United States v. Regenerative Sciences, LLC

United States Court of Appeals

FOR THE DISTRICT OF COLUMBIA CIRCUIT

Argued October 21, 2013 Decided February 4, 2014

No. 12-5254

UNITED STATES OF AMERICA,

APPELLEE

v.

REGENERATIVE SCIENCES, LLC, A CORPORATION, ET AL.,

APPELLANTS

Appeal from the United States District Court

for the District of Columbia

(No. 1:10-cv-01327)

Andrew S. Ittleman argued the cause for appellants. With

him on the briefs was Mitchell S. Fuerst.

Jonathan W. Emord was on the brief for amicus curiae

American Association of Orthopaedic Medicine in support of

appellants.

Lawrence J. Joseph was on the brief for amicus curiae

Association of American Physicians and Surgeons, Inc., in

support of appellants.

James S. Turner was on the brief for amicus curiae Tim

Moore in support of appellants.

2

Abby C. Wright, Attorney, U.S. Department of Justice,

argued the cause for appellee. With her on the brief were

Stuart F. Delery, Principal Deputy Assistant Attorney

General, Ronald C. Machen, Jr., U.S. Attorney, Mark B.

Stern, Attorney, William B. Shultz, Acting General Counsel,

Food and Drug Administration, and Eric M. Blumberg,

Deputy Chief Counsel. Alisa B. Klein, Attorney, U.S.

Department of Justice, entered an appearance.

Before: GRIFFITH and SRINIVASAN, Circuit Judges, and

EDWARDS, Senior Circuit Judge.

Opinion for the court filed by Circuit Judge GRIFFITH.

GRIFFITH, Circuit Judge: In this civil enforcement action,

we must decide whether the appellants—three individuals and

a related corporate entity—violated federal laws regulating

the manufacture and labeling of drugs and biological products

by producing, as part of their medical practice, a substance

consisting of a mixture of a patient’s stem cells and the

antibiotic doxycycline. Because we conclude that they did, we

affirm the district court’s judgment and the permanent

injunction it entered against appellants.

I

A

This case involves two statutes under which the Food and

Drug Administration (FDA) regulates the healthcare industry:

the Federal Food, Drug & Cosmetic Act (FDCA), 21 U.S.C.

§ 301 et seq., and the Public Health Service Act (PHSA), 42

U.S.C. § 201 et seq. Those statutes promote the safety of

drugs and biological products, respectively, by setting forth

detailed requirements for how such substances are to be

3

manufactured and labeled. See 21 U.S.C. §§ 351 (FDCA

manufacturing requirements), 352 (FDCA labeling

requirements); 42 U.S.C. § 262(j) (incorporating by reference

most of the FDCA’s provisions, including its manufacturing

and labeling requirements, into the PHSA). Drugs and

biological products not satisfying those requirements are

deemed “adulterated” or “misbranded,” see 21 U.S.C. §§ 351,

352, 353(b)(4); 42 U.S.C. § 262(j), and doing any act that

causes a drug or biological product to be adulterated or

misbranded is a violation of federal law, 21 U.S.C. § 331(k);

42 U.S.C. § 262(j). The FDA may seek an injunction to

prohibit such violations. 21 U.S.C. § 332(a); 42 U.S.C.

§ 262(j).

B

The substance at issue in this case is produced by

appellants Dr. Christopher Centeno, Dr. John Schultz,

Michelle Cheever, and Regenerative Sciences, LLC, as part of

a medical therapy that they market as the “Cultured Regenexx

Procedure” (the Procedure). Drs. Centeno and Schultz, who

practice medicine together at the Centeno-Schultz Clinic in

Colorado, jointly developed the Procedure to treat patients’

orthopedic conditions. They are the majority shareholders of

Regenerative Sciences, which they founded and which, in

turn, owns the Procedure and licenses it exclusively to the

Centeno-Schultz Clinic. Michelle Cheever is the laboratory

director for Regenerative Sciences.

The Procedure begins with the extraction of a sample of a

patient’s bone marrow or synovial fluid. From that sample,

Regenerative Sciences isolates mesenchymal stem cells

(MSCs), which are capable of differentiating into bone and

cartilage cells. The MSCs are then placed in a solution to

culture them—that is, to cause them to divide and proliferate.

4

Other substances are sometimes added to the solution that

affect the MSCs’ differentiation. The culturing process

determines the growth and biological characteristics of the

resulting cell population. When the MSCs are sufficiently

numerous for re-injection, they are combined with

doxycycline, an antibiotic obtained in interstate commerce

and used to prevent bacterial contamination of the MSCs. The

resulting mixture (the Mixture) is injected into the patient

from whom the stem cell sample was initially taken, at the site

of the damaged tissue.

Appellants promote the Procedure as an alternative to

surgery for various orthopedic conditions and diseases. In

court filings, they have described the Procedure as a

“treatment [for] orthopedic injuries and arthritis” and for

“musculoskeletal and spinal injury.” Their promotional

materials recommend the Procedure for treatment of

osteoarthritis, non-healing bone fractures, chronic bulging

lumbar discs, and soft tissue injuries.

In August 2010, the government filed this action for a

permanent injunction against appellants, alleging that the

Mixture is both a drug and a biological product that is

adulterated and misbranded in violation of § 331(k) of the

FDCA and § 262(j) of the PHSA, which incorporates § 331(k)

by reference. Appellants counterclaimed, asserting that the

Mixture is not subject to federal regulation and that, even if it

is, the FDA’s effort to regulate the Mixture is defective under

both the PHSA and the Administrative Procedure Act (APA),

5 U.S.C. § 706(2).

The district court granted the government’s motion for

summary judgment and dismissed appellants’ counterclaims,

holding that they had violated the FDCA and the PHSA.

United States v. Regenerative Scis., LLC, 878 F. Supp. 2d

5

248, 263 (D.D.C. 2012). Then, finding a “cognizable danger

of a recurrent violation,” the district court entered a

permanent injunction prohibiting appellants from committing

further violations of the FDCA’s adulteration and

misbranding restrictions. Id. at 262-63 (internal quotation

marks omitted). Appellants timely appealed both orders.

We have jurisdiction to review the district court’s orders

under 28 U.S.C. § 1291. We review the grant of summary

judgment and dismissal of appellants’ counterclaims de novo,

“drawing all reasonable inferences from the evidence in the

light most favorable to the nonmoving party,” Geleta v. Gray,

645 F.3d 408, 410 (D.C. Cir. 2011), and affirming only if

“there is no genuine dispute as to any material fact and the

movant is entitled to judgment as a matter of law,” FED. R.

CIV. P. 56(a). We review the district court’s entry of a

permanent injunction for abuse of discretion and its factual

findings for clear error. United States v. Philip Morris USA

Inc., 566 F.3d 1095, 1110 (D.C. Cir. 2009) (per curiam).

II

Appellants’ principal argument is that the Mixture is not

subject to regulation under the FDCA or PHSA because it is

neither a drug nor a biological product but is, rather, a

medical procedure. The text of those statutes forecloses this

argument.

The FDCA defines a “drug” as any “article[] intended for

use in the diagnosis, cure, mitigation, treatment, or prevention

of disease” or “intended to affect the structure or any function

of the body.” 21 U.S.C. § 321(g)(1); see also 21 C.F.R.

§ 201.128 (providing that a drug’s intended use is shown by

“the objective intent of the persons legally responsible for the

labeling of [the] drug[],” which “may . . . be shown by

6

labeling claims, advertising matter, or oral or written

statements by such persons or their representatives”). The

PHSA defines “biological product” in similarly broad terms

as any “virus, therapeutic serum, toxin, antitoxin, vaccine,

blood, blood component or derivative . . . or analogous

product . . . applicable to the prevention, treatment, or cure of

a disease or condition of human beings.” 42 U.S.C.

§ 262(i)(1). Both of these wide-ranging definitions clearly

apply to the Mixture, an article derived mainly from human

tissue and intended to treat orthopedic diseases and to affect

musculoskeletal function. Indeed, appellants do not actually

dispute that the plain language of the statutes compels this

conclusion.

Rather, appellants urge us to construe the FDCA in light

of purported federalism concerns. 1 But appellants’ concerns

lack merit. They boil down to the following syllogism: the

FDCA was not intended to infringe on states’ traditional role

in regulating the practice of medicine; the Procedure fits

Colorado’s statutory definition of the “practice of medicine”;

therefore, the FDA’s regulation of the Procedure exceeds the

FDA’s authority under the FDCA. This syllogism is flawed

twice over.

First, it misapprehends what this case is about.

Notwithstanding appellants’ attempt to characterize this case

1

Because the PHSA simply incorporates the FDCA’s

substantive provisions by reference, the scope of the FDCA’s

provisions is determinative of the reach of the PHSA’s provisions

as well. Thus, the parties’ arguments and our discussion focus on

the scope and application of the FDCA—keeping in mind that to

adulterate and misbrand a substance that is both a drug and a

biological product violates the PHSA as well as the FDCA.

7

as an effort by the FDA to “restrict[] the use of an autologous

stem cell procedure,” 2 Appellants’ Br. 8 (emphasis added),

the focus of the FDA’s regulation is the Mixture. That is, the

FDA does not claim that the procedures used to administer the

Mixture are unsafe; it claims that the Mixture itself is unsafe.

Appellants’ arguments about the practice-of-medicine

exemption are therefore wide of the mark.

Second, appellants are wrong to suggest that the scope of

the FDCA depends on state-by-state definitions of the

“practice of medicine.” The FDCA enacts a comprehensive,

uniform regulatory scheme for the distribution of drugs. The

scheme’s breadth—and, more specifically, its applicability to

doctors—is evident in the fact that the FDCA carves out

certain exceptions from its requirements for doctors who

manufacture and administer drugs in the course of their

professional practice. See, e.g., 21 U.S.C. § 360(g)(2)

(exempting licensed healthcare practitioners engaged in

certain activities from the FDCA’s registration requirements);

id. § 374(a)(2)(B) (narrowing the FDA’s ability to review the

records of licensed healthcare practitioners “who

manufacture, prepare, propagate, compound, or process drugs

. . . solely for use in the course of their professional practice”).

Those exceptions would be unnecessary if the FDCA did not

otherwise regulate the distribution of drugs by licensed

physicians. See United States v. Evers, 643 F.2d 1043, 1048

(5th Cir. 1981) (“[W]hile the [FDCA] was not intended to

regulate the practice of medicine, it was obviously intended to

control the availability of drugs for prescribing by

physicians.”). Appellants’ construction of the FDCA, by

contrast, would allow states to gut the FDCA’s regulation of

2

An “autologous” stem cell procedure is one in which cells

are implanted back into the individual from whom they were

initially taken. See 21 C.F.R. § 1271.3(a).

8

doctors, and thereby create an enormous gap in the FDCA’s

coverage, by classifying the distribution of drugs by doctors

as the practice of medicine. Given Congress’s intent that the

FDCA’s “coverage be as broad as its literal language

indicates,” United States v. An Article of Drug . . . Bacto-

Unidisk, 394 U.S. 784, 798 (1969), such a construction is not

tenable.

Equally untenable is appellants’ contention that because

the Procedure occurs entirely within the state of Colorado, the

Mixture lacks a sufficient connection to interstate commerce

to permit federal regulation under the Commerce Clause. It is

simply impossible to square this argument with the last

seventy years of Commerce Clause jurisprudence, which, in

recognition of Congress’s authority to regulate even “purely

local activities that are part of an economic ‘class of

activities’ that have a substantial effect on interstate

commerce,” Gonzales v. Raich, 545 U.S. 1, 17 (2005), has

upheld federal laws prohibiting the possession of home-grown

marijuana intended solely for personal use, id. at 32-33, and

restricting the amount of wheat a farmer can grow purely for

his farm’s consumption, Wickard v. Filburn, 317 U.S. 111,

128-29 (1942). Here, not only does the Mixture undoubtedly

have effects on interstate markets for orthopedic care, but it

actually includes an article shipped in interstate commerce,

namely, doxycycline. Cf. Raich, 545 U.S. at 17 (noting that

when Congress concludes that a class of activities

substantially affects interstate commerce, “the de minimis

character of individual instances [of those activities] is of no

consequence” (internal quotation marks omitted)). The

Commerce Clause poses no obstacle to regulating the Mixture

under the FDCA.

Nor can appellants prevail on their argument that even if

the Mixture may be federally regulated in principle, it falls

9

outside the scope of the statute appellants are charged with

violating, 21 U.S.C. § 331(k). That provision prohibits “the

doing of any . . . act with respect to[] a . . . drug . . . if such act

is done while such [drug] is held for sale . . . after shipment in

interstate commerce and results in such [drug] being

adulterated or misbranded.” Id. (emphasis added). Appellants

read § 331(k) to require that the entire Mixture have been

shipped in interstate commerce. They contend that merely

using an ingredient that travelled in interstate commerce—

here, doxycycline—is insufficient to trigger the bar. We

disagree. Not only does the FDCA define the term “drug” to

include a drug’s components, but to interpret § 331(k) as

appellants suggest would severely narrow a statutory scheme

designed to regulate the safety of drugs at every stage of their

distribution. See Evers, 643 F.2d at 1049 (explaining that

§ 331 is “designed to prevent misbranding at each stage of the

distribution process”); id. at 1050 (“Doctors holding drugs for

use in their practice are clearly one part of the distribution

process . . . .”). The two circuits to have considered this issue

have reached the same conclusion. In United States v.

Dianovin Pharmaceuticals, Inc., which involved a

pharmaceutical company that used raw vitamin K purchased

in interstate commerce to manufacture injectable vitamin K,

the First Circuit held that the company’s “use of components

shipped in interstate commerce . . . brought their activities

within § 331(k).” 475 F.2d 100, 102-03 (1st Cir. 1973); see

also United States v. Cassaro, Inc., 443 F.2d 153, 156 (1st

Cir. 1971) (explaining that, under the Supreme Court’s

decision in United States v. Sullivan, 332 U.S. 689 (1948),

“interstate commerce in drugs continue[s] even after the first

purely intrastate sale”). Similarly, in Baker v. United States,

the Ninth Circuit held that § 331(k)’s “‘shipment in interstate

commerce’ requirement is satisfied even when only an

ingredient is transported interstate.” 932 F.2d 813, 814 (9th

Cir. 1991). We therefore hold that, by virtue of its use of

10

doxycycline, the Mixture is within the scope of drugs—and,

by extension, biological products, see 42 U.S.C. § 262(j)—

regulated by § 331(k).

III

Appellants next advance two arguments why the Mixture

is exempt from the FDCA’s manufacturing and labeling

requirements even if it is otherwise subject to federal

regulation. Each argument fails.

A

In addition to regulating biological products directly, the

PHSA gives the FDA authority to issue regulations to prevent

the interstate spread of communicable disease. See 42 U.S.C.

§ 264(a). Pursuant to that authority, in 2001 the FDA

promulgated regulations to ensure the safety of human cells,

tissues, and cellular or tissue-based products (HCT/Ps) used

for therapeutic purposes. Those regulations, which appear at

21 C.F.R. part 1271, define HCT/Ps, in relevant part, as

“articles containing or consisting of human cells or tissues

that are intended for implantation, transplantation, infusion, or

transfer into a human recipient.” 21 C.F.R. § 1271.3(d).

HCT/Ps may qualify as drugs or biological products, and

when they do, the FDA generally regulates them accordingly

under the FDCA, PHSA, and corresponding regulations. See

id. § 1271.20; see also Application of Current Statutory

Authorities to Human Somatic Cell Therapy Products and

Gene Therapy Products, 58 Fed. Reg. 53,248, 53,249 (Oct.

14, 1993) (“Cellular products intended for use as somatic cell

therapy are biological products subject to regulation pursuant

to the [PHSA] and also fall within the definition of drugs in

the [FDCA].”). The Part 1271 Regulations, however, create a

regulatory exemption from the manufacturing and labeling

11

requirements that normally apply to drugs and biological

products for any HCT/P that is no more than “minimally

manipulated.” 3 See 21 C.F.R. § 1271.10(a). “Minimal

manipulation” of cells means “processing that does not alter

the relevant biological characteristics.” Id. § 1271.3(f)(2).

Appellants claim this exemption applies to the Mixture, but

the government offers several reasons why appellants’

culturing process alters the MSCs’ relevant biological

characteristics and is therefore more than minimal

manipulation. As to some of those reasons, such as the

government’s claim that culturing MSCs alters the genes and

proteins they express, appellants have created genuine issues

of fact by submitting expert affidavits arguing that the

government’s views are based on scientific studies that are

inapplicable to appellants’ culturing process. But appellants

give no response to other reasons offered by the government.

For example, appellants admit that the culturing process is

designed to “determine the growth and biological

characteristics of the resulting cell population.” It is also

undisputed that, in at least some cases, appellants add

substances to the cell culture that affect the differentiation of

bone marrow cells.

These concessions are fatal to appellants’ attempt to

claim refuge under § 1271.10(a). Given that § 1271.10(a) is

an exemption from the otherwise applicable provisions of the

FDCA, appellants ultimately bear the burden of establishing

that it applies to the Mixture. See United States v. First City

Nat’l Bank of Houston, 386 U.S. 361, 366 (1967) (stating the

3

To qualify for this regulatory exemption, an HCT/P must

meet several other criteria as well, pertaining to its method of

manufacture and intended use. See 21 C.F.R. § 1271.10(a). The

government does not claim, however, that the Mixture fails to meet

any of those additional criteria.

12

“general rule” of statutory construction that the party who

“claims the benefits of an exception to the prohibition of a

statute” carries the burden of establishing that the exception

applies); FTC v. Morton Salt Co., 334 U.S. 37, 44-45 (1948).

Because appellants concede that culturing MSCs affects their

characteristics and offer no evidence that those effects

constitute only minimal manipulation, they fail to carry that

burden as a matter of law.

We emphasize that we reach this conclusion based on the

evidence in the record, and not merely by deferring to the

FDA’s statement in the preamble to the Part 1271 Regulations

that expansion of MSCs in culture automatically constitutes

more than minimal manipulation. See Human Cells, Tissues,

and Cellular and Tissue-Based Products; Establishment

Registration and Listing, 66 Fed. Reg. 5447, 5457 (Jan. 19,

2001) (“We do not agree that the expansion of mesenchymal

cells in culture . . . [is] minimal manipulation.”). Appellants

devote considerable energy to challenging that statement as an

invalid legislative rule that the FDA now seeks to enforce

against them. That is, they claim that the FDA seeks to give

legal effect to a statement that was not promulgated through

formal rule-making procedures, which the APA forbids. Our

decision, however, is based on, and gives effect to, the Part

1271 Regulations, not the preamble. Appellants’ procedural

challenge to the preamble is therefore irrelevant.

Surprisingly, appellants also challenge the Part 1271

Regulations as ultra vires if applied to autologous stem cell

procedures because, they argue, such procedures do not carry

the risk of spreading communicable disease and thus are not

subject to regulation under 42 U.S.C. § 264. It is unclear what

appellants hope to achieve with this claim; to prevail would

only mean invalidating the very exemption from the FDCA in

which they hope to take refuge. In any case, the FDA’s

13

findings, which appellants do not challenge, undercut

appellants’ argument. In promulgating the Part 1271

Regulations, the FDA noted that any procedure involving

HCT/Ps risks spreading disease through, for example,

“[e]rrors in labeling, mixups of testing records, failure to

adequately clean work areas, and faulty packaging.” Current

Good Tissue Practice for Human Cell, Tissue, and Cellular

and Tissue-Based Product Establishments; Inspection and

Enforcement, 69 Fed. Reg. 68,612, 68,613 (Nov. 24, 2004).

Indeed, Regenerative Sciences’ own standard operating

procedure takes a similar view, recognizing the risk of

“[c]ontamination” as a “major problem in tissue culture” and

stressing the need for “good tissue practices” to “prevent the

introduction, transmission, or spread of communicable

diseases.” Appellants thus offer no basis to conclude that the

Part 1271 Regulations exceed the FDA’s authority to issue

regulations “to prevent the introduction, transmission, or

spread of communicable diseases” between states. 42 U.S.C.

§ 264(a).

B

Alternatively, appellants contend that the Mixture is

exempt from the FDCA’s manufacturing and labeling

requirements because it is a compounded drug. See 21 U.S.C.

§ 353a(a). A compounded drug must be produced using

certain types of “bulk drug substances,” one of which is “bulk

drug substances . . . that . . . are components of drugs

approved by the [government].” Id. § 353a(b)(1)(A).

Appellants assert that the Mixture meets this definition

because cultured MSCs are a component of the FDA-

approved drug Carticel. But even if that were the case—and

the affidavits appellants cite only suggest that it might be—it

would not be enough to bring the Mixture within § 353a. To

qualify as a “bulk drug substance,” an item must be

14

“represented for use in a drug,” 21 C.F.R. § 207.3(a)(4), and

appellants point to no evidence in the record even suggesting

that MSCs are held out for use in Carticel, or any other drug

for that matter. Appellants therefore fail to establish that the

Mixture is exempt from the FDCA’s manufacturing and

labeling requirements, and we proceed to consider whether

the Mixture violated them.

IV

A

The FDCA provides that a drug “shall be deemed to be

adulterated . . . if . . . the methods used in, or the facilities or

controls used for, its manufacture, processing, packing, or

holding do not conform to or are not operated or administered

in conformity with current good manufacturing practice.” 21

U.S.C. § 351(a) (emphasis added). The FDA has established

the specific elements of current good manufacturing practice

at 21 C.F.R. parts 210-211. Here, it is undisputed that

appellants’ facilities, methods, and controls for processing the

Mixture violated federal manufacturing standards in

numerous respects. Therefore, the Mixture is per se

adulterated, regardless of any other safety protocols appellants

happen to use. See John D. Copanos & Sons, Inc. v. FDA, 854

F.2d 510, 514 (D.C. Cir. 1988) (“Drugs produced in violation

of [federal manufacturing] regulations are deemed to be

adulterated without the agency having to show that they are

actually contaminated.”).

B

The FDCA also provides that a drug “shall be deemed to

be misbranded” if its label omits certain information. As

relevant here, the FDCA requires that a drug’s label provide

15

“adequate directions for use,” 21 U.S.C. § 352(f)(1), and, in

the case of prescription drugs, bear the symbol “Rx only,” id.

§ 353(b)(4)(A). Appellants admit that the Mixture’s labeling

satisfies neither of these requirements. 4

Appellants nevertheless argue that it is inappropriate to

hold them liable for not providing adequate directions because

they produced the Mixture only for their own use. This

argument, however, misunderstands how the FDCA’s labeling

scheme applies to prescription drugs. To satisfy § 352(f)’s

requirement of providing “adequate directions for use,” a

drug’s label must provide “directions under which the layman

can use a drug safely and for the purposes for which it is

intended.” 21 C.F.R. § 201.5 (emphasis added). A

prescription drug, however, is by definition “not safe for use

except under the supervision of a practitioner licensed by law

to administer such drug.” 21 U.S.C. § 353(b)(1)(A) (emphasis

added). It is thus impossible to provide “adequate directions

for use” for prescription drugs. As the Seventh Circuit has

observed, this means that prescription drugs are

“presumptively misbranded.” United States v. An Article of

Device, 731 F.2d 1253, 1261 (7th Cir. 1984); see United

States v. Articles of Drug, 625 F.2d 665, 673 (5th Cir. 1980)

(holding that § 352(f)(1) requires a drug’s labeling to “contain

adequate directions for a consumer to engage in self-

medication” and noting that a “prescription drug by definition

. . . is unsuitable for self-medication”). A prescription drug

can avoid being actually misbranded only by qualifying for

4

The Mixture’s label would have to bear the symbol “Rx

only” even if the Mixture were a compounded drug. See 21 U.S.C.

§ 353a(a) (exempting compounded drugs from the labeling

requirements of § 352(f)(1) but not § 353(b)(4)). Thus, even if we

were to accept appellants’ compounding argument, the Mixture still

would be misbranded. See id. § 353(b)(4).

16

either of two exemptions from § 352(f): the statutory

exemption, which applies when licensed practitioners

distribute drugs to patients via prescriptions, see 21 U.S.C.

§ 353(b)(2), or the regulatory exemption, which applies to

prescription drugs at any stage of distribution, see 21 C.F.R.

§ 201.100; Articles of Drug, 625 F.2d at 673. A prescription

drug’s label must contain specific information in order for

either exemption to apply. If the label does not contain every

piece of required information, the prescription drug will

remain subject to the impossible mandate of § 352(f) and will

be misbranded.

Here, there is no doubt that the Mixture qualifies as a

prescription drug. Before the Mixture can be injected into a

patient, a physician must review the cultured MSCs to ensure

that there are no visible signs of bacterial contamination or

genetic mutation. Then, if the MSCs are safe, appellants inject

the Mixture using sophisticated imaging devices to ensure that

it reaches the right spot on a patient’s bone or tissue so that it

has the intended therapeutic effect. Because the Mixture can

be safely administered only under a physician’s supervision,

the question for us is whether the Mixture qualifies for either

§ 352(f) exemption. The answer is clear. Both exemptions

require that the label bear the symbol “Rx only,” see 21

U.S.C. § 353(b)(4)(A); 21 C.F.R. § 201.l00(b)(1), and it is

undisputed that the Mixture’s label does not. Because its label

fails to provide the minimum information necessary to qualify

for either exemption from § 352(f), the Mixture is

misbranded.

In reaching this conclusion, we reject appellants’ broad

reading of United States v. Evers, in which the Fifth Circuit

held that a doctor was not liable for violating § 352(f)(1) by

advertising his off-label use of a prescription drug without

providing adequate directions for that use. See Evers, 643

17

F.2d at 1053-54. Appellants read Evers for the proposition

that doctors need not comply with the FDCA’s labeling

requirements when they prescribe drugs only within their own

practices. But Evers cannot bear the weight of this

interpretation, which is inconsistent with the fact that the

FDCA does not exempt doctors in such a categorical manner.

As the Fifth Circuit made clear, the “object of the

government’s case” in Evers was not the off-label

“prescription” of the drug at issue, but rather the “promotion

and advertising” of such off-label use. Id. at 1049 (emphases

added). Evers thus differs from this case in two important

ways: the drug at issue in Evers was FDA approved, and the

FDA did not question Evers’s right to prescribe that drug to

his patients. Neither of those circumstances is present here.

The FDA has not approved the Mixture as safe for any use

and hence challenges appellants’ right to prescribe the

Mixture at all. We will not broaden Evers to vitiate the

FDCA’s labeling requirements in these circumstances. The

strict exemption criteria presumably reflect the judgment of

both Congress and the FDA about the minimum information

necessary to safely distribute prescription drugs. Because

appellants did not meet those criteria, they misbranded their

drug.

V

Having found that the government is entitled to summary

judgment that appellants adulterated and misbranded the

Mixture, we review the district court’s entry of a permanent

injunction. Appellants attack the injunction on two fronts.

They contend that in entering the injunction, the district court

failed to make the necessary findings and that, in any event,

the facts do not warrant injunctive relief.

18

The FDCA gives courts jurisdiction to enjoin violations

of 21 U.S.C. § 331(k). See 21 U.S.C. § 332(a). To obtain

injunctive relief, the government “must demonstrate a

‘reasonable likelihood of further violation[s] in the future.’”

United States v. Philip Morris USA Inc., 566 F.3d 1095, 1132

(D.C. Cir. 2009) (per curiam) (quoting SEC v. Savoy Indus.,

Inc., 587 F.2d 1149, 1168 (D.C. Cir. 1978)) (alteration in

original). A district court should consider three factors in

determining whether a reasonable likelihood exists:

“‘[1] whether a defendant’s violation was isolated or part of a

pattern, [2] whether the violation was flagrant and deliberate

or merely technical in nature, and [3] whether the defendant’s

business will present opportunities to violate the law in the

future.’” Id. (quoting SEC v. First City Fin. Corp., 890 F.2d

1215, 1228 (D.C. Cir. 1989)).

Appellants argue that the district court failed to make

findings regarding these three factors. Though it is true that

the district court did not explicitly list the factors, there can be

no serious dispute that its factual findings implicate them. In

justifying the injunction, the district court stated:

[The] FDA notified [appellants] that their RegenexxTM

Procedure may be in violation of the [FDCA]. It then

twice inspected [appellants’] laboratories and found a

number of [current good manufacturing practice]

violations. [Appellants] maintained that the FDA

could not regulate their cell product and did not bring

their processes into compliance with [current good

manufacturing practice]. Although [appellants] agreed

to stop using their RegenexxTM Procedure during the

pendency of this lawsuit, there remains a “cognizable

danger of recurrent violation.”

19

Regenerative Scis., 878 F. Supp. 2d at 262-63. These findings

speak to the existence of each relevant factor. The fact that the

FDA found violations on two separate occasions and that

appellants refused to take corrective action even after multiple

FDA notices suggests a pattern of deliberate, even flagrant

violations. And, of course, these violations were inextricably

linked to the operation of appellants’ business.

Even so, appellants maintain that the district court abused

its discretion. They insist that they have shown “the utmost

respect for the judicial system” by discontinuing use of the

Procedure during the pendency of this litigation and that the

Procedure employed robust safety protocols, albeit not those

federal regulations required. These facts, however, do not

establish an abuse of discretion. That appellants suspended

use of the Procedure does not in itself preclude injunctive

relief. See United States v. Article of Drug Designated B-

Complex Cholinos Capsules, 362 F.2d 923, 928 (3d Cir.

1966) (“It is well settled that the cessation of activities, either

before or after suit is begun, does not in itself bar issuance of

the injunction.”). Furthermore, appellants have admitted to

over a dozen violations of federal manufacturing regulations,

and evidence in the record supports the serious nature of those

violations. Appellants also admit that they did not improve

their manufacturing process even after receiving FDA

warnings. Such conduct is sufficient to warrant the permanent

injunction.

VI

For the foregoing reasons, we affirm the district court’s

orders granting summary judgment to the government,

dismissing appellants’ counterclaims, and permanently

enjoining appellants from committing future violations of the

FDCA’s manufacturing and labeling provisions.