PTO Clarifies PTE Availability in Post-PhotoCure and Post-Ortho-McNeil World; PhotoCure Takes Advantage of . . . . PhotoCure

By Kurt R. Karst –      

In a series of letters, the U.S. Patent and Trademark Office (“PTO”) has clarified when patents covering certain drug products are eligible for a Patent Term Extension (“PTE”).  The PTO issued the letters as a result of recent decisions from the U.S. Court of Appeals for the Federal Circuit in PhotoCure v. Kappos, 603 F.3d 1372 (Fed. Cir. 2010) and Ortho-McNeil Pharm., Inc. v. Lupin Pharms., Inc., 603 F.3d 1377 (Fed. Cir. 2010).  Both decisions (here and here) were issued on May 10, 2010 and concern the proper interpretation of 35 U.S.C. § 156(a)(5)(A), which states that the term of a patent claiming a drug shall be extended from the original expiration date of the patent if, among other things, “the permission for the commercial marketing or use of the product . . . is the first permitted commercial marketing or use of the product under the provision of law under which such regulatory review period occurred.” 

The term “product” at 35 U.S.C. § 156(a)(5)(A) is defined at 35 U.S.C. 156(f)(2) to mean, in relevant part, “the active ingredient of – a new drug, antibiotic drug, or human biological product . . . including any salt or ester of the active ingredient, as a single entity or in combination with another active ingredient.”  (The term “active ingredient” is defined in FDA’s regulations to mean “any component that is intended to furnish pharmacological activity or other direct effect in the diagnosis, cure, mitigation, treatment, or prevention of disease, or to affect the structure of any function of the body of man or of animals.”) 

For several years, the PTO interpreted the term “product” in 35 U.S.C. § 156(a)(5)(A) to mean “active moiety” (i.e., the molecule in a drug product responsible for pharmacological action, regardless of whether the active moiety is formulated as a salt, ester, or other non-covalent derivative) rather than “active ingredient” (i.e., the active ingredient physically found in the drug product, which would include any salt, ester, or other non-covalent derivative of the active ingredient physically found in the drug product).  In contrast, the Federal Circuit’s 1990 decision in Glaxo Operations UK Ltd. v. Quigg, 894 F.2d 392 (Fed. Cir. 1990) (“Glaxo II”), which affirmed a 1989 district court decision in Glaxo v. Quigg, 706 F. Supp 1224 (E.D. Va. 1989) (“Glaxo I”), construed the term “product” in 35 U.S.C. § 156(a)(5)(A) to mean “active ingredient.”  The Federal Circuit’s May 2010 decisions in PhotoCure and Ortho-McNeil ruled that the Glaxo II decision and its “active ingredient” interpretation of the PTE statute should be applied for PTE purposes.  The Federal Circuit also pointed out that according to the Court’s 1997 decision in Hoechst-Roussel Pharms. Inc. v. Lehman, 109 F.3d 756 (Fed. Cir. 1997), “[f]or purposes of patent term extension, [the] active ingredient must be present in the drug product when administered.”

PhotoCure stems from the PTO’s denial of a PTE for U.S. Patent No. 6,034,267 (“the ‘267 patent”) covering the drug product METVIXIA (methyl aminoevulinate HCl).  Applying the active moiety interpretation of the law, the PTO determined that METVIXIA, a prodrug, did not represent the first permitted commercial marketing or use of the product because of FDA’s previous approval of an NDA for Dusa Pharmaceuticals Inc.’s LEVULAN KERASTICK (aminolevulinic acid HCl) Topical Solution, which contains the active moiety aminolevulinic acid (“ALA”).  Thus, according to the PTO, METVIXIA did not represent the first permitted commercial marketing or use of ALA and the ‘267 patent was ineligible for a PTE.

Given the Federal Circuit’s May 2010 decision that an “active ingredient” interpretation instead of an “active moiety” interpretation of the PTE statute should be applied for PTE purposes, the PTO recently issued a letter stating that the ‘267 patent is eligible for a PTE.  The PTO’s letter states, in part, that:

Applying the Hoeschet [sic] and Glaxo I analyses here, the active ingredient of Metvixia is methyl aminolevulinate hydrochloride.  Neither it, nor any salt or ester of methyl aminolevulinate hydrochloride has been previously approved by FDA.  Because no salt or ester of methyl aminolevulinate hydrochloride had been approved prior to the approval of Metvixia, the grant of permission to commercially market or use Metvixia is the first permitted commercial marketing or use of the product/active ingredient as required by section 156(a)(5)(A).  Accordingly, the ‘267 patent is eligible for extension under the provisions of section 156.

The PTO issued a similar letter with respect to a PTE application for U.S. Patent No. 5,362,718 covering TORISEL (temsirolimus).  In that letter, which is substantially similar to the letter concerning the '267 patent, the PTO emphasizes that the order of drug product approval is important, stating, in relevant part with respect to PhotoCure, that "the requirement in section 156(a)(5)(A) that the permission for the commercial marketing or use of the product claimed in the patent must be the first permitted commercial marketing or use was met where a drug substance, formulated as an ester (Metvixia), is approved after an approval of the same drug substance formulated as a salt (Levulan)."

The PhotoCure decision applying an “active ingredient” interpretation to 35 U.S.C. § 156(a)(5)(A) (and 35 U.S.C. 156(f)(2)) means that more patents may be eligible for a PTE.  And, in fact, PhotoCure, is already taking advantage of the Federal Circuit’s decision.  The company recently requested a PTE for U.S. Patent No. 7,348,361 (“the ‘361 patent”) covering CYSVIEW, which contains the active ingredient hexaminolevulinate HCl.  Pre-PhotoCure, the ‘361 patent presumably would not have qualified for a PTE. 

(Interestingly, in a recent decision from the U.S. Court of Appeals for the District of Columbia Circuit concerning the availability of New Chemical Entity (“NCE”) exclusivity, the Court notes the PhotoCure decision and comments that “the Federal Circuit has held that ‘active ingredient’ has a plain meaning that, if adopted, would allow more prodrugs to attain five-year exclusivity than the FDA’s current interpretation.”  FDA has as stated – in the preamble to the Agency’s 1989 proposed regulations implementing the Hatch-Waxman Amendments – that “[a] compound (other than an ester) that requires metabolic conversion to produce an already approved active moiety is considered a ‘new molecular entity,’ . . . and will be considered a new chemical entity entitled to 5 years of exclusivity.”) 

The Federal Circuit’s PhotoCure decision also contains dicta to the effect that the ‘267 patent is eligible for a PTE because “[methyl aminoevulinate] hydrochloride is a different chemical compound from ALA hydrochloride, and it is not disputed that they differ in their biological properties, warranting separate patenting and separate regulatory approval, although their chemical structure is similar.”  Sounds like an interesting basis on which to request a PTE for a drug product containing a previously approved active ingredient.  (And, in fact, we’ll be tackling that issue soon, because such a request has already been made to the PTO.)

Ortho-McNeil stems from the PTO’s decision to grant a PTE with respect to U.S. Patent No. 5,053,407 (“the ‘407 patent”) covering Ortho McNeil’s LEVAQUIN (levofloxacin).  Levofloxacin is an enantiomer in the previously approved Ortho racemate drug product FLOXIN (ofloxacin).  Lupin initially challenged the ‘407 patent PTE in the context of ANDA Paragraph IV Certification patent infringement litigation on the grounds that the PTE is invalid because FDA previously approved the active ingredient levofloxacin when the Agency approved the racemate ofloxacin.  In upholding the validity of the PTE for the ‘407 patent, the Federal Circuit concluded that “the enantiomer [levofloxacin] is a different drug product from the racemate ofloxacin. . . .”  (In July 2010, the Federal Circuit denied Lupin’s Petition for Rehearing en banc.)

Now that the Federal Circuit has affirmed the PTO’s position with respect to PTE availability for a patent covering an enantiomer in a previously approved racemate, the PTO is apparently clearing its docket of old PTE requests that could have been affected by the Federal Circuit’s decision.  For example, in one letter concerning a 2006 PTE application for U.S. Patent No. 6,589,508 covering BROVANA (arformoterol tartrate), which contains an enantiomer in the previously approved racemate FORADIL (formoterol fumarate), the PTO stated:

The USPTO maintains that a patent which claims an enantiomer, which was subject to regulatory review before FDA before its commercial marketing or use, is eligible for extension even if a racemate having the same chemical formula had been previously approved.  That is, the approval of a racemate does not exhaust patent term extension for either an R or S enantiomer of the racemate. . . .  In accordance with the holding of Ortho-McNeil Pharm., Inc. v Lupin Pharms., Inc., it is the position oft he USPTO that the patent claiming a method of using arformoterol (Brovana®) is eligible for patent term extension since the approval of Brovana® complies with the requirement of section 156(a)(5)(A).

As we previously commented, the PTO’s position, as affirmed by the Federal Circuit, leaves standing an interesting dichotomy with respect to the treatment of single enantiomers in previously approved racemates insofar as the availability of PTEs and NCE exclusivity are concerned.  Notwithstanding FDC Act § 505(u), which permits the sponsor of an NDA for an enantiomer that is contained in a previously approved racemic mixture to “elect to have the single enantiomer not be considered the same active ingredient as that contained in the approved racemic drug” (and thus be eligible for NCE exclusivity), FDA has for decades treated single enantiomers of previously approved racemates as previously approved drugs not eligible for 5-year NCE exclusivity (but eligible for three-year new clinical investigation exclusivity).