UNITED STATES PATENT AND TRADEMARK OFFICE

DEC 20 201iInRe:Thomas G. Rowan

JONES DAY222 East 41 st St.New York, NY 10017

An application for extension of the patent term of U.S. Patent No. RE38115 (the '115 patent) under35 U.S.C. § 156 was filed in the United States Patent and Trademark Office (USPTO) on December17,2010. The application was fied by Center for Neurologic Study (Applicant) the owner ofrecord of the patent. Extension was sought based upon the premarket review under § 505 of theFederal Food, Drug, and Cosmetic Act (FFDCA) of a human drug product known by the tradenameNEUDEXTA(Ê and having the active ingredients dextromethorphanhydrobromide and quinidinesulfate. The application indicated that NUEDEXT A(Ê (dextromethorphan hydro bromide andquinidine sulfate) had been approved for commercial use and sale by the Food and DrugAdministration (FDA) on October 29,2010.

On May 31,2011 (correcting the March 29,2011 USPTO letter to FDA), the USPTO sent a letter tothe FDA stating, "Our review ofthe application to date indicates that the subject patent would NOTbe eligible for extension of the patent term under § 156." In the March 29, 2011 letter, the USPTOindicated that the' 115 patent would not be eligible for extension based on the regulatory review ofNEUDEXTA because both active ingredients, i.e., dextromethorphan hydrobromide and quinidinesulfate, were previQusly approved under section 505 of the Federal Food, Drug and Cosmetic Act

(FFDCA). The USPTO requested the FDA's assistance in determining whether NUEDEXTA(Ê(dextromethorphan hydrobromide and quinidine sulfate) had been subject to a regulatory reviewperiod in accordance with § 156(g) before its first permitted commercial marketing or use inaccordance with section 156(a)(5)(A).

In a letter dated June 9, 2011 from the FDA to the USPTO (FDA letter), the FDA indicated thatNUEDEXTA(Ê (dextromethorphan hydro bromide and quinidine sulfate) had been subject toregulatory review under new drug application (NDA) 21-879 in accordance with section 505 of theFFDCA, and confirmed that NDA 21-879 did not represent the first permitted commercialmarketing or use of the active ingredients of NUED EXT A (Ê (dextromethorphan hydro bromide andquinidine sulfate). -

A single request for reconsideration of this FINAL DETERMINATION OF INELIGIBILITY maybe made if fied by Applicant within TWO MONTHS of the mailing date of this letter. The periodfor response may be extendedpursuant to 37 C.F.R. § 1.136. See 37 C.F.R. § 1.750. A failure torespond to this letter wil result in the application papers being placed into the patent file with nofurther action taken on the PTE Application.

U.S. Patent No. RE38115 Page 2

A. U.S. Patent No. RE38115 Is Not Eligible for Patent Term Extension

A determination has been made that the '115 patent is NOT eligible for patent term extension under§ 156 based upon the regulatory review period of NUEDEXT A(Ê (dextromethorphan hydro bromideand quinidine sulfate).

The FDA offcial records indicate that each of the two active ingredients comprising NUEDEXT A(Ê,i.e., dextromethorphan hydrobromide and quinidine sulfate, has been previously approved forcommercial marketing or use, prior to the approval ofNUEDEXTA(Ê (dextromethorphanhydrobromide and quinidine sulfate). In the FDA letter, FDA stated:

A review of the Food and Drug Administration's official records indicatesthat this product was subj ect to a regulatory review period. before its commercialmarketing or use, as required under 35 U.S.c. § 156(a)(4). However, our recordsalso indicate that it does not represent the first permitted commercial marketing oruse of the product, as defined under 35 U.S.C. § 156(£)(1). The active ingredientsin NUEDEXTA, dextromethorphan hydrobromide and quinidine sulfate, have beenindividually approved previously for commercial marketing or use in several otherapproved products including but not limited not to the following:

Active Ingredient Companies Products ApplicationNumbers

Dextromethorphan Reckitt Benckiser MucinexDM NDA 21-620Hydrobromide ( dextromethorpha

n hydro bromide

and guaifenisin),

" Multiple (Hi- Dextromethorpha ANDAs 40-027,Tech Pharma, n Hydrobromide 40-649,88-811,Vintage, Actavis, in combination 88-762, 88-864,

midAtlantic) with either 90-575PseudoephedrineHydrochloride orPromethazineHydrochloride

Quinidine Sulfate Wyeth Pharms, Quinidex NDA 12-796Inc.

u.s. Patent No. RE38115 Page 3,'

" Multiple (Teva Quinidine sulfate ANDAs 40-045,Pharms,Mutual 81-030-81-031-Phar, Sandoz, 88-072-83-288-Watson 85-583

Laboratories

Under § 156( a) a term of a patent which claims a product shall be extended if, inter qlia, theproduct has been subject to a regulatory review period before its commercial marketing or use.In addition, § 156(a)(5)(A) provides in pertinent part that "the permission for the commercialmarketing or use of the product. . . is the first permitted commercial marketing or use of theproduct under the provision of law under which such regulatory review period occurred."

(Emphases added.)

Thus, whether the '115 patent is eligible for patent term extension turns on the requirement in§ 156(a)(5)(A) that the permission for the commercial marketing or use is the first permittedcommercial marketing or use of the product.

The term "product"is defined in § 156(f) as follows:

(f) For purposes ofthis section:

(1) The term "product" means:

(A) A drug product. . .(2) The term "drug product" means the active ingredient of-

(A) Anew drug, antibiotic drug, or human biological product . . . .including anysalt or ester of the active ingredient, as a single entity or in combination withanother active ingredient. (Emphasis added.)

By the explicit terms of § 156(f)(2), the term "product" as it relates to a human drug productmeans the aCtive ingredient of the new drug product. . See In re Fisons Pharmaceuticals Limited,231 USPQ 305 (Comrr'rPats.1 986); aftd, Fisons pIc v. Quigg, 8 USPQ2d149t(DDC 1988);aftd, 10 USPQ2d 1869 (Fed. Cir~ 1988) (holding that the term "product" as used in § 156(f)referstò the activeingredient); Glaxo Operations UK Ltd. v. Quigg, 13 USPQ1628(Fed. Cir.1990) (holding that the term "product" as used in § 156(f) refers to the active ingredient).Moreover, the issue of compliance with 35 U.S.C. § 156(a)(5)(A) was squarely addressed by theFederal Circuit in Photocurev. Kappos, 603 F.3d 1372 (Fed. Cir. 2010), where

the court reliedon its previous decision in Glaxo v. Quigg, 894 F.2d 392 (Fed. Cir. 1990) (Glaxo IJ),for its .determination of eligibility of a patent for extension based on the regulatory review ofPhoto cure ' s Metvixia product. There the analysis centered around determining what activeingredient is present in the drug product and whether the permission for commercial marketing oruse of the active ingredient is the first permitted commercial marketing or use.

In addressing compliance with section 156 (a)(5)(A) for a drug product including two activeingredients, the cour in Arnold P'ship v. Dudas, 362 F.3d 1338, 1341 (Fed. Cir. 2004) held that acomposition comprised of multiple active ingredients is eligible for patent term extension only if

U.S. Patent RE38115 Page 4

at least one of the active ingredients complies with the first commercüil marketing requirement of§ 156(a)(5)(A)). Thus, for regulatory review ofci drug product

with more than one 'active '

ingredient to give rise to eligibility for extension of a patent claiming the drug product,permission to commercially market and use the product must be the first permitted commercialmarketing or use at least one of the active ingredients. The active ingredients in the

approved

product NUEDEXTACI are dextromethorphan hydrobromide and quinidine sulfate. As noted inthe FDA letter, the active ingredients dextromethorphan hydrobromideand quinidine

sulfate had

each been approved for commercial marketing and use prior to theapproval ofNUEDEXTA(Ê.

Furthermore, the prior approval of each of the active ingredients dextromethorphanhydrobromide and quinidine sulfate by theFDA occurred under

section 505 ofthe FFDCA, the

same provision oflaw under which regulatory review of the product NUEDEXTA(Ê

(dextromethorphanhydrobromide and quinidine sulfate) occurred. Thus, since neither activeingredient, dextromethorphan hydro bromide nor quinidine sulfate, constitute the firstpermittedcommercial marketing or use, the' 115 does not appear to be eligible for extension based on theregulatory review ofNUEDEXTA(Ê.

Applying the definition of "product" provided in § 156(f) to the extension requirement of§ 156( a)(5)(A), Applicant's product NUEDEXTA(Ê (dextromethorphan hydro

bromide and

quinidine sulfate) does not qualify as the first permitted marketing or use of either active

ingredient., Since the approval ofNUEDEXTA(Ê was notthe first permitted marketing or use ofat least one of the active ingredients thereof, dextromethorphan hydrobromide or quinidinesulfate, the patent is not eligible for patent term extension based upon the regulatory review ofNUEDEXTA(Ê.

The Applicant for patent term extension has argued in their application that the '115 patent i~entitled to an extension under § 156 because section 505 of the FFDCA asarrended by the Drug

Price Competition and Patent Term Restoration Act of 1984 constitutes a different "provision oflaw" as that phrase appears in § 156(a)(5)(A)fromthe previous approvals.

Applicant is mistaken in its reading of § 156(a)(5)(A). As previously explained by FDA in asimilar situation, FDA maintains that the phrase "provision of law" refers "to the statutoryprovision under which the regulatory review occurs for a particular class of

products that is

eligible for patent term restoration, regardless of whether that statutory provision is amended."See U.S. PatentNo. 4,868,179, FDA letter of April 20, 2007 (2007 FDA letter) (copy attached

hereto). The FDA statedthete, and the USPTO concurs, thatthe phrase is unambiguous on its

face. However, as explained in the 2007 FDA letter, even if the phrase is ambiguous, this

interpretation is permissible in light oflegislative intent, public policy concerns, and applicable

case law. There is no suggestion in the legislative history thaÚhe phrase "first permitted

commercial marketing or use of the product under the provision of law under which suchregulatory review period occurred" as used in § 156(a)(5)(A) is intended to treat amendedversions of section 505 as different provisions of law. Rather,

as explained by the FDA at page 6

of the 2007 FDA letter, to treat each different amended version of section 505 as a different

provision of law would contravene the legislative intent of Congress by allowing the term of

more than one patent to be extended if a product received more than one approval as a memberof a particular class of products. Furthermore, as Applicant acknowledges at p'ages 11-12 of their

u.s. Patent RE381 15 Page 5

PTE application and the FDA points out, at pages 8-9 of the 2007 FDA letter, the only federal

cour decision to have addressed the question at issue, Westwood Pharms., Inc. v. Quigg" 1989WL 205631,13 U.S.P.Q.2d2067 (D.D.C. 1989), supports the interpretation of the FDA and the

USPTO. Finally, the Supreme Court in Eli Lily and Co. v. Medtronic, Inc., 496 U.S. 661,667,674,15 USPQ2d 1121, 1125-26, 1128 (1990), while making a distinction between the term"law" as broadly construed and a "provision oflaw," identified 21 U.S.C.§ 355 (the codificationof section 505), as the "provision" of the FFDCA under which new drugs are subject topremarket approval.

In view of the foregoing reasons, the term of the' 115 patent. is not eligible for extension under§ 156 basedupon the regulatory review period and approval of the human drug product

NUEDEXTA(Ê (dextromethorphan hydrobromide and quinidine sulfate). Thus, the applicationfor patent term extension is dismissed.

B. Conclusion

Because the approval ofNUEDEXTA(Ê fails to comply with the requirement of section156(a)(5)(A), the application for patent term extension under 35 U.S.C. 156(d)(1) is

dismissed.

Any correspondence with respect to this matter should be addressed as follows:

By mail: Mail Stop Hatch-Waxman PTECommissioner for PatentsP.O. Box 1450Alexandria, VA 22313-1450

By FAX: (571) 273-7755

Telephone inquiries related to this determination should be directed to Mary C. Til

Senior Legal Advisor, at (571) 272-7755.

)jß~_ edi~Senior Legal AdvisorOffice of Patent Legal Addiinistration

cc: Offce of Regulatory PolicyFood and Drug Administration10903 New Hampshire Ave., Bldg. 51, Rm. 6222Silver Spring, MD 20993-0002

Re: NUEDEXTA(Ê( dextromethorphanhydro bromide and quinidinesulfate)

Docket No. FDA-2011-E-0269

Attention: Beverly Friedman

"~+".4...vlr~...&,.

( E~'+.

""IIQ. . .

DEPARTMENT OF HEATH &. HUMA SERVICES Public Health Service

APR 2 a 2007

Food and Drug Administation

Rockvile MD 20857

Re: BiDilcIDoçket No.: 2006E~0003

The Honorable Jon W. DudasUndersecretay of Commerce for Intellectu Propert and

Director of the United States Patent' and Trademark OffceMail Stop Hatch~ Waxan PTEP.O. Box 1450Alexandra, VA 22313-1450

Dear Director Dudas:

, Ths is in regard to the åpplication for patent extension for US Patent No. 4,868,179 ('179. patent), fied by Nitromed, Inc. under Title II of the Drug Price Competition and Patent TermRestoration Act of 1984 (Public Law 98-417 codified at 35 U.S.C. § 156) (Title II). The patentclais a method of using the two active ingredients in the new drg BiDilCI: hydralazinehydrochloride (hydralazine) and isosorbide dinitrate (ISDN). FDA approved BiDilcI for'marketing on June 23,2005, under new drg application (NDA) 20-727.

A review of the Food and Drug Admnistration's official records indicates that BiDilOO wassubject to a regulatory review period under section 505 of the Federal Food, Drug, and CosmeticAct (FFDCA) before its commercial marketing or use. However, our review also indicates thatNDA 20-727 does not represent the first commercial marketing or use of either hydralazne orISDN. FDA has previously approved several new drgs containig these active ingredients. i

Under Title II, the term of a patent that claims a product, method of using a product, or a methodof manufactug a product can be extended. Ths extension is intended to compensate fordelayed market entry resulting from the reguatory review that must first occur for the product toreceive marketing approval. :ratent term restoration is, however, available only "with the firstpermtted commercial marketing or use of the product under the provision a/law under whichsuch regulatory review period occured: . . ." (emphasis added) (the first commercial marketingor use eligibilty requirement). For puroses of patent term restoration, hydralazine and ISDN,as active ingredients of a new drg, are each a "product.", '

, FDA has received two sets of correspondence, dated November 4, 2005, and Februar 22, 2006,from the law fi Fox Kiser, submitted on behalf of NitroMed. In this correspondence, FoxKiser assert that NitroMed may be eligible for patent term restoration even though FDA haspreviously approved new drgs that contain hydrazine and ISDN. Essentially, Fox Kiserargues that amending section 505 of the FFDCA would result in a new "provision of law" for

,~P-PJ'ovals ofNDAs for new drugs containing hydralaze occured prior to Title U'senactment in September1984, including in i 982, i 983, and May i 984.NDAs have also been approved for other new drgs containinghydrlaze and ISDN after enactment of Title II but prior to approval of BiD iI, in 1985, 1986, 1991 and 2001 forhydralazie, and in 1981, 1988, 1991, 1993, 1995, 1998, 1999,2000 and 2005 for ISDN. ' .

puroses of patent term extension and that NitroMed should, therefore, be entitled to, a patentterm extension if BiDillI was the first new drug, containg either of th~se active ingredients tobe approved subsequent to any such amendment. .We disagree. As explained more fully below, we view the term "provision of law" as referring tothe statutory provision under which the regulatory review occurs for a pariêular class of.products that is eligible for patent term restoration, regardless of whether that statutory provisionis amended. As indicated in section 156(g) of Title II, the "provision oflaw" for new drugswould be section 505 of the FFDCA; For licensed biologics, it would be section 505 of theFFDCA and section 351 of the Public Heath Service Act; for medical devices,lt would besection 515 of the FFDCA; and for new anal drgs, it would be section 512 ofthe'FFDCA.

, 'Inclusion of the phrase "under the ,provision oflaw" limits the scope of the first commercialmarketing or use eligibilty requirement. Specifically, this phrase makes patent term restoration

available only in connection with the first permitted commercial marketing or use of a product asa member of the class of products subject to regulatory review under that parcular sttutory

authònty. For example, only the first approval of an active ingredient for use in a new drg for .hwnan u~e reviewed wider section 505 of the FFDCA would .be eligible, but patent temirestoration could still be available for a patent in connection with review and approval undersection 512 of that same active ingredient for use in a new. anmal drg.

A. Relevant provisions of section 156.

Section 156(a) states, in pertinent par that:

The term of a patent which claims a product, a method of uS,ing a product, or a method of,manufactug a product shall be extended in accordance with ths section from theonginal expiration date of the patent. " . if-

'" '" '"

(4), the product has been subject to a regulatory review period before its commercialmarketig or use; (and)

(S)(A) . . . the pemiission for the commercial'marketing or use of the product after suchreguatory review penod is. the first permitted commercial marketing or use of theproduçt under the provision of law und,er wWch such reguatory review period occured;

For puroses of section 156, a "procluct" is: a food or color additive; medical device; or an activeingredient of a new dig, biological product, new anmal drg, or vetennar biologicii product. 2

2 Section i 56(t)(1) defines "product" as a "drg product," medical device, food additive, or color additive. Section. 156(f)(2) defines'''drg product" in pertinent par as:

. .. the active ingredient of--

(A) a new drg . . . human biological product (as those terms are used in the Federal Food, Drug, and CosmeticAct and the Public Health Service Act), or

(B) a new animal drg or veterinar ,biological product (as those terms are used in the Federal Food, Drug, and

2

Section 1 56(g)' defines the tenn '''regulatory review period," statingin pertinent par:

(g) For puroses of this section, the tenn "regulatory review period" has the following

meanings:

(1)(A) In th~ case of a product which is a new drg . . . or hwnan biological product. . .

(B) The regulatory review period. . . is the sum of--

(i) the period beginnng on the date an exemption under' subsection (i) of section 505 . . .

became effective for the approved product and ending on the date an application wasinitially submitted for such drg product uider section 351 (or) 505 . . . , and

(ii) the period beginng on the date the application was initially ~ubmitted for theapproved product under section 351 (or) subsection (b) of section 505 . . . 'and ending onthe date such application was approved under such section.

(3)(A) In the case of a product which. is a medical device. . .

(B) The regulatory review period for a medical device is the sum of-~

(i)' the period beginnng on the date a clinical investigation on human involving thedevice was begun and ending on the date an application was intially submitted withrespect to the device Under section 515, and

(ii) the period beging on the date an application was intially submitted with respect to

the device under section 515 and ending on the date such application was approved undersuch Act or the peri~d beginng on the date a notice of completion of a productdevelopment protocol was initially submitted under'section 515(f)(5) and ending on thedate the protocol was declared completed undersectioll 515(f)(6).

(4)(A) In the case ofa product which is a new anmal dr . ..

(B) Thedregulatory review period. . . is the sum of-~

(i) the period beginnng on, the earlier of the date a major health or environmental effectstest on the drug was initiated or the date an exemption.under subsection G) of section 512became effective for the approved new anmal drug product and ending on the date anapplication was initially'submitted for such anmal drg productunder section 512, and

(ii) the period. beging on the date the application was initially submitted for the '

Cosmetic Act and the Virus-Serum- Toxin Act) . . .

See a/so 37 CFR 1.71O(b); 21 CFR 60.3.

3

approved.an~al drg pro,du~t under subsectio? (b l 9f ~ection 5 1 ~ and en~ing on the datesuch application was approved under such, section. .',

B~ FDA's Position.

FDA believes that the use of the terr "provision of law" in section 156 is facially unambiguousand that the interpretation FDA and PTO have consistently applied to date must be applied: that"the provision of law" refers to the statutory provision wider which the regulatory review occursfor the class of products to wlúch that statutory provision applies, regardless of how thatstatutory provision may be amended. To the extent it might be argUed that section 156 is notclear on its face, FDA 'and PTO's established interpretation is, nonetheless, permissible. Thsinterpretation comports with the legislative lústorY' by allowig only one patent term extension inconnection with the approval of an active ingredjent in a new drg under section 505 (or, morebroadly, in connection with the authonzation of any "product" as a member of a paricular class ,of eligible products under the statutory provisi,on applicable to that p~icular class of products).It also fuers equitable treatment of regulated ~ntities and fosters marketplace certnty by

providing a bnght line standard. Furer, the only cour to considetthis interpretative q'uestionhas endorsed FDA and PTO's established interpretation. See Westwood Pharmaceuticals, Inc. v.

Quigg, i 989 WL 205631, 13 USPQ2d 2067 (D.D.C. 1989). . .

1. The statute is, unambiguous.

Section 156(a) states that patent term restoration is available if the approval at issue is "the firstpermitted commercial marketing or use of the product under the provision of law under whichsuch regulatory review period occured" (emphasis added). Section i 56(g) identifies thestatutory authorities ~dei which the reguatory review penod occursÎor vanous classes ofproducts for wlúch patent term restoration is available. Specifically, section 156(g) reflects thestatutory provisions under wlúch regulatory review occur: as section 505 of the FFDCA fornew drugs; as section 505 of the FFDCA and section 35 i of the Public Health Service Act forlicensed biologics; ~s section 515 of the FFDCA for medical devices; and as section 512 of the

-'FFDCA for new anmal drugs;

For the remaining classes of products eligible for patent term extension".food and color additivesand veterinary biological products--section 156(g) refers only to the statutes under which the 'regulatory review occurs--the FFDCA for food and ,color additives and the Virus-Seru- ToxinAct for vetennary biological products. However, the implementig regulations for theseprovisions of section 156(g)indicate the specific statutory provisions under which the regulatoryreview occurs. See 9 CFR 124.2 (indicating that the provision oflaw for veterinar biologicalproducts is section 102 of the Viru-Seru- Toxin Act); 21 CFR 60.3 (b)(6) (indicating that the

3 Seètion I S6(1)( 4)(A) states that "Any reference to section 3 SL is a reference to section 3S1 of the Public Health.

Service Act." ,Section IS6(1)(4)(8) states that "any reference to section S03, SOS, S12, or 515 is a reference tosection S03, SOS; S12, or SiS of the Federal Food, Drug, and Cosmetic Act."

Section lS6(g) also defines "regulatory review period" for food ard color additives and for veterinary biologicalproducts, referencing the FFDCA and the Virs-Serum-Toxins Act, respectively. without identifYing theparicular provisions of these acts under which the regulatory review for these two classes of pro duet occurs.

4

provision of law for color additives is section 721 of the FFDCA); 21 CFR 60.3(b)(9) (indicatingthat the provision of law for food additives is section 409 of the FFDCA).4 . , "

Nowhere, however, does section 156 (nor its. implementing regulations) 'suggest that amending'any of these statutory authorities renders them new provisions oflaw under which patent termextensions can be granted for products that have already undergone the regulatory reviewapplicable to that class of product. 5 Furer, a rule of statutory constrction support viewing ageneral reference such as "the provision of law" as intend,ed to refer to the law on a subjectgenerally, including as that law might be amended.6

It seems unambiguous, therefore, that the term "the provision of lawlt is intended to mean thestatutory,authority under which regulatory review occurs for a specific class of products,including any amendments tq that statutory authority. Under this interpretation, a patent

, 'extension is only granted the first time the product is approved for marketing as a member of thatspecific class of products. For example, only one patent extension could be granted in

4 Contrary to Fox Kiser's suggestion, it is not only the numeric designation ofthe statutory provision thatis

control1ing, but also the class of product statutorily regulated. For example, Section 505 is a different "provision oflaw" from Section 512 not only because the two have different numerical designations, but also because one, appliesto regulatory review of human drgs, while the other applies to regulatory review of animal drgs. See Eli Lily and

Co. v. Medtronic, Inc., 496 U.S. 661, 667, 674,15 USPQ2d i 121, i 125-26, 1128 (1990) (while making a distinctionbetween the term "law" as broadly constred and a "provision oflaw," identifying section 505 as a "provision" ofthe FFDCA under which new drugs are subject to premarket approval).

5 Fox Kiser assert that a provjsion of the Patent and Trademark Offce's 'regulations support Fox Kiser's proposed,

contrar interpretation. Specifical1y, Fox Kiser argues that the reference to "the provision oflaw" in 37 CFR 'i. 740(a)(4) support its position that an amendment constitutes, a new provision oflaw. Section 1.740(a) states inpertinent part: '

. . . A forial application for the extension of a' patent must include:

.. .,

(4) 'In the case of a drug ,product, an identification of each active ingredient in the product and as to each active'ingredient, a statement that it has not been previously approved for commercial marketing or use under theFederal Food, Drug. and Cosmetic Act, the Public Health Service Act, or the Virus-Seru-Toxin Act, or astatement of when the active ingredient was approved for commercial marketing or use (either alone or incombination with other active ingredients), the use for which it was approved, and the provision of law underwhich it was approved. (emphasis added)

Contrary to Fox Kiser's assertion, the lie of "the provision of law" in section i ,740(a)(4) need not be interpreted asindicating that amendments should be considered to produce new "provisions oflaw." Rather, section 1.740(a)(4) isreadily interpreted a,S'equiring applicants either: (I) to state that t~e active ingredients at issue have never beenapproved for marketing under any of the statutes under which approval occurs for the classes of products eligible forpatent term restoration and, therefore, that none of those active ingredients has ever been eligible for patent termrestoration, or (2) to identify any paricular provisions of law under which any of those active ingredients haspreviously been approved, so that PTO can determine for which c~asses of products any of them have been approvedand are" therefore, no longer eligible for patent extension.

6 See Panama RR. Co, v. Johnson, 264 U.S. 3'75,391-92 (1924) ("generic reference" was "readily understood" as a

reference to the Employers' Liability ACt and its amendments); see also United States v, One Big'Six Wheel, 987F.Supp. 169 (E.D,N.Y. 1997).

5

connection with åpproval of an active ingredient for use in a new drg fo'r human use. However,if, for example, that same active ingredient were subsequently approved for the fist time for usein a new anmal drug, and a second patent claimed the active ingredient for that use, pate:it term ,rest()ration c'ould be available for that second patent in connection with the anmal drg approval.

In short, inclusion of the term lithe provision of law" makes patent tern restoration available onlyin connection with the first approval qf a product as a meipber of the class of products subject toregulatory review under that paricular statutory provision. hic~usion of this term does not,serveto make previously approved members of a class of products once agai eligible for patent termextension,based upon whether the applicable statutory provision ha subsequently been amended., ,

2. The established interpretation comports with legislative intent to avoidmultiple patent term exten'sions for the same product.

,The legislative history for Title II relevant to this issue is limted. Nonetheless, it supports aninterpretation of "the provision oflawll that avoids,the same product's being eligible for multiplepatent term extensions. '

A'report considering an earlier version of section 156 that contaed the same "under theprovision of law . . ." languge U1timately encted in Title n, reflects,the House ofRepresentatives' Committee on the Judiciar's consideration, and rejection, of a proposal to granta patent term extension for each regulatory review period for a product, not just for theregulatory review period associated with the first approval of the product. The report explaithat liThe net result" of this amenâment would have been lito permt multiple patent termextensions on what was essentially the sam"e drug product.

ii HR Rep No 98-857, pt 2, at 22

(1984), reprinted in 1984 USCCAN 2686, 7. The Commttee rejected the amendment on thegrounds that patents other than the first productpatent "frequentlyll do not represent lithe samemagntude ofinn~v~tion." H.R. Rep. No. 98-857, at 8. '

This same report describes the "under the provision of law" languge as permitting" an extensionif the approval. . . is the first . . . ofthat product under an applicable Federal law.'! HR Rep No98-857, at 2706. It follows that, ,if a product had previously been approved under an applicableFederal law, no additiona patent term restoration would be available, regardless of whether thatapplicable Federal law were subsequently amended. .

FDA and PTO's established interpretation comports With this legislati\;e history because ourinterpretation makes patent term restoration available oruy in connection with tlie first marketingauthorization for a product as a member of the class of products subject to review under theparicular statutory authority. IIi,contrast, treating each amendment as generating a newprovision of law would be inconsistent with this legislative history, as such an interpretationwould make patent term extensions potentially available in connection with multiple approvalsof the same product.

6

3. The established interpretation prevents inequitable treatment of applicants and

fosters marketplace certainty.

Granting a patent term extension to one product but not another due to the timing of anamendment to the statutory authority under which the product is reviewed would be inequitable,1and such a practice would undermine marketplace certinty. '

If, for example, applicant A has been granted a patent for a use of an active ingredient, andapplicant B has also been granted a patent for another use of the same active ingredient, we seeno sound policy grounds for makg one of these applicants, but not the other, eligible for patentterm restoration because of the timing of a. legislative amendment. As the plain languageindicates and the legislative history reflects, we believe Congress intended to distinguish onlybetween the first approval and subsequent approvals of a product as a member of a paricularclass of regulated products, having judged that patents associated with'the first approval of aproduct as a member of such ~ class likely reflect the most iriovative developments.

In addition, unlike Fox Kiser's proposed interpretation, the curent, long-standing interpretationis straight-forward and predictable. It has resulted in litigation only once, over 17 years ago, andthe cour upheld our interpretation: In cnntrast, applying Fox Kiser's proposed interpretationwould produce 'marketplace uncertinty and spark additional litigation.

Most basically, if eligibilty for patent term restoration were dependent upon the timing ofstatutory amendments, it would be impossible to predict with certty the availabilty of patent

term extensions for patents relating to subsequent applications for previously approved products.Eligibilty would depend on whether an amendment happens to occur during the review of thatsubsequent application and,whether that application then happèns to be the first- approvedfollowing that amendment. ', ,'Fox Kiser argues that circumstaces under which its interpretation would come into play wouldarse rarely and affect few pharaceuticals. However, section 505 alone of the FFDCAhas, for.example, been' amendéd four times since enactment of Title II in 1984. The FFDCA has beenamended seventeen times over this same' time' period, and Congress regularly considers new bilsto amend the FFDCA. Under Fox Kiser's interpretation, patent term restoration might be 'available in coimection with approval of any previously approved product every time anamendment occurs to the statutory authority under which a prior reguatory review occured forthat product.

1 Fox Kiser argues that failure to treat amendments to these statutory authorities as new provisions of law would

somehow unfairly har those applicants for whom regulatory review occurs after such an amendment. Wedisagree. For example, if section 505 were' amended in such a maner. that the'time needed for regulatory review 'would increase (or decrease), the regulatory review period could expand (or contract) accordingly. See 35 USCI 56(g)( I). As a consequence, an applicant eligible for patent term restoration after such an amendment couldreceive a commensurately lengtened (or shortened) extension of its patent. In short, such amendments could affectthe length of the patent restoration, though not its availabilty, consistent with the apparent legislative intent forsection 156,

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Furer, Fox Kiser's interpretation raises additional interpretive questions thãt will serve only toincrease uncertinty and litigation. For example, Fox Kiser argues that only non-techncal 'modifications should trigger renewed ellgibilty for patent tenn restoration. Another applicantmight be expected to disagree. And this question is just one of many that could arse concernngwhether an amendment should be considered to have had a meangful effect on the reguhitoryreview process. For example, it might be debated whether the amendment was made to arelevant section of the statutory authority and, if so, whether the change: had a significant effecton the review standards and/or tiing.8

4. The established interpretation has been upheld by the courts.

In WestwoodPhqrmaceuticals (1989 WI 205631), a district cour for the District of ColumbiaCircuit addressed the precise interpretative question at issue here: whether an amendment ofsection 505 ofthe FFDCA results in a new "provision oflaw" under which patent termrestoration becomes available again for an active ingredient previoui)lY apprôved under section505 prior to the amendment. The cour upheld FDA's determination that an amendment ofsection 505 does not produce a new provision of law for puroses of patent tenn restorationeligibiIity. "

, Fox Kiser argues thatthe cour gave undue deference to the agency's interpretation. It claimsthat the cour should have applied the review stadard ariculated in Chevron u.s.A., Inc. v.Natural Resources Defense Counçi/, Inc., 461 U.S. 837 (1984).9 It argues that, 'in accordancewith that stadard, the coùr should have: found that the statutory language unambiguously, ,establishes that an amendment produces a new provision of law; given no deference to FDA'scontry interpretation as a result; and rued in favor of Westwood.

8 Another interpretative question. present~d by BìDil and other previously approved ,hydralazine and ISDN products,

. might arse as follows: The regulatory review periods for BìDil and other hydrlaze and ISDN products occuredsubsequent to multiple amendments to section 505. The'egulatory review period for BiDil, for ex~ple, occtied

from April i; i 993, through, June 23, 2005. Consequently, this review spaned four amendments to section 505 (in1997, 1999,2002, and 2003). Ths might raise the interpretive question ç¡fwhetheran applicant could be eligible formultiple patent term extensions relating to the same appljcation if the application is the fist approved for thatproduct subsequent to multiple amendments to the statutory authority under which the review ofthat applicationocciued. .9 Under Chevron, when a cour is reviewing an agency's constrction of a statutory provision, the first step is to

detennine whether Congress has spoken to the precise question at ~ssue. To the extnt there exists any ambiguity inthe statutory language, the court must uphoid the agency's interpretation if that constrction is pennssible under thestatute; the court need not conclude that the agency's constrction was the only permissible one, or that the court\yould have selected the same constrction. As detailed aboye, to the extent that the statutory language of sectioni 56 is ambiguous, FDA and PTO's long-stading interpretation is clearly permissible; it is consistent with thestatutory language and comports with the legilative history, as well as fuhers sound policy'goals.

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IUs tre that the cour deferred to 'the agency's inteipretati,on. However, Fox Kiser fails to notethat the cour also concluded that the agency's interpretation "is,consistent wjth the statutórylanguage and with the legislative history associated with ths provision." Westwood; 1989 WL205631, "'3. In short, the only cour to address ths interpretive question expressly endorsed theagency's statutory' constction.' '

C. Conclusion.

For all the reasons stated above, we conclude that an amendment made to section 505 of theFFDCA, or any other statutory authority under which regulatory review occurs for a class ofproducts eligible for patent term restoration; does not produce a new "provision of law" forpuroses of eligibilty for patent term res~oration under 35 USC 156. Therefore, since new drugs'containg hydralaze and ISDN have previously been reviewed and approved by FDA under

section 505, BiDilGD is not eligible for patent term restoration.

Sincerely,

..~,a~e -A. Axeira~, Associate Director for Policy

Center for Drug Evaluation and'Research

ap.

cc: Diane Robertson, Fox' Kiser

,Matt Peterson, Fox Kiser750 17th Street, N.W., Suite 1100

'Washington, DC 20006

Michael Sabolinski, M.D.Senior Vice PresidentClinical Development and Reguatory Affairs.NitroMed, Inc.125 Spring Street

, Lexington, MA 02421

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