31764 Federal Register / Vol. 83, No. 131 / Monday, July 9, 2018 / Notices 

Coast Guard will refer to NVIC 01–2011 

for process information and guidance in 

evaluating SPLNG’s WSA. NVIC 01– 

2011 is available in the docket where 

indicated under ADDRESSES and also on 

the Coast Guard’s website at https://

www.dco.uscg.mil/Portals/9/ 

DCO%20Documents/5p/5ps/NVIC/ 

2011/NVIC%2001-2011%20Final.pdf. 

IV. Public Participation and Request for 

Comments 

We encourage you to submit 

comments through the Federal portal at 

http://www.regulations.gov. If your 

material cannot be submitted using 

http://www.regulations.gov, contact the 

person in the FOR FURTHER INFORMATION

CONTACT section of this document for 

alternate instructions. In your 

submission, please include the docket 

number for this notice of inquiry and 

provide a reason for each suggestion or 

recommendation. 

We accept anonymous comments. All 

comments received will be posted 

without change to http://

www.regulations.gov and will include 

any personal information you have 

provided. For more about privacy and 

the docket, visit http://

www.regulations.gov/privacyNotice. 

Documents mentioned in this notice 

of inquiry as being available in the 

docket, and all public comments, will 

be in our online docket at http://

www.regulations.gov and can be viewed 

by following that website’s instructions. 

This document is issued under 

authority of 5 U.S.C. 552 (a). 

Dated: July 2, 2018. 

Jacqueline Twomey, 

Captain, U.S. Coast Guard, Captain of the 

Port Marine Safety Unit Port Arthur. 

[FR Doc. 2018–14596 Filed 7–6–18; 8:45 am] 

BILLING CODE 9110–04–P 

DEPARTMENT OF HOMELAND 

SECURITY 

U.S. Customs and Border Protection 

Notice of Issuance of Final 

Determination Concerning Malarone 

Tablets 

AGENCY: U.S. Customs and Border 

Protection, Department of Homeland 

Security. 

ACTION: Notice of final determination. 

SUMMARY: This document provides 

notice that U.S. Customs and Border 

Protection (‘‘CBP’’) has issued a final 

determination concerning the country of 

origin of Malarone tablets. Based upon 

the facts presented, CBP has concluded 

that the country of origin of the 

Malarone tablets is Canada for purposes 

of U.S. Government procurement. 

DATES: This final determination was 

issued on July 2, 2018. A copy of the 

final determination is attached. Any 

party-at-interest may seek judicial 

review of this final determination 

within August 8, 2018. 

FOR FURTHER INFORMATION CONTACT: Ross 

M. Cunningham, Valuation and Special 

Programs Branch, Regulations and 

Rulings, Office of Trade, (202) 325– 

0034. 

SUPPLEMENTARY INFORMATION: Notice is 

hereby given that on July 2, 2018, 

pursuant to subpart B of Part 177, U.S. 

Customs and Border Protection 

Regulations (19 CFR part 177, subpart 

B), CBP issued one final determination 

concerning the country of origin of 

Malarone tablets, which may be offered 

to the U.S. Government under an 

undesignated government procurement 

contract. This final determination (HQ 

H290684) was issued under procedures 

set forth at 19 CFR part 177, subpart B, 

which implements Title III of the Trade 

Agreements Act of 1979, as amended 

(19 U.S.C. 2511–18). In the final 

determination, CBP concluded that the 

processing in Canada will result in a 

substantial transformation. Therefore, 

the country of origin for purposes of 

U.S. Government procurement of the 

Malarone tablets is Canada. 

Section 177.29, CBP Regulations (19 

CFR 177.29), provides that a notice of 

final determination shall be published 

in the Federal Register within 60 days 

of the date the final determination is 

issued. Section 177.30, CBP Regulations 

(19 CFR 177.30), provides that any 

party-at-interest, as defined in 19 CFR 

177.22(d), may seek judicial review of a 

final determination within 30 days of 

publication of such determination in the 

Federal Register. 

Dated: July 2, 2018. 

Alice A. Kipel, 

Executive Director, Regulations and Rulings, 

Office of Trade. 

HQ H290684 

July 2, 2018 

OT:RR:CTF:VS H290684 RMC 

CATEGORY: Origin 

Nicolas Guzman 

Drinker Biddle & Reath LLP 

1500 K Street NW 

Suite 1100 

Washington, DC 20005–1209 

Re: U.S. Government Procurement; 

Country of Origin of Malarone 

Tablets; Substantial Transformation 

Dear Mr. Guzman: 

This is in response to your letter, 

dated September 13, 2017, requesting a 

final determination on behalf of 

GlaxoSmithKline LLP (‘‘GSK’’) pursuant 

to subpart B of Part 177 of the U.S. 

Customs and Border Protection (‘‘CBP’’) 

Regulations (19 C.F.R. Part 177). A 

teleconference was held with counsel 

for GSK on June 8, 2018. 

This final determination concerns the 

country of origin of Malarone tablets. As 

a U.S. importer, GSK is a party-atinterest within the meaning of 19 C.F.R. 

§ 177.22(d)(1) and is entitled to request 

this final determination. 

FACTS: 

GSK is a global healthcare company 

that researches, develops, and 

manufactures pharmaceutical 

medicines, vaccines, and consumer 

healthcare products. At issue in this 

case are tablets sold under the brand 

name Malarone, which are indicated for 

the prevention and treatment of acute, 

uncomplicated Plasmodium falciparum 

malaria. GSK states that Malarone 

tablets have been shown to be effective 

in regions where other malaria drugs 

such as chloroquine, halofantrine, 

mefloquine, and amodiaquine may have 

unacceptable failure rates, presumably 

due to drug resistance. 

According to the FDA prescribing 

information, Malarone is a fixed-dose 

combination of atovaquone and 

proguanil hydrochloride. See 

Prescribing Information, https://

www.fda.gov/ohrms/dockets/ac/05/ 

briefing/2005-4089b1_05_05_

atovaquone.pdf (last visited Dec. 11, 

2017). The chemical name of 

atovaquone 11 is trans-2-[4-(4 

chlorophenyl)cyclohexyl]-3-hydroxy1,4-naphthalenedione and the molecular 

formula for atovaquone is C22H19ClO3. 

The chemical name of proguanil 

hydrochloride is 1-(4-chlorophenyl)-5- 

isopropyl-biguanide hydrochloride and 

the chemical formula for proguanil 

hydrochloride is C11H16ClN5•HCl. 

Each Malarone Tablet contains 250 

milligrams of atovaquone and 100 

milligrams of proguanil hydrochloride. 

The FDA prescribing information also 

describes the microbiology or 

‘‘mechanism of action’’ of atovaquone 

and proguanil hydrochloride. It states 

that atovaquone and proguanil 

hydrochloride ‘‘interfere with 2 

different pathways involved in the 

biosynthesis of pyrimidines required for 

nucleic acid replication. Atovaquone is 

a selective inhibitor of parasite 

mitochondrial electron transport. 

Proguanil hydrochloride primarily 

exerts its effect by means of the 

metabolite cycloguanil, a dihydrofolate 

reductase inhibitor. Inhibition of 

dihydrofolate reductase in the malaria 


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Federal Register / Vol. 83, No. 131 / Monday, July 9, 2018 / Notices 31765 

parasite disrupts deoxythymidylate 

synthesis.’’ 

GSK notes that atovaquone by itself is 

not indicated for the prevention or 

treatment of malaria. By itself, 

atovaquone is used for other purposes, 

such as the treatment of acute 

pneumocystis carinii pneumonia and 

cerebral toxoplasmosis. In contrast, 

proguanil hydrochloride can be used to 

treat malaria. However, GSK cites to 

several academic studies that conclude 

that the combination of atovaquone and 

proguanil hydrochloride provides a 

more effective treatment compared to 

taking proguanil hydrochloride alone. 

GSK therefore states that atovaquone 

and proguanil are ‘‘synergistic in their 

mechanisms of action,’’ resulting in the 

increased effectiveness of Malarone 

tablets compared to taking atovaquone 

or proguanil hydrochloride alone. 

The manufacturing process for GSK’s 

Malarone tablets begins in India, where 

the Malarone tablets’ two active 

pharmaceutical ingredients (‘‘APIs’’), 

atovaquone and proguanil 

hydrochloride, are manufactured. After 

the two APIs are manufactured in India, 

they are imported into Canada for 

further processing at GSK’s Mississauga, 

Ontario facility (‘‘GSK Canada’’). At 

GSK Canada, the two APIs are combined 

in a process that begins by producing a 

dry mix of the APIs, low-substituted 

hydroxpropyl cellulose NF, 

microcrystalline cellulose NF, and 

sodium starch glycolate NF. The dry 

mix is then combined with the 

following inactive ingredients, which 

are each sourced from the United States 

or a TAA-eligible country, to produce 

granules: 

• Povidone K30 USP 

• Polaxamer 188 NF 

• Sofium Starch Glycolate NF 

• Hydroxy Propyl Cellulose NF 

• Purified Water USP 

• Microcrystalline Cellulose NF 

• Alcohol USP 

Next, the granules are dried, milled 

into a dry powder, blended with 

magnesium stearate NF, and 

compressed into tablets. Finally, a film 

coat mix is added and the tablets are 

polished. 

Once the manufacturing process is 

complete, the finished Malarone tablets 

are exported to a GSK facility in 

Zebulon, North Carolina. There, the 

tablets are packaged and labeled for sale 

to Prasco Laboratories, which markets 

and distributes the tablets under their 

own labeling as an authorized generic 

product under an agreement with GSK. 

ISSUE: 

What is the country of origin of the 

Malarone tablets for purposes of U.S. 

Government procurement? 

LAW AND ANALYSIS: 

CBP issues country of origin advisory 

rulings and final determinations as to 

whether an article is or would be a 

product of a designated country or 

instrumentality for the purposes of 

granting waivers of certain ‘‘Buy 

American’’ restrictions in U.S. law or 

practice for products offered for sale to 

the U.S. Government, pursuant to 

subpart B of Part 177, 19 C.F.R. § 177.21 

et seq., which implements Title III of the 

Trade Agreements Act of 1979, as 

amended (19 U.S.C. § 2511 et seq.). 

Under the rule of origin set forth 

under 19 U.S.C. § 2518(4)(B): 

An article is a product of a country or 

instrumentality only if (i) it is wholly the 

growth, product, or manufacture of that 

country or instrumentality, or (ii) in the case 

of an article which consists in whole or in 

part of materials from another country or 

instrumentality, it has been substantially 

transformed into a new and different article 

of commerce with a name, character, or use 

distinct from that of the article or articles 

from which it was so transformed. 

See also 19 C.F.R. § 177.22(a). 

A substantial transformation occurs 

when an article emerges from a process 

with a new name, character, and use 

different from that possessed by the 

article prior to processing. A substantial 

transformation will not result from a 

minor manufacturing or combining 

process that leaves the identity of the 

article intact. See United States v. 

Gibson-Thomsen Co., 27 C.C.P.A. 267 

(1940); and National Juice Products 

Ass’n v. United States, 628 F. Supp. 978 

(Ct. Int’l Trade 1986). 

In determining whether a substantial 

transformation occurs in the 

manufacture of chemical products such 

as pharmaceuticals, CBP has 

consistently examined the complexity of 

the processing and whether the final 

article retains the essential identity and 

character of the raw material. To that 

end, CBP has generally held that the 

processing of pharmaceutical products 

from bulk form into measured doses 

does not result in a substantial 

transformation of the product. See, e.g., 

Headquarters Ruling (‘‘HQ’’) 561975, 

dated April 3, 2002; HQ 561544, dated 

May 1, 2000; HQ 735146, dated 

November 15, 1993; HQ H267177, dated 

November 5, 2016; HQ H233356, dated 

December 26, 2012; and, HQ 561975, 

dated April 3, 2002. However, where the 

processing from bulk form into 

measured doses involves the 

combination of two or more APIs, and 

the resulting combination offers 

additional medicinal benefits compared 

to taking each API alone, CBP has held 

that a substantial transformation 

occurred. See, e.g., HQ 563207, dated 

June 1, 2005. 

For example, in HQ 563207, CBP held 

that the combination of two APIs to 

form Actoplus Met, an alternative 

treatment for type 2 diabetes, 

constituted a substantial transformation. 

The first API, Pioglitazone HCI sourced 

from Japan or other countries, 

functioned as an insulin sensitizer that 

targets insulin resistance in the body. 

The second API, biguanide sourced 

from Japan, Spain, and other countries, 

functioned to decrease the amount of 

glucose produced by the liver and make 

muscle tissue more sensitive to insulin 

so glucose can be absorbed. In Japan, the 

two APIs were mixed together to form 

a fixed-combination drug called 

Actoplus Met. In holding that a 

substantial transformation occurred 

when the APIs were combined in Japan 

to produce Actoplus Met, CBP 

emphasized that ‘‘[w]hile we note that 

pioglitazone and metformin may be 

prescribed separately, the final product, 

Actoplus Met, increases the individual 

effectiveness of piofliazone and 

metformin in treating type 2 diabetes 

patients.’’ 

Similarly, in HQ H253443, dated 

March 13, 2015, CBP held that the 

combination of two APIs in China to 

produce Prepopik, ‘‘a dual-acting 

osmotic and stimulant laxative bowel 

preparation for a colonoscopy in 

adults,’’ constituted a substantial 

transformation. Although the importer 

claimed that Country A-origin sodium 

picosulfate was the only API in 

Prepopik, CBP found that the Country 

B-origin magnesium oxide ingredient 

also qualified as an API. CBP further 

found that taking Prepopik had ‘‘a more 

stimulative laxative effect’’ than taking 

each of the APIs individually and 

therefore held that a substantial 

transformation occurred when the APIs 

were combined in China. 

Here, as in HQ 563207 and HQ 

H253443, two separate APIs are mixed 

to create a fixed combination drug that 

offers additional medicinal benefits 

compared to taking each API alone. The 

first API, atovaquone, is not indicated 

for the prevention or treatment of 

malaria. The second API, proguanil 

hydrochloride, is used to treat malaria, 

but is less effective than Malarone. This 

is because of the ‘‘synergies in [the 

APIs’] method of action,’’ which result 

in a product that ‘‘interfere[s] with 2 

different pathways’’ to prevent and treat 

malaria. Under these circumstances, the 

combination of atovaquone, proguanil 


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31766 Federal Register / Vol. 83, No. 131 / Monday, July 9, 2018 / Notices 

hydrochloride, and inactive ingredients 

to form Malarone tablets in Canada 

results in a substantial transformation. 

The country of origin of the Malarone 

tablets is therefore Canada. 

HOLDING: 

The country of origin of the Malarone 

tablets for purposes of U.S. Government 

procurement is Canada. 

Notice of this final determination will 

be given in the Federal Register, as 

required by 19 C.F.R. § 177.29. Any 

party-at-interest other than the party 

which requested this final 

determination may request, pursuant to 

19 C.F.R. § 177.31, that CBP reexamine 

the matter anew and issue a new final 

determination. Pursuant to 19 C.F.R. 

§ 177.30, any party-at-interest may, 

within 30 days of publication of the 

Federal Register Notice referenced 

above, seek judicial review of this final 

determination before the Court of 

International Trade. 

Sincerely, 

Alice A. Kipel, 

Executive Director, Regulations & Rulings 

Office of Trade. 

[FR Doc. 2018–14632 Filed 7–6–18; 8:45 am] 

BILLING CODE 9111–14–P 

DEPARTMENT OF THE INTERIOR 

Fish and Wildlife Service 

[FWS–R4–ES–2015–N040; 

FXES11130400000C2–156–FF04E00000] 

Endangered and Threatened Wildlife 

and Plants; Draft Recovery Plan for 

Coquı ́ Llanero 

AGENCY: Fish and Wildlife Service, 

Interior. 

ACTION: Notice of availability and 

request for public comment. 

SUMMARY: We, the U.S. Fish and 

Wildlife Service, announce the 

availability of the draft recovery plan for 

the endangered coquı ́ llanero, a frog 

endemic to Puerto Rico. The draft 

recovery plan includes specific recovery 

objectives and criteria that must be met 

in order for us to remove this species 

from listing under the Endangered 

Species Act of 1973, as amended. We 

request review and comment on this 

draft recovery plan from local, State, 

and Federal agencies, and the public. 

DATES: In order to be considered, 

comments on the draft recovery plan 

must be received on or before 

September 7, 2018. 

ADDRESSES: 

Document availability: You may 

obtain a copy of this draft recovery plan 

by contacting Jan Zegarra, U.S. Fish and 

Wildlife Service, Caribbean Ecological 

Services Field Office, P.O. Box 491, 

Boquero ́n, PR 00622; tel. (787) 851– 

7297; or by visiting the Service’s 

Caribbean Field Office website at 

https://www.fws.gov/caribbean/ES/ 

Index.html. 

Comment submission: You may 

submit comments by one of the 

following methods: 

1. Submit written comments and 

materials by mail or hand-delivery to 

Jan Zegarra, at the above address. 

2. Fax them to (787) 851–7440. 

3. Send comments by email to jan_

zegarra@fws.gov. Please include ‘‘Coquı ́

llanero Draft Recovery Plan Comments’’ 

in the subject line. 

For additional information about 

submitting comments, see Request for 

Public Comments. 

FOR FURTHER INFORMATION CONTACT: Jan 

Zegarra at (787) 851–7297, or see 

ADDRESSES for further methods of 

contact. 

SUPPLEMENTARY INFORMATION: We, the 

U.S. Fish and Wildlife Service, 

announce the availability of the draft 

recovery plan for the endangered coquı ́

llanero (Eleutherodactylus juanariveroi). 

The draft recovery plan includes 

specific recovery objectives and criteria 

that must be met in order for us to 

remove this species from listing under 

the Endangered Species Act of 1973, as 

amended (ESA; 16 U.S.C. 1531 et seq.). 

We request review and comment on this 

draft recovery plan from local, State, 

and Federal agencies and the public. 

Background 

The coquı ́ llanero is a small frog 

species endemic to Puerto Rico. In 2007, 

it was described as a new species of the 

genus Eleutherodactylus, family 

Leptodactylidae. Males measure 

approximately 0.58 in (14.7 mm), and 

females 0.62 in (15.8 mm). It has the 

smallest clutch size of all 

Eleutherodactylus species on Puerto 

Rico, and a high-frequency call. The 

only population estimate available for 

the coquı ́ llanero indicates a mean 

population size of 473.3 ± 186 

individuals per ha (or 192 per ac; Rı ́osLo ́pez pers. comm. 2011). 

The coquı ́ llanero is currently known 

to be restricted to one freshwater 

herbaceous wetland in the municipality 

of Toa Baja, Puerto Rico. The 

herbaceous vegetation in the wetland 

consists of Blechnum serrulatum 

(toothed midsorus fern), Thelypteris 

interrupta (willdenow’s maiden fern), 

Sagittaria lancifolia (bulltongue 

arrowhead), Cyperus sp. (flatsedges), 

Eleocharis sp. (spike rushes), and vines 

and grasses (Rı ́os-Lo ́pez and Thomas 

2007). The species is currently 

threatened by the combined influences 

of urban development, activities 

associated with the operation and future 

closure of the Toa Baja municipal 

landfill, activities associated with 

clearing water channels for flood 

control, and invasive wetland plant 

species. Additional threats include 

restricted distribution and highly 

specialized ecological requirements, 

which may exacerbate other potential 

threats like landfill leachate pollution, 

the use of herbicides, brush fires, 

competition, and environmental effects 

resulting from climate change. 

Under the ESA, the Service added the 

coquı ́ llanero as an endangered species 

to the Federal List of Endangered and 

Threatened Wildlife in title 50 of the 

Code of Federal Regulations on October 

4, 2012 (77 FR 60778). The 2012 final 

rule also designated critical habitat, 

covering an area of 615 ac (249 ha), for 

the species. 

The recovery strategy for the coquı ́

llanero includes protection and 

management of occupied habitat and 

suitable unoccupied habitat for 

potential future introductions, and 

addresses immediate threats that led to 

its listing. Because of stressors like 

reduced geographic distribution, limited 

dispersal capabilities, and the species’ 

specialized breeding requirements, the 

species is likely to have reduced 

adaptive capacity. Therefore, in order to 

meet the recovery goal of delisting, we 

must increase the number of coquı ́

llanero populations. This strategy seeks 

to safeguard the only existing coquı ́

llanero population in case the species 

does not withstand or recover from a 

stochastic or catastrophic event. 

Section 4(f) of the ESA requires the 

development of recovery plans for listed 

species, unless such a plan would not 

promote the conservation of a particular 

species. Recovery plans describe actions 

considered necessary for conservation of 

the species, establish criteria for 

downlisting or delisting, and estimate 

time and cost for implementing recovery 

measures. Section 4(f) of the ESA also 

requires us to provide public notice and 

an opportunity for public review and 

comment during recovery plan 

development. We will consider all 

information presented during a public 

comment period prior to approval of 

each new or revised recovery plan. We 

and other Federal agencies will take 

these comments into account in the 

course of implementing approved 

recovery plans. 


sradovich on DSK3GMQ082PROD with NOTICES