Open Science Drug Discovery Business Model, 3 WELLCOME OPEN RES. 1, 5 (2018) https://doi.org/
10.12688/wellcomeopenres.14947.1 (“After the introduction of NCE [new chemical entity] protection in
the US through the Hatch–Waxman Act, at least 26 drugs containing novel active ingredients were brought
to market in the US reliant entirely on NCE exclusivity without listing any patents against the product in
the FDA Orange Book.”).
5 See Drug Price Competition and Patent Term Restoration Act of 1984, Pub. L. No. 98-417, 98 Stat.
1585 (codified as amended at 21 U.S.C. §§ 355(b)(1), (c)(2)); see also 21 C.F.R. § 314.53(e) (2021).
6 See Robin Feldman, Evan Frondorf, Andrew K. Cordova & Connie Wang, Empirical Evidence of
Drug Pricing Games—A Citizen’s Pathway Gone Astray, 20 STAN. TECH. L. REV. 39, 46 (2017) (“Over
80% of small-molecule drugs have generic equivalents . . . . After generic competition begins, the price of
most drugs eventually falls to 80–85% below the original brand-name cost.”); Herbert Hovenkamp,
Antitrust and the Patent System: A Reexamination, 76 OHIO ST. L.J. 467, 491 (2015) (“[C]ompetition among
generics drives prices to the competitive level,” which can be “as little as 20% of pre-generic-entry prices.”);
Elisabeth Rosenthal, Lawmakers Look for Ways to Provide Relief for Rising Cost of Generic Drugs, N.Y.
TIMES (Nov. 24, 2014), https://www.nytimes.com/2014/11/25/us/lawmakers-look-for-ways-to-provide-
relief-for-rising-cost-of-generic-drugs.html [https://perma.cc/W3CY-4KSG] (“Historically, after the patent
expires, generic copies have entered the fray, bringing prices down, often sharply.”); Zombie Patents: Free
Exchange, THE ECONOMIST (June 21, 2014), https://www.economist.com/finance-and-economics/
2014/06/21/zombie-patents [https://perma.cc/M7R7-TZFZ] (“When the patent reaches its expiry date, the
comfortable monopoly evaporates, replaced by cut-throat competition.”); C. Scott Hemphill & Bhaven N.
Sampat, When Do Generics Challenge Drug Patents, 8 J. EMPIRICAL LEGAL STUD. 613, 614 (2011) (“Once
generic firms enter the market, prices fall, often to less than 10 percent of the price of the brand-name
drug.”); Eric L. Cramer & Daniel Berger, The Superiority of Direct Proof of Monopoly Power and
Anticompetitive Effects in Antitrust Cases Involving Delayed Entry of Generic Drugs, 39 U.S.F. L. REV. 81,
124 (2004) (noting “the dramatic price declines that typically accompany generic entry”); see also Victor
Van de Wiele, Jonathan J. Darrow & Aaron S. Kesselheim, No Parking Here: A Review of Generic Drug
180-day Exclusivity and Recent Reform Proposals, 20 YALE J. HEALTH L. POL’Y & ETHICS 131, 135 (2021)
(“Following patent expiration, drug prices can drop dramatically.”); Ike Brannon & Devorah Goldman, How
Are Generics Affecting Drug Prices, 42 REGULATION 2, 2 (2019–2020) (“Generally, when a drug goes off
patent and generic drugs hit the market, prices steadily fall as more generic makers enter . . . .”); Ravi Gupta,
Nilay D. Shah & Joseph S. Ross, Generic Drugs in the United States: Policies to Address Pricing and
Competition, 105 CLINICAL PHARMACOLOGY & THERAPEUTICS 329, 329 (2019) (“[D]rug prices typically
decline rapidly once generic drugs . . . enter the market.”); Mariana Mazzucato, Heidi Chow, Saoirse
2022 ORANGE BOOK LANDSCAPE 53

occurred following the end of exclusivity, these outlier events are not representative
of most drug product life cycles, making them a poor foundation from which to build
policies that will affect the entire pharmaceutical system. Nevertheless, the repetition
of such broad statements has led some observers to conclude that patents and other
exclusivities are the primary barrier standing in the way of lower prices.7
In fact, while marketed products may embody patented inventions, they are not
required to (and often do not) precisely correspond to them, and competition therefore
does not necessarily depend on the existence of a patent or its expiration date. For
example, when a patent covers only a particular formulation of a drug or one of its
uses rather than its active ingredient, competing firms can often market generic
versions without waiting for the patent period to end.8 Conversely, the expiration of
patents does not necessarily herald the end of a monopolistic market, since markets
may not be sufficiently attractive to competitors even when no exclusive rights bar
generic entry.9
Over-broad assertions of the impact of patent expiration have also distracted well-
intentioned academics and policymakers from more important underlying issues, such

Fitzpatrick, Andrea Laplane, Tiziana Masini, Diarmaid McDonald, Victor Roy & Ellen ‘t Hoen, The
People’s Prescription: Reimagining Health Innovation to Deliver Public Value, UNIV. COLL. LONDON INST.
FOR INNOVATION & PUB. PURPOSE (Oct. 15, 2018), https://www.ucl.ac.uk/bartlett/public-purpose/wp2018-
10 [https://perma.cc/9W4G-4GGT] (“[G]eneric competition can . . . drive the price of a product down,
closer to the marginal costs of production.”).
At times, even FDA has contributed to the general narrative that patent expiration is followed by
dramatically lower prices. See Facts About Generic Drugs, U.S. FOOD & DRUG ADMIN. (June 28, 2016),
http://perma.cc/GQ92-QEN4 (stating, without citation: “FACT: . . . On average, the cost of a generic drug
is 80 to 85 percent lower than the brand name product.”). FDA appears to have since revised this statement
to make it more accurate. See Facts About Generic Drugs, U.S. FOOD & DRUG ADMIN. (Nov. 1, 2021),
http://www.fda.gov/Drugs/ResourcesForYou/Consumers/BuyingUsingMedicineSafely/UnderstandingGen
ericDrugs/ucm167991.htm [https://perma.cc/A7WB-66JH] (“For example, a single generic competitor can
lead to price reductions of 30%, while five generics competing are associated with prices drops of nearly
85%.”).
7 Aaron S. Kesselheim, Jerry Avorn & Ameet Sarpatwari, The High Cost of Prescription Drugs in
the United States: Origins and Prospects for Reform, 316 JAMA 858, 858 (2016) (abstract) (“The most
important factor that allows manufacturers to set high drug prices is market exclusivity, protected by
monopoly rights awarded upon Food and Drug Administration approval and by patents.”).
8 See, e.g., U.S. FOOD & DRUG ADMIN., GUIDANCE FOR INDUSTRY: ANDA SUBMISSIONS—
AMENDMENTS AND REQUESTS FOR FINAL APPROVAL TO TENTATIVELY APPROVED ANDAS at 3 n.11 (Sept.
2020) (“[W]hen a patent is listed only for a method of use, an ANDA applicant seeking to omit that approved
method of use from the generic drug’s labeling can submit a ‘section viii statement’ that acknowledges that
patent information has been submitted to FDA for a patent claiming a given method of use, but states that
the patent at issue does not claim a use for which the applicant seeks approval.”).
9 See generally Jonathan D. Alpern, Arman A. Shahriar, Min Xi, Sunita Thapa, Amy J. Kodet,
William M. Stauffer, Gabriela Vazquez Benitez, Pamala A. Pawloski & Steven P. Dehmer, Characteristics
and Price Increases Among Sole-source, Off-patent Drugs in the United States, 2008 to 2018, JAMA
NETWORK OPEN, Aug. 17, 2020, at 1 (examining 300 off-patent drugs for which only a single manufacturer
exists).
54 FOOD AND DRUG LAW JOURNAL VOL. 77

as low drug value10 and the role of insurance in allowing drug prices to rise.11 Because
access to low-value drugs will not provide patients with good health, efforts to enact
laws mandating coverage of such drugs exacerbate high healthcare expenditures while
largely failing to address patient needs.
Regulatory exclusivities, added by Congress between 1983 to 2010 to incentivize
particular types of products,12 have also received criticism for their role in limiting
pharmaceutical competition. Layered over the 200-year-old patent system, the 1983
Orphan Drug Act, as amended, provided seven years of protection for new drugs
treating rare diseases affecting fewer than 200,000 people.13 The following year, the
Hatch–Waxman Act provided a waiting period before modifications to existing drugs
(three years)14 or new small-molecule drugs (five years)15 could expect generic
competition. Then, in 1997, Congress authorized a six-month extension to FDA-listed
patents or regulatory exclusivities if manufacturers conducted trials in pediatric
populations at the request of FDA.16 The Biologics Price Competition and Innovation
Act of 2009 provided twelve years of exclusivity for new biologic drugs.17
All of these periods, except six-month pediatric exclusivity, run concurrently with
any patent protection18 and tend to end before patent expiration,19 creating uncertainty
as to the additional effect, if any, of regulatory exclusivities on competition. Unlike
patent exclusivities, however, which depend on administrative determinations of

10 See, e.g., Jonathan J. Darrow, Few New Drugs Deserve Expedited Regulatory Treatment, 27 J.
MANAGED CARE & SPECIALTY PHARMACY 685, 686 tbl.1 (2021); Jonathan J. Darrow & Aaron S.
Kesselheim, Nearly One-Third of New Drugs Are No Better than Older Drugs, and Some Are Worse,
HEALTH AFFS. FOREFRONT (Oct. 6, 2017), https://www.healthaffairs.org/do/10.1377/hblog20171021.
268271/full/ [https://perma.cc/PYB7-HTDA]; Jonathan J. Darrow, Pharmaceutical Efficacy: The Illusory
Legal Standard, 70 WASH. & LEE L. REV. 2073, 2076–78 (2013) (examining the low effectiveness bar for
drug approval).
11 Jonathan J. Darrow & Donald W. Light, Beyond the High Prices of Prescription Drugs: A
Framework to Assess Costs, Resource Allocation, and Public Funding, 40 HEALTH AFFS. 281, 285 (2021)
(“The layering of a prescription drug insurance system over an existing patent regime has led to dramatic
price increases in the US.”).
12 See Jonathan J. Darrow, Jerry Avorn & Aaron S. Kesselheim, FDA Regulation and Approval of
Pharmaceuticals, 1983–2018, 323 JAMA 164, 168–69 & Box 2 (2020) (describing the evolution of
expedited FDA development and approval programs).
13 Orphan Drug Act of 1983, Pub. L. No. 97–414, 96 Stat. 2049 (codified as amended at 21 U.S.C.
§ 360bb(a)(2)).
14 See Drug Price Competition and Patent Term Restoration Act of 1984, Pub. L. No. 98-417, 98 Stat.
1585, 1590 (codified as amended at 21 U.S.C. § 355(j)(5)(F)(iv)); 21 C.F.R. § 314.108(b)(4)–(5) (2021).
15 Drug Price Competition and Patent Term Restoration Act of 1984, Pub. L. No. 98-417, 98 Stat. at
1590 (codified as amended at 21 U.S.C. § 355(j)(5)(F)(ii)); see also 21 C.F.R. § 314.108(b)(2) (2021).
16 Food and Drug Administration Modernization Act of 1997, Pub. L. No. 105-115, 111 Stat. 2296,
§ 111 (codified as amended at 21 U.S.C. § 355a).
17 Biologics Price Competition and Innovation Act of 2009, Pub. L. No. 111-148, tit. VII, 124 Stat.
119, 804 (codified as amended at 42 U.S.C. § 262(k)(7)(A)).
18 See, e.g., 21 U.S.C. § 355(c)(3)(E)(ii) (measuring the four- and five-year periods from the date of
approval of a new drug application); id. § 355a(b)(1) (noting pediatric exclusivity is added to the end of
other exclusivities).
19 See Reed F. Beall, Jonathan J. Darrow & Aaron S. Kesselheim, Patent Term Restoration for Top-
Selling Drugs in the United States, 24 DRUG DISCOVERY TODAY 20, 23 fig.2 (2018) (illustrating median
time segments since FDA approval for a cohort of eighty-three drugs with patent term restoration, which
yield a median total exclusivity period of 13.75 years, or substantially more than the regulatory exclusivity
periods that typically span three to seven years).
2022 ORANGE BOOK LANDSCAPE 55

nonobviousness or other patentability criteria that courts may later overturn, regulatory
exclusivities are virtually immune from judicial invalidation because the legal bases
for their grant tend to be less vulnerable to alternate interpretations.20
Concern over this accumulation of patents and overlapping regulatory exclusivities
has fueled efforts to measure the increase over time in the average number of
exclusivities per brand-name drug, particularly patents. For example, Hemphill and
Sampat21 examined drugs approved from 1985–2002, finding that the number of
patents at any time during a drug’s lifespan (through 2009) increased from an average
of 1.9 patents per drug in the 1985–1987 cohort, to 3.9 patents per drug for the final
2000–2002 cohort. However, they excluded all injectable drugs and 449 (30%) of the
remaining 1,481 drugs because those 449 drugs had no Orange Book patents, leaving
just 1,032 drugs in their data set.22 By focusing on only patent-protected drugs, such
studies do not address the full pharmacopeia of potentially available brand-name
products. These studies also generally include Orange Book patents that have expired
and are no longer relevant to generic competition.23
The focus on expiration dates and rates of patenting has left important questions
about drugs and exclusivities largely unaddressed, including the extent to which
approved drugs are currently encumbered by patents and exclusivities. To more
comprehensively evaluate the landscape of brand-name drugs and their exclusivities
in a way that is most relevant to today’s patients, who are not adversely affected by
patents that have expired (or that have not yet issued), we examined all brand-name
prescription drugs currently approved by FDA. We also sought to evaluate the
association between exclusivity and the availability of generic drug products.
Specifically, we sought to determine how many drugs lacked exclusivity yet
nevertheless had no approved generic counterparts, and how many already faced
generic competition despite still having unexpired patent or regulatory exclusivities.

II. METHODS
We obtained a list of all brand and generic drugs currently approved by FDA and
not discontinued from marketing by downloading the data files of FDA’s Approved
Drug Products with Therapeutic Equivalence Evaluations (“Orange Book”) on
February 19, 2021.24 We excluded biologic drugs, which are listed in a separate

20 Litigation challenging the award vel non of non-patent exclusivity does occur but is uncommon.
See, e.g., AstraZeneca Pharm. LP v. Food & Drug Admin., 872 F. Supp. 2d 60, 64 n.3 (D.D.C. 2012)
(challenging FDA’s approval of generic versions of quetiapine despite asserted three-year exclusivity).
21 Hemphill & Sampat, supra note 6, at 619.
22See id. (“Removing those drugs that have no Orange Book patents . . . yields a set of 1,032 drugs.”).
The previous year Ouellette, relying in part on Sampat’s data, examined 938 drugs approved from 1988–
2005 and found a mean of 2.97 (median: 2) patents per drug. Lisa Larrimore Ouellette, Note, How Many
Patents Does It Take to Make a Drug: Follow-On Pharmaceutical Patents and University Licensing, 17
MICH. TELECOMM. & TECH. L. REV. 299, 314 (2010).
23 Id. (“Our measure is the number of unique patents that are listed in (any edition of) the Orange
Book”) (emphasis added).
24 Orange Book Data Files, U.S. FOOD & DRUG ADMIN. (July 18, 2019),
https://www.fda.gov/drugs/drug-approvals-and-databases/orange-book-data-files [https://perma.cc/2KNV-
7V4M].
56 FOOD AND DRUG LAW JOURNAL VOL. 77

“Purple Book” that does not disclose most patents.25 From these files, we extracted
new drug application (NDA) numbers, abbreviated new drug application (ANDA)
numbers, approval years, therapeutic equivalence codes, dosage forms, manufacturers,
patents, patent type codes, and regulatory exclusivities. Over-the-counter and
discontinued products, and different doses listed under the same NDA, were excluded
from NDA counts. Author judgment was used to categorize manufacturers with similar
names (e.g., “Allergan” and “Allergan Inc.” were considered together as a single
manufacturer).
NDAs are used both for new molecular entities (NME) and for modifications of
existing drugs, such as a chewable version of a drug previously approved in tablet
form.26 ANDAs are used for the approval of generic drugs that generally have the same
strength, dosage form, and route of administration as their brand name counterpart,
although a petition process is available that allows products to be approved via the
ANDA pathway with different active ingredients (e.g., different salt forms of the same
active moiety), dosage forms, or strengths.27 Patent type codes include drug substance
(DS), drug product (DP), and method of use (U). Patents of these types generally
claim, respectively, active ingredients (DS), features of the product such as its
formulation (DP), and uses of the drug, for example, to treat a particular patient group
or a particular disease (U).28 Patents with more than one patent type code were
assigned a single code in the following order of precedence: drug substance, drug
product, and method of use. Dosage forms were grouped into broad categories of oral
(including, e.g., sublingual), injectable (including, e.g., intravenous), and “other” (e.g.,
topical, nasal, suppository). FDA generally assigns therapeutic equivalence codes to
products having the same strength, dosage form, and route of administration as one
another, with the codes identifying the products as either bioequivalent and therefore
substitutable (A-codes or A-rated) or not established as bioequivalent and therefore
not substitutable (B-codes or B-rated).29

III. RESULTS
A review of the Orange Book revealed a total of 2,410 NDAs and 8,516 ANDAs,
which were associated with 4,535 patents and 501 manufacturers. Of all NDAs, 1,479
(61.4%) were associated with no patents, 101 (4.2%) with one patent, 232 (9.6%) with
two patents, 113 (4.7%) with three patents, 94 (3.9%) with four patents, 263 (10.9%)
with five to ten patents, 110 (4.6%) with eleven to twenty patents, and eighteen (0.7%)

25 The Biological Product Patent Transparency section of the Consolidated Appropriations Act of
2021 required FDA to include patents in the Purple Book once the reference product sponsor provides a list
of such patents as part of the biosimilar litigation process. Consolidated Appropriations Act of 2021, Pub.
L. No. 116–260, Div. BB, Sec. 325, 134 Stat. 1182, 2936 (codified at 42 U.S.C. § 262(k)(9)(A)(iii)).
26 See OFF. OF PHARM. QUALITY, CTR. FOR DRUG EVALUATION & RSCH., MAPP 5018.2 NDA
CLASSIFICATION CODES 2–3 (2015) (explaining, for example, that NDAs can be assigned “Type 1” codes,
which correspond to new molecular entities and “Type 3” codes, which correspond to new dosage forms);
Jonathan J. Darrow, Mengdong He & Kristina Stefanini, The 505(b)(2) Drug Approval Pathway, 74 FOOD
& DRUG L. J. 403, 425 (2019) (describing chewable and otherwise modified versions of drugs).
27 21 U.S.C. § 355(j)(2)(C); see also 21 C.F.R. § 314.92(a)(3) (2021).
28See generally U.S. FOOD & DRUG ADMIN., APPROVED DRUG PRODUCTS WITH THERAPEUTIC
EQUIVALENCE EVALUATIONS iv, vi, xxi, xxv (41st ed. 2021) [hereinafter FDA, APPROVED DRUG
PRODUCTS].
29 Id. at xii–xiii.
2022 ORANGE BOOK LANDSCAPE 57

with twenty-one or more (Figure). Of the 2,410 NDAs, 208 (8.6%) had at least one
drug substance patent, 485 (20.1%) had at least one drug product patent but no drug
substance patent, and 238 (9.9%) had at least one method of use patent but neither
drug product nor drug substance patents. An additional ninety-two (3.8%) NDAs had
only regulatory exclusivity (such as Orphan Drug Act exclusivity), including eleven
(<0.5%) that had only pediatric exclusivity. The product with the greatest number of
patents was icosapent ethyl (Vascepa) with sixty-two, followed by ibrutinib
(Imbruvica) with thirty-five, aripiprazole (Abilify Mycite Kit) with thirty-one, and
epinephrine (Auvi-Q) with twenty-nine.
Of all NDAs, 1,147 (48%) were oral dosage forms, 730 (30%) were injectable
dosage forms, and 533 (22%) had other dosage forms. Two NDAs included both
injectable and oral formulations, but were counted only once, as injectable. Most
drugs, regardless of dosage form, had no patents, including 525 (72% of 730)
injectable drugs, 613 (53% of 1,147) oral drugs, and 331 (62% of 533) “other” drugs.
Manufacturers with the most NDAs included Novartis (91, 4%), Baxter (77, 3%), and
Pfizer (70, 3%).
A. Generic Competition
Of all NDAs, 1,185 (49.2%) were associated with no A-rated ANDAs, 187 (7.8%)
with one A-rated ANDA, 184 (7.6%) with two A-rated ANDAs, 126 (5.2%) with three
A-rated ANDAs, 109 (4.5%) with four A-rated ANDAs, 388 (16.1%) with five to ten
A-rated ANDAs, and 231 (9.6%) with eleven or more A-rated ANDAs. (To facilitate
comparison with an earlier study, we also found that 259 [10.7%] NDAs had ten or
more approved ANDAs.) Of all NDAs, 1,208 (50.1%) had A-rated ANDAs only,
sixteen (0.7%) had A- and B-rated ANDAs, and five (0.2%) had B-rated ANDAs only.
Of the 1,387 NDAs with no remaining patent or regulatory exclusivity, 448 (32.3%)
nevertheless had no A-rated ANDAs, 447 (32.2%) had no A- or B-rated ANDAs (only
one NDA had a B-rated ANDA but no A-rated ANDA), 124 (8.9%) had one A-rated
ANDA, 143 (10.3%) had two A-rated ANDAs, 101 (7.3%) had three A-rated ANDAs,
84 (6.1%) had four A-rated ANDAs, 302 (21.8%) had five to ten A-rated ANDAs, and
185 (13.3%) had eleven or more A-rated ANDAs. Of the 1,023 NDAs with remaining
patent or regulatory exclusivity, 286 (28.0%) nevertheless had at least one A-rated
ANDA, an additional three (0.3%) had B-rated ANDAs (B-rated ANDAs can
sometimes be converted to A-rated ANDAs upon the submission of equivalence data),
and 737 (72.0%) had no A-rated ANDAs. Specifically, sixty-three (6.2%) had one A-
rated ANDA, forty-one (4.0%) had two A-rated ANDAs, twenty-five (2.4%) had three
A-rated ANDAs, twenty-five (2.4%) had four A-rated ANDAs, eighty-six (8.4%) had
five to ten A-rated ANDAs, and forty-six (4.5%) had eleven or more A-rated ANDAs.
B. “Orphaned” Generic Products
Of the 8,516 ANDAs, 2,899 (34.0%) were not associated with an NDA. This could
occur if, for example, the NDA was withdrawn for reasons other than safety or
efficacy. When ANDAs were grouped such that all ANDAs with the same active
ingredient (or same multiple ingredients for fixed-dose combination products), dosage
form, and route of administration were considered as a single product, 39.6% (629 of
1,587) of ANDA products had no corresponding NDA.
If the 2,410 NDAs and the 629 orphaned ANDA product-groups are considered
together, 2,108 (69.4%) of 3,039 products were associated with no patents, 101 (3.3%)
with one patent, 232 (7.6%) with two patents, 113 (3.7%) with three patents, 94 (3.1%)
58 FOOD AND DRUG LAW JOURNAL VOL. 77

with four patents, 263 (8.7%) with five to ten patents, 110 (3.6%) with eleven to twenty
patents, and 18 (0.6%) with twenty-one or more patents.
C. Time Elapsed Since Approval
The median approval year was 2005 for NDAs and 2013 for ANDAs. Of the 2,410
drugs, 559 (23%) were approved in the 1980s or before, 352 (15%) from 1990–1999,
538 (22%) from 2000–2009, 837 (35%) from 2010–2019, and 124 (5%) in 2020. Of
the 2,899 orphaned ANDAs, 1,092 (37.7%) were approved in 2010 or later.
Figure
Patent, exclusivity, and ANDA information associated with 2,410 NDAs listed in
the Orange Book as of February 19, 2021.

Legend. (a) Of 2,410 unique NDAs, eighteen (0.7%) had twenty-one or more
patents at the time of our study; (b) Eighty-two NDAs (3.4%) had only regulatory
exclusivity (“Exclusivity only”) at the time of our study, of which ten (0.4%) had only
pediatric exclusivity (“PED only”), and 8.6% had drug substance patents, which are
generally regarded as the strongest patent type; (c) Approximately half of NDAs
(49.2%) had no ANDAs, and fewer than one in ten (9.6%) had eleven or more ANDAs;
(d) Of the 1,023 NDAs with remaining patent or regulatory exclusivity (top portion of
bar), 286 (28.0%) nevertheless had at least one A-rated ANDA (top box with asterisk);
of the 1,387 NDAs with no remaining patent or regulatory exclusivity (bottom portion
of bar), 448 (32.3%) nevertheless had no A-rated ANDAs (bottom box with asterisk);
2022 ORANGE BOOK LANDSCAPE 59

(e) nearly 40% of drugs listed in the 2021 Orange Book were approved in 2010 or
later. The percent figures in all columns are presented as a share of the 2,410 NDAs.

IV. DISCUSSION
In this landscape analysis of FDA-approved prescription brand-name and generic
drugs as of February 2021, we found that the presence of exclusive rights frequently
did not preclude generic competition: more than a quarter (28%) of NDAs with
remaining exclusivity nevertheless had at least one approved ANDA. This finding
cannot be accounted for by “tentative approvals,” which FDA grants when generic
drug application requirements have been satisfied but certain types of patent or non-
patent exclusivity remain, because tentative approvals are not approvals, are not
included in the Orange Book, and therefore were intentionally not captured in our
data.30 It is also possible that approved generic drugs remain off the market due to
pending patent litigation, but this appears to occur infrequently. A previous study
found that of fifty-one first generics approved from 2013–2015 that sought to enter the
market before patent expiry, a third (seventeen, or 37%) did not result in Hatch–
Waxman litigation at all.31 Of the twenty-nine actually launched by 2020, approval
occurred an average of about 4.6 years after litigation began,32 leaving ample time for
most litigation to resolve.33
Conversely, the expiration or other absence of exclusive rights frequently did not
lead to the entry of generic products. Of NDAs with no remaining patent or regulatory
exclusivity, nearly one-third nevertheless had no corresponding therapeutically
equivalent ANDAs. This finding contrasts with that of Gupta et al., who found that
only 17.1% of drugs with no exclusivity had no approved ANDAs.34 Gupta et al.
examined only tablet or capsule dosage forms approved between 1984–2016 and
excluded certain combination tablets or capsules, yielding just 210 exclusivity-free
drugs (thirty-six of which had no generic counterparts).35 The present study was seven
times larger (n=1,387), comprehensively considering the full population of
exclusivity-free brand-name drugs.

30 See FDA, APPROVED DRUG PRODUCTS, supra note 28 at vi (“The Agency will not include drug
products with tentative approvals in the Orange Book because a drug product that is granted tentative
approval is not an approved drug product.”).
31 Sunand Kannappan, Jonathan J. Darrow, Aaron S. Kesselheim & Reed F. Beall, The Timing of 30-
Month Stay Expirations and Generic Entry: A Cohort Study of First Generics, 2013–2020, 14 CLINICAL &
TRANSLATIONAL SCI. 1917, 1920 fig.2 (2021).
32 Id. at 1921 tbl.1 (stays expire thirty months after the patent challenge begins, and stay expiration
was found to occur a median of 2.1 years before generic drug approval). The remaining five generic drugs
had not launched by 2020.
33 See Aaron S. Kesselheim & Jonathan J. Darrow, Hatch–Waxman Turns Thirty: Do We Need a
Redesigned Approach for the Modern Era?, 15 YALE J. HEALTH POL’Y L. & ETHICS 293, 300 n.29 (2015)
(“[T]he average time to a district court decision [in Hatch–Waxman cases] was 2.3 years, with an additional
1.2 years to reach an appellate court decision.”).
34 Ravi Gupta, Aaron S. Kesselheim, Nicholas Downing, Jeremy Greene & Joseph S. Ross, Generic
Drug Approvals Since the 1984 Hatch–Waxman Act, 176 JAMA INTERNAL MED. 1391, 1392 tbl. (2016).
35 Id.
60 FOOD AND DRUG LAW JOURNAL VOL. 77

These findings have important implications for drug pricing policy. Published
articles frequently state that prices decline dramatically after patent expiration,36
suggesting that policy solutions aimed at shortening or eliminating patent protection
will lead to substantially lower prices. However, such descriptions are premised on the
faulty assumption that patents preclude generic entry and that their expiration leads to
entry. Reports suggesting that 80% reductions in price can be expected following
generic entry are typically accurate only in those cases when ten or more generic
competitors enter the market,37 but we found that only about one in ten (10.7%) NDAs
had this many approved ANDAs. Even considering only those drugs with no
remaining patent or regulatory exclusivity, just 14.9% (206 of 1,387) had ten or more
competitors. If orphaned ANDA products are included, then 13.0% (263 of 2,016) of
products with no remaining patent or regulatory exclusivity had ten or more
competitors.
Even in the minority of cases in which multiple generics enter the market, the
impact of patent expiration on expenditures may be overstated. Financial savings
depend not only on the price of a drug, but also on the number of patients who use the
drug and the number of years over which that drug is used. To the extent that loss of
exclusivity leads to declining use (for example, due to discontinuation of product
promotion),38 efforts to challenge drug patents or shorten exclusivity periods may
simply be accelerating the time at which that product fades from relevance rather than
expanding access and improving patient health. In our study, fewer than one in four
(23.2%) listed NDAs were approved before 1990, and nearly 40% were approved in
2010 or later even though many more NMEs were approved from 1963–2009

36 See id. at 1391 (“[The] availability of at least 4 generic drugs has been associated with brand-name
price reductions of approximately 60% when compared with fewer or no generics.”); see also sources cited
supra, note 6.
37 See Chintan V. Dave, Abraham Hartzema & Aaron S. Kesselheim, Prices of Generic Drugs
Associated with Numbers of Manufacturers, 377 NEW ENG. J. MED. 2597, 2598 fig.1 (2017) (finding that
prices decline by an average of 79% following patent expiration when ten or more generic competitors enter
the market.).
38 Studies finding increases in product volume after generic entry are few in number, tend to examine
only a limited number of products, and usually measure only a short time horizon after generic entry, when
the effects of brand-name promotion may continue to linger. See Xiaodong Guan, Interrupted Time-Series
Analysis of the Impact of Generic Market Entry of Antineoplastic Products in China, 8 BMJ OPEN e022328,
at 4 fig.1 (2018) (finding increased volume following generic entry for four oncology treatments over a 2.5
to 3.5 year time horizon in Chinese hospitals). Other studies have found that total volume decreases or does
not change after generic entry, despite lower prices. See Micael Castanheira, Carmine Ornaghi & Georges
Siotis, The Unexpected Consequences of Generic Entry, 68 J. HEALTH ECON. 102243, at 4 (2019) (“[Despite
lower prices,] sales in volume drop, on average, by more than 25% within three years of patent expiry
. . . . Put differently, few new patients are directed to the cheap genericized molecule, and a number of
existing patients switch to competing molecules just when their treatment becomes cheaper.”); Ernst R.
Berndt, Margaret K. Kyle & Davina C. Ling, The Long Shadow of Patent Expiration: Generic Entry and
Rx-to-OTC Switches, in SCANNER DATA AND PRICE INDICES 229, 251 (Robert C. Feenstra & Matthew D.
Shapiro eds., 2003) (“Total quantity of brand plus generic Rx cimetidine sales . . . shrunk by about one-third
since Tagamet lost patent protection, even though the average price . . . declined precipitously.”); Gautier
Duflos & Frank R. Lichtenberg, Does Competition Stimulate Drug Utilization? The Impact of Changes in
Market Structure on US Drug Prices, Marketing and Utilization, 32 INT’L REV. L. ECON. 95, 101 (2012)
(“[I]ncreased utilization of prescriptions for generics after patent expiration is almost perfectly offset by
reduced utilization of branded prescriptions.”); Darius Lakdawalla & Tomas Philipson, Does Intellectual
Property Restrict Output? An Analysis of Pharmaceutical Markets, 55 J. L. ECON. 151, 152 (2012) (“For
about 40 percent of drugs, output falls [in the month] after patent expiration and expands only modestly for
many others.”); see also id. at 168 fig.7 (illustrating that, based on data of 101 drugs, average total quantity
remained essentially unchanged in the eighteen months after patent expiry).
2022 ORANGE BOOK LANDSCAPE 61

compared to 2010–2020.39 Given historical approvals, this chronological distribution

of current NDAs raises the possibility that drug product life cycles may be shorter than
assumed, even before considering that product volume generally declines for older
products prior to discontinuation40 and that sales may cease before products are moved
to the discontinued section of the Orange Book. Greater efforts are therefore needed
to understand patterns of clinical use following generic entry, such as the frequency
with which drug volume remains high ten or more years after generic entry and
whether patent expiration or generic entry itself tends to trigger a sequence of events
that lead to the end of a product’s life cycle.
The impact of patent expiration on health may also be overstated. Aggregate health
value depends not only on the number of patients using a drug and the number of years
of use, but also on the incremental benefit that product confers.41 Multiple independent
studies by academics, nonprofit entities, and government-affiliated bodies have
concluded that the incremental benefit of most (69% to 98%) new drugs is modest or
zero,42 or occasionally even negative.43 Although the expiration of patents on highly
effective new drugs could produce large health benefits if patent expiration leads to
substantially wider use, such drugs and patterns of use are not representative of most
drugs.
The dynamics of patent expiration, generic entry, and product decline also raise
important questions about the value of post-approval evidence collection. Expedited
drug development programs have increasingly deferred some evidence collection to
the post-approval period, but these studies are often not completed for five or more
years.44 To the extent that products have short life cycles, information generated years
after approval may have little enduring relevance to clinical care. Brand name
manufacturers, who recognize the profit loss that coincides with patent expiration,
have an incentive to not only reduce promotion, but also to delay the release of
disappointing post-approval evidence until the end of exclusivity periods. In doing so,

39 Jonathan J. Darrow & Aaron S. Kesselheim, Drug Development and FDA Approval, 1938–2013,
370 NEW ENG. J. MED. 2465, 2465 (2014) (one of the authors maintains an updated version of the database
underlying this Article).
40 See Hans H. Bauer & Marc Fischer, Product Life Cycle Patterns for Pharmaceuticals and Their
Impact on R&D Profitability of Late Mover Products, 9 INT’L BUS. REV. 703, 714 & fig.2 (2000) (describing
a sales peak followed by decline); Marc Fischer, Peter S. H. Leeflang & Peter C. Verhoef, Drivers of Peak
Sales for Pharmaceutical Brands, 8 QUANTITATIVE MARKETING & ECON. 429, 434 fig.1 (2010) (illustrating
the decline phase for calcium channel blockers); see generally Henry Grabowski, Tracy Lewis, Rahul Guha,
Zoya Ivanova, Maria Salgado & Sally Woodhouse, Does Generic Entry Always Increase Consumer
Welfare?, 67 FOOD & DRUG L.J. 373, 381–82 (2012) (summarizing studies showing that quantity can
decrease after generic entry due to reduced promotional efforts).
41 See generally WORLD HEALTH ORG., WHO METHODS AND DATA SOURCES FOR GLOBAL BURDEN
OF DISEASE ESTIMATES 2000-2019 (Dec. 2020), https://cdn.who.int/media/docs/default-source/gho-
documents/global-health-estimates/ghe2019_daly-methods.pdf?sfvrsn=31b25009_7 (describing the burden
of disease over a particular time period as “the number of incident cases in that period [] multiplied by the
average duration of the disease and a weight factor that reflects the severity of the disease”). Since
pharmaceuticals aim to reverse the burden of disease, the calculation for aggregate health value follows
essentially the same formula, but with the opposite sign.
42 Darrow, supra note 10, at 686 tbl. (summarizing ten studies collectively concluding that most drugs
provide modest incremental value).
43 Darrow & Kesselheim, supra note 10.
44 Steven Woloshin, Lisa M. Schwartz, Brian While & Thomas J. Moore, The Fate of FDA
Postapproval Studies, 377 NEW ENG. J. MED. 1114, 1114 tbl.1 (2017).
62 FOOD AND DRUG LAW JOURNAL VOL. 77

their goal is to encourage the market to switch to patented, more expensive, and newer
products (for which FDA may in turn allow the deferral of higher-quality evidence
collection to the post-approval period). Earlier patent expiration could simply
accelerate such tactics, with unclear health benefits except in the minority of cases in
which the incremental therapeutic value of the newer product is substantial.
Another surprising finding was that most (61%) drugs are not protected by patents,
regardless of dosage form. If orphaned ANDA products are included, this figure rises
to 69.4% (2,108 of 3,039). Although many of these drugs were likely protected by
patents at the time of approval, the expiration or invalidation of those patents means
the majority of approved drugs are now in the public domain and can be used freely
without payment to the holder of the now-expired patents—the intended outcome of
the patent system. Even if regulatory exclusivity is included, most drugs (57.6%) still
had no exclusivity at the time of our study. Policymakers considering legislative
changes that would shorten exclusivity periods must consider not only the immediate
impact of such changes on costs and access to the latest popular medicine, but also the
long-term impact on the flow of medicines of lasting value into the pharmacopeia.
Despite concern that the number of patents per drug has increased, drugs with a
large number of patents were rare. Of all 2,410 NDAs listed in the Orange Book as of
2021, less than 1% (eighteen, or 0.7%) had twenty-one or more patents. The Orange
Book-listed drug with the greatest number of patents was icosapent ethyl (Vascepa),
with sixty-two patents. Including icosapent ethyl, only three (0.1%) of the 2,410 listed
NDAs had more than thirty patents, and only about one in ten (9.6%) had more than
ten patents. Regulatory exclusivity in the absence of patent exclusivity was rare,
affecting only 3.8% of NDAs (including those with only pediatric exclusivity
remaining). Pediatric exclusivity stood alone as the only remaining exclusivity for just
0.5% of NDAs, reflecting its short six-month duration.
These data contrast with claims suggesting that drugs often have “dozens” or
“hundreds” of patents protecting them.45 Frequent commentaries expressing concern
over the large number of patents covering drugs such as adalimumab (Humira) or
certain HIV medications46 describe circumstances that are not representative of
traditional small-molecule products. Adalimumab is atypical because it is a biologic,

45 See Tahir Amin, We Need to Take On Drug Companies’ Abuse of the Patent System, JACOBIN
MAG. (Dec. 18, 2020), https://www.jacobinmag.com/2020/12/pharmeceutical-industry-patent-system-
antitrust-law [https://perma.cc/XE5F-6SED] (“Pharmaceutical companies regularly file dozens, and
increasingly hundreds, of patents on a single drug.”); Aaron S. Kesselheim, Improving Competition to Lower
U.S. Prescription Drug Costs, WASH. CTR. FOR EQUITABLE GROWTH (Feb. 18, 2020), https://equitable
growth.org/improving-competition-to-lower-u-s-prescription-drug-costs/ [https://perma.cc/2ZKD-NNV6]
(“[P]harmaceutical manufacturers usually build a broad thicket of dozens, or hundreds, of patents around
the product prior to approval.”); Mark E. Miller, The Four Arguments You’re Likely to Hear from Drug
Executives, ARNOLD VENTURES (Feb. 26, 2019), https://www.arnoldventures.org/stories/the-four-argument
s-youre-likely-to-hear-from-drug-executives-at-tuesdays-hearing/ [https://perma.cc/NWC2-D3Z5] (“Drug
manufacturers apply for hundreds of patents on drugs—after they have gone to market.”). Such claims
possibly originate from the patent estate of a single biologic drug, adalimumab (Humira), and perhaps from
a small number of other biologic or non-biologics for which patent data are available (biologics are not
listed in the Orange Book), but their outlier nature is not always apparent when these sweeping claims are
made.
46 See, e.g., Diane Bartz, Lawmakers Say AbbVie Exploits U.S. Patents to Protect Humira Profits,
Price Hikes, REUTERS (May 18, 2021), https://www.reuters.com/business/legal/abbvie-exploits-us-patents-
protect-profits-congress-report-2021-05-18/; Tahir Amin & Aaron S. Kesselheim, Secondary Patenting of
Branded Pharmaceuticals: A Case Study on How Patents on Two HIV Drugs Could Be Extended for Years,
31 HEALTH AFFS. 2286, 2289 exh.1 (2012).
2022 ORANGE BOOK LANDSCAPE 63

an emerging class of complex therapeutic molecules, often directed to limited patient

populations, for which challenges in manufacturing, dosing, treatment regimens, and
storage has created a need for solutions that can then be patented.47 It is not yet clear
whether, as biologics technology ages, biologics manufacturers will be able to obtain
as many patents on future biologic products. Similarly, HIV was a new infectious
disease in the 1980s that presented numerous new scientific problems in formulation,
methods of manufacturing, stability, etc. that were required to be solved.48 These are
not typical circumstances for most new drugs, which are often additions to existing
classes, variations of existing products, or new drugs that address long-known
diseases.
Among the minority of drugs in our study that had unexpired patents, those patents
had an incomplete exclusionary effect. Fewer than one in ten (8.6%) NDAs had drug
substance patents, which cover the active ingredient and are generally considered to
be the most difficult to design around or invalidate. The remaining patents were
characterized by FDA as drug product or method of use patents, which may cover
aspects of a drug such as new formulations or uses in treating particular diseases or
patient populations. Generic manufacturers can often design around such patents by
using a different excipient or omitting the patented indication from the labeling
(“skinny labeling”49) to avoid infringement and facilitate on-label or off-label generic
use. More than one quarter (28%) of drugs with unexpired patents nevertheless had
approved generic counterparts.
Even when drugs are associated with large patent thickets, generic competition may
emerge sooner than expected. For instance, when competitors sought to market generic
versions of icosapent ethyl (the most patented product in the Orange Book), the NDA
holder asserted only six of its patents and all asserted claims were held invalid as
obvious.50 Three generic versions of icosapent ethyl were approved in 2020, including
one by Hikma Pharmaceuticals PLC that was launched in November of that year.51
The first generic version thus became available less than eight years after the originator

47 Ameet Sarpatwari, Rachel Barenie, Gregory Curfman, Jonathan J. Darrow & Aaron S. Kesselheim,
The US Biosimilar Market: Stunted Growth and Possible Reforms, 105 CLINICAL PHARMACOLOGY &
THERAPEUTICS 92, 95 (2019) (“Manufacturing biosimilars is more challenging and costly than generics.”);
Jonathan J. Darrow, Biosimilar Approvals and the BPCIA: Too Soon to Give Up, HEALTH AFFS. BLOG (July
19, 2019), https://www.healthaffairs.org/do/10.1377/hblog20190718.722161/full/ [https://perma.cc/R72T-
XD4J] (“The complexity of biologics is associated with technical challenges in their discovery,
manufacturing, storage, packaging, administration, and use. As these challenges are overcome,
manufacturers have been able to obtain larger numbers of patents than is typical of small-molecule drugs.”).
Adalimumab is likely not representative even of biologics, given its approval years before the Biologics
Price Competition and Innovation Act of 2009, its status as the best-selling drug in the world, and its
unusually large patent estate.
48 See Amin & Kesselheim, supra note 47, at 2289 exh.1 (classifying 210 patents on ritonavir and
lopinavir/ritonavir into categories such as formulations, manufacturing methods, and new uses).
49 See generally Bryan S. Walsh, Ameet Sarpatwari, Benjamin N. Rome & Aaron S. Kesselheim,
Frequency of First Generic Drug Approvals With “Skinny Labels” in the United States, 181 JAMA
INTERNAL MED. 995, 995 (2021) (finding that 43% of those drugs for which skinny labels were possible in
fact had generic competition that used skinny labels).
50 Amarin Pharma, Inc. v. Hikma Pharm. USA Inc., 449 F. Supp. 3d 967, 1015 (D. Nev. 2020), aff’d
819 F. App’x 932 (Fed. Cir. 2020), cert. denied, 141 S. Ct. 2794 (2021).
51 Press Release, Hikma Pharm. PLC, Hikma Launches Icosapent Ethyl Capsules (Nov. 5, 2020),
https://www.hikma.com/newsroom/article-i4928-hikma-launches-icosapent-ethyl-capsules/
[https://perma.cc/9E9Y-CKFB].
64 FOOD AND DRUG LAW JOURNAL VOL. 77

product was first introduced,52 substantially less than the empirically measured 13.6-
year average exclusivity period for new drugs.53
Although patents and other exclusivities are potentially important for the 42% of
drugs with remaining exclusivity,54 the large number of approved products no longer
covered by any type of exclusivity suggests greater scholarly attention is needed to
study the end, as well as the beginning, of drug life cycles. More specifically, greater
research is needed to determine why generic entry does not always occur after patent
expiration, whether older generic products that exist might be more frequently
substituted for therapeutically similar but more costly new products, and why such
substitution has not already occurred.55 Although the generic prescription fill rate has
risen to approximately 90% from just 19% in 198456—a testament to the tremendous
success of the Hatch–Waxman Act in promoting generic competition—the amounts
spent on the remaining 10% of prescriptions impose a disproportionate financial
burden on patients and payers, and their therapeutic value deserves closer scrutiny.
Finally, our research raises questions about whether the common narrative
surrounding high-cost patented drugs may be drawing excess attention to those
products because of their patent status and increasing their use beyond what is justified
by their therapeutic value. Commentators should consider whether this traditional
scholarly criticism of patents and high drug prices is inadvertently contributing
unintended publicity57 that helps to drive the market toward those drugs that are the
most expensive58 and away from effective, older products with longer safety records
and lower costs.
A. Limitations
Categorization of patents into substance, product, or use categories was based on
Orange Book listings; we did not independently review or categorize patents. FDA
moves drugs to its discontinued product list when notified that these products are no

52 See Press Release, Amarin Corp. PLC, Amarin Announces Market Introduction of Vascepa(R)
(icosapent ethyl) Capsules for the Treatment of Very High Triglycerides (VHTG) (Jan. 24, 2013),
https://www.globenewswire.com/news-release/2013/01/24/518253/10019128/en/Amarin-Announces-
Market-Introduction-of-Vascepa-R-icosapent-ethyl-Capsules-for-the-Treatment-of-Very-High-
Triglycerides-VHTG.html [https://perma.cc/Q5PQ-5NWZ].
53 Henry Grabowski, Genia Long, Richard Mortimer & Ani Boyo, Updated Trends in US Brand-
Name and Generic Drug Competition, 19 J. MED. ECON. 836, 839 (2016).
54 See supra Figure, column (b).
55 See, e.g., Jonathan J. Darrow, Jessica E. Chong & Aaron S. Kesselheim, Reconsidering the Scope
of State Laws Allowing Pharmacist Substitution of Generic Drugs, 369 BRIT. MED. J. m2236 (2020)
(suggesting that state legislatures provide pharmacists with greater authority to substitute therapeutically
equivalent but lower cost products to serve as a backup when physicians fail to prescribe those drugs in the
first instance); Mark L. Metersky, Is There Any Reliable Clinical Evidence to Suggest that Acthar Is More
Effective than Other forms of Corticosteroids in Treating Sarcoidosis and Other Diseases it Is Being
Marketed to Treat?, 149 CHEST 866, 866 (2016) (describing pennies-per-pill corticosteroids and the extent
to which they are therapeutically equivalent to corticotrophin injection, which costs nearly $29,000).
56 Kesselheim & Darrow, supra note 33, at 324.
57See Jonah Berger, Alan T. Sorensen & Scott J. Rasmussen, Positive Effects of Negative Publicity:
When Negative Reviews Increase Sales, 29 MKTG. SCI. 815, 816 (2021) (noting that even “negative publicity
may have positive effects . . . by increasing product awareness or accessibility”).
58 See Jonathan J. Darrow, Pharmaceutical Gatekeepers, 47 IND. L. REV. 363, 392 (2014) (describing
the “premium price halo,” by which the high price of drugs or other credence goods may serve to increase
their perceived value).
2022 ORANGE BOOK LANDSCAPE 65

longer being marketed, but manufacturers may not always timely notify FDA.
Approved products are not necessarily marketed. This study is intended to present a
cross-sectional view of the current exclusivity landscape associated with approved
drugs. Historical patents and exclusivities that no longer appear in the Orange Book
due to expiration or other reasons, and pending or not-yet-filed patents that may be
granted in the future, were intentionally excluded from the data because they were not
relevant to our research question. Measures of the frequency of regulatory exclusivities
may understate their importance because concurrently running patents are frequently
invalidated in court or administrative proceedings,59 while regulatory exclusivities are
relatively immune from invalidation. Pediatric exclusivity, although serving as the
only remaining exclusivity for approximately one in two hundred drugs at the time of
our study, is likely to be pursued for those drugs with the largest markets, magnifying
its importance. Even weak patents can deter generic entry by increasing uncertainty
and litigation costs.

V. CONCLUSION
Considered together, patent and regulatory exclusivities may have a smaller impact
on drug expenditures and public health than previously believed because patents do
not affect most currently approved drugs, the presence or absence of patents does not
necessarily determine the availability or use of approved generics, and the availability
of high-cost medicines does not necessarily mean that they should be purchased or
consumed. Policymakers wishing to reduce unnecessary spending on prescription
drugs must consider not only the legal exclusivities affecting the prices of a minority
of approved drugs, but also the various business, regulatory, and other factors that
deter potential competitors from entering the market. Moreover, policymakers should
seek to understand why prescribers use high-cost medicines when therapeutically
similar lower-cost medicines are available.

59 Jonathan J. Darrow, Reed F. Beall & Aaron S. Kesselheim, Will Inter Partes Review Speed US
Generic Drug Entry?, 35 NATURE BIOTECHNOLOGY 1139, 1139 (2017).