Source: s3://data.kl3m.ai/documents/govinfo/USCOURTS/USCOURTS-caDC-12-05254/USCOURTS-caDC-12-05254-0/pdf.json

Nature of Suit Code: 890
Nature of Suit: Other Statutory Actions
Cause of Action: 

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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. 

USCA Case #12-5254 Document #1478137 Filed: 02/04/2014 Page 1 of 19
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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 

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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. 

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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 

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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 

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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.

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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).

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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 . . . BactoUnidisk, 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 

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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 

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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 

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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. 

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“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 

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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 FDAapproved 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 

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“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 

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“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 selfmedication” 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).

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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 

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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.

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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.”

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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 BComplex 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.

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