Under the Hatch-Waxman Act, a patent term extension is permitted for a patent that claims a drug that required regulatory approval prior to being put on the market (the Drug Price Competition and Patent Term Restoration Act, codified in part at 35 U.S.C. § 156 et seq.).

The district court agreed with the positions of the Patent and Trademark Office and the FDA, and held that the statutory requirements for term extension were met for the ’407 patent. The court then prevented Lupin Pharmaceuticals from making and selling the drug during the extended term of the patent. Needless to say, Lupin was crestfallen and appealed but the US Court of Appeals for the Federal Circuit affirmed the district court’s judgment in Ortho-McNeil Pharma v. Lupin Pharma (09-1362).

The ’407 patent is for an antimicrobial compound having the common name levofloxacin. Levofloxacin is the levorotatory enantiomer (also designated the S(-) enantiomer) of the racemate ofloxacin, which is a known antimicrobial product. A racemate consists of equal amounts of spatial isomers called enantiomers, molecules that are mirror images of each other.

Due to their spatial orientation, enantiomers are optically active and are characterized by whether they rotate plane-polarized light clockwise (dextrorotatory) or counter-clockwise (levorotatory). Although enantiomers and their racemates have the same chemical composition, they may differ in their physical, chemical, or biological properties. It is often the case that one of the enantiomers possesses a substantially greater portion, if not all, of the biological activity of the racemic mixture. This raises the question of the status of separated enantiomers as “new drug products” and whether they can be “first commercial marketing or use” if the racemate has previously been granted market approval, pursuant to 35 U.S.C. § 156(a)(5)(A).

The inventors determined that levofloxacin has properties that are significantly superior to those of ofloxacin. The ’407 patent describes this synthesis, and presents data showing that levofloxacin is more effective as an antimicrobial agent, more rapidly available for biological effectiveness, and has lower acute toxicity and thus may be administered in higher doses than ofloxacin.

The PTO concluded that extension of the patent term was warranted, and the PTO and FDA collaborated in calculation of the applicable extension of 810 days, in accordance with §156(d)(2)(A). Lupin the tried to block the extension under 21 U.S.C. §355(j)(2)(A)(vii)(IV) (Paragraph IV certification).

The law, in 35 U.S.C. §156(a), states that:

The term of a patent which claims a product, a method of using a product, or a method of manufacturing a product shall be extended in accordance with this section . . . , if– . . . (a)(4) the product has been subject to a regulatory review period before its commercial marketing or use; (a)(5)(A) except as provided in subparagraph (B) or (C) [not here relevant], the permission for the commercial marketing or use of the product after such regulatory review period 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 “drug product” means the active ingredient of (A) a new drug, antibiotic drug, or human biological product (as those terms are used in the Federal Food, Drug, and Cosmetic Act and the Public Health Service Act), . . . including any salt or ester of the active ingredient, as a single entity or in combination with another active ingredient.

The issue was whether this was the first permitted commercial marketing or use of levofloxacin, as required by 35 U.S.C. §156(a)(5)(A), for the racemate had previously been marketed. The district court held that the extension was in conformity with the practices of the PTO and the FDA with respect to enantiomers, and that the PTO’s determination that levofloxacin is a different “product” than the racemate ofloxacin must be afforded “great deference.”

Lupin argued that the PTO and the FDA incorrectly interpreted the statute as far as enantiomers are concerned. Lupin insisted that an enantiomer is half of its racemate, and thus that the enantiomer levofloxacin was an “active ingredient” or component of the previously marketed racemate ofloxacin. That is, the racemate was merely a composition containing two drugs: the R and the S enantiomers. Thus, levofloxacin is the same “drug product” as ofloxacin meaning that levofloxacin was not “the first permitted commercial marketing or use of the product” as required by §156(a)(5)(A).

Ortho countered that an enantiomer has consistently been recognized, by the FDA and the PTO, as a different “drug product” from its racemate. The FDA practices were explained by Dr. David Lin, a former acting Division Director in the FDA’s Division of New Drug Chemistry, declaring that “in each and every instance in which it has considered the question, the FDA has described a racemate as a single active ingredient, distinct from its enantiomers, and each enantiomer as a single active ingredient distinct from the other and from the racemate.”

Lupin tried arguing that the status of enantiomers with was legislatively changed in 2007, in the statute that changed the FDA policy concerning data exclusivity for new enantiomer products. 21 U.S.C. §355(u)(1) (Supp. II 2008). The new provision authorizes an applicant “for a non-racemic drug containing as an active ingredient (including any ester or salt of the active ingredient) a single enantiomer that is contained in a racemic drug approved in another application” to, under certain conditions, “elect to have the single enantiomer not be considered the same active ingredient as that contained in the approved racemic drug.” Lupin felt that by specifically allowing an applicant to “elect” this separate treatment for enantiomers, Congress expressed its understanding that enantiomers were the same active ingredient as the racemate for all other purposes, including patent term extension.

The Federal Circuit said it couldn’t find any support for this theory in the legislative record, or elsewhere and affirmed the district court’s ruling that the ’407 patent on levofloxacin was properly granted the statutory term extension, for the enantiomer is a different drug product from the racemate ofloxacin, and was subject to regulatory approval before it could be commercially marketed and used.

This case clarifies that separate enantiomers can obtain independent patent protection and be entitled to patent term extension for “first commercial marketing or use” as new drug products. However, the Federal Circuit has said that patents for separated enantiomers can be invalidated on obviousness grounds.  So, pharmaceutical companies that can show (very?) good reasons that separation of enantiomers was not obvious can look forward to a much longer patent term – for now.

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Consumer Reports

While patients have spent about $286 billion on prescription drugs in 2007 alone, about 75 percent of it on brand-name products, drug makers spent about $5.4 billion in 2007 on advertising medicines.  The companies also spend about $15 to $20 billion annually on trade journal advertising and other outreach including in-person sales calls, professional symposia and gifts to spread their message to doctors, pharmacists, benefit managers, and others.

You can stop by and pick up a copy of their latest publication, Best Drugs for Less or learn about Best Drugs for Less online. Best Drugs for Less is supposed to provide “unbiased, independent evaluations to help people choose medicines that are safe, effective, and affordable.”  The magazine is aimed at helping patients and doctors cut through the clutter of drug advertising so they can make informed decisions about their medications.

You can also check out their list of 10 ways to reduce your drug costs.

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The Patent Office has now finished those proceedings dealing with Genentech’s Cabilly patent under concurrent proceedings for an Inter Partes Reexamination (RE Appl. No. 90/007,542) and an Ex Parte Reexamination (RE Appl. No. 90/007,859).  While an earlier ruling by the Office declared the the claims invalid as being anticipated under various earlier patents and references, the Patent Office has now issued a Notice of Intent to Issue a Reexamination Certificate (NIRC) confirming the patentability of all claims of the Cabilly patent.  A fancy way of saying that the claims are good to go.

Note, during the reexamination process, Genentech did amend claims 21 through 32 but claims that there were amended in a way that does not affect the commercial viability of the patent. More importantly, this decision by the Patent Office is final and unappealable.

The Notice set out that the invention is for a method for producing an immunologically functional immunoglobulin molecule or an immunologically functional immunoglobulin fragment by transforming a single host cell with a first DNA sequence encoding immunoglobulin heavy chain and a second DNA sequence encoding immunoglobulin light chain and independently expressing the first DNA sequence and second DNA sequence so that said immunoglobulin heavy chain and light chain are produced as separate molecules in said transformed single host cell.

Based on the prosecution history of the patent at issue, and the interference record from Interference No. 102,572, the Examiner determined that the term “immunoglobulin molecule” in claims 1 and 33 is considered to be an immunologically functional molecule and capable of binding to a known antigen.

The following is an examiner’s statement of reasons for patentability and/or confirmation of the claims found patentable in this reexamination proceeding:

The combination of the Cabilly I patent claims and the teachings of Axel, Rice, Kaplan, Builder, Accolla, Dallas, Moore patent, Deacon and Valle and Ochi references do not suggest or contain an enabling disclosure of a method to produce an immunologically functional immunoglobulin molecule by independently expressing immunoglobulin heavy chain and light chain in a single transformed host cell.

Claims 1-20, 33-36 are confirmed and amended claims 21-32 are allowed.

Genentech’s controversial patent will not expire now until the end of 2018, an expiration date that is over 29 years after the Cabilly I patent issued.  While we don’t know the details of the final settlement, I imagine that MedImmune is probably feeling pretty good right about now that they didn’t breach their license in order to bring their earlier action contesting the patents.

See the Patent Office documents here:

Notice of Intent to Issue a Reexamination Certificate
Notice of Intent to Issue a Reexamination Certificate

Earlier:

MedImmune and Genentech Settle, Lawyers Look For New Topic of Discussion
USPTO Smacks Down Genentech’s Antibody Patent
Supreme Court High-Fives MedImmune

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The Hatch-Waxman Act requires a pioneer drug manufacturer to notify the FDA of all patents that “claim[ ] the drug for which the [NDA] applicant submitted the application.”  The FDA lists the patents in its Approved Drug Products With Therapeutic Equivalence Evaluations (Orange Book).  Under the law, a generic manufacturer infringes a patent by filing an ANDA to obtain approval for a generic drug product claimed by a valid and unexpired patent.

In this case, Lilly holds the approved NDA for raloxifene hydrochloride tablets, which is marketed under the brand name Evista® for the treatment and prevention of postmenopausal osteoporosis.  Lilly lists twelve patents that claim Evista® in the Orange Book.

Teva filed an ANDA with the FDA to get approval to manufacture and market generic raloxifene filing paragraph IV certifications, i.e., a patent is invalid or will not be infringed.  Lilly sued Teva for infringement of four method patents listed in the Orange Book: U.S. Patent Nos. RE38,968, RE39,049, RE39,050, and 6,906,086.  The FDA gave a 30 month stay on approval from the date that Lilly received Teva’s paragraph IV notifications, expiring on November 16, 2008.

Lilly later amended its complaint to assert that Teva infringed three additional Evista® patents—U.S. Patent Nos. 6,458,811, 6,797,719, and 6,894,064—covering raloxifene particle size and formulation.

On July 8, 2008, Teva amended its ANDA to include a new particle-size measuring methodology for the active pharmaceutical ingredient in its proposed raloxifene tablets.    Teva disclosed this amendment to Lilly on July 10, 2008, and provided it three batch samples on July 28, August 19, and September 17, 2008.  The district court, however, previously set a discovery deadline of August 18, 2008.  Teva allegedly began changing its particle-size measuring methodology as early as November 2007 with the goal of avoiding infringement of Lilly’s asserted patents.

Lilly asked the district court to extend the statutory thirty-month stay due to Teva’s alleged discovery violations, which extended the stay from the original November 16, 2008, until the beginning of trial on March 9, 2009.

The U.S. District Court found that Teva had “recast its product more than eighteen months after it provided the original sample to Lilly and only eight months before trial is set to commence.”

Teva appealed.

The Court of Appeals upheld the extension saying that the district court acted within its discretion in this area and it has the discretion to adjust the statutory thirty-month stay of ANDAs if “either party to the action failed to reasonably cooperate in expediting the action.”  Trial courts may shorten or extend the thirty-month statutory period based on the parties’ uncooperative discovery practices.

Take-Home Lesson:  Don’t mess around in turning over materials in discovery.  It will cost you dearly.  Think two weeks is not much to fuss over?  Think again.  Last year, Eli Lilly reported sales of Evista® of $1,075,600,000.  That works out to over $41 million for a mere two weeks of exclusive sales.

—————————-

Note that Circuit Judge Prost, disagreed with the majority saying “[t]he thirty-month stay … may be extended for one reason and one reason only:  “because either party to the action failed to reasonably cooperate in expediting the action.”

Although Teva did not complete production until September 5, 2008, the court did not purport to base any finding that Teva “failed to reasonably cooperate in expediting the action” on this eighteen-day delay. …  Not once in this order did the court indicate, much less unambiguously state, that it found Teva had failed to reasonably cooperate in expediting the action.

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Clopidogrel is the common name of the dextrorotatory isomer of the chemical compound named methyl alpha-5(4,5,6,7-tetrahydro(3,2-c)thienopyridyl)(2-chlorophenyl) -acetate.  The product has the property of inhibiting the aggregation of blood platelets, and is used to treat or prevent blood-thrombotic events such as heart attacks and strokes.  Claim 3 of the patent is for:

Hydrogen sulfate of the dextro-rotatory isomer of methyl alpha-5(4,5,6,7-tetrahydro(3,2-c)thienopyridyl)(2-chlorophenyl)-acetate substantially separated from the levo-rotatory isomer.

Sanofi sued after Apotex filed an Abbreviated New Drug Application (ANDA) for FDA approval to sell clopidogrel bisulfate, along with a paragraph IV certification that the ’265 patent is invalid.  A proposed settlement fell apart, the statutory stay expired, the FDA approved the Apotex ANDA, and Apotex starting selling its generic clopidogrel bisulfate product.

Sanofi then moved for a preliminary injunction, noting that infringement was conceded by Apotex.  The district court found that Sanofi was likely to succeed on the merits of the validity and enforceability of the ’265 patent, granting the injunction.  The Court of Appeals for the Federal Circuit affirmed the district court’s rulings and sent it back so that the district court could review all aspects at trial and the district court ruled that the ’265 patent is valid and enforceable.

This appeal is focused on the question of patentability of this dextrorotatory isomer in view of its known racemate described in earlier Sanofi patents, specifically, Sanofi’s US Pat. No. 4,529,596 and Canadian Pat. No. 1,194,875.  Both reference patents are derived from the same French priority filing and are prior art against the ’265 patent.

Sanofi discovered that certain compounds of the class known as thienopyridines (compounds having a thiene ring fused to a pyridine ring) have the property of inhibiting blood platelet aggregation.  Sanofi initially synthesized and evaluated several hundred chemical modifications and derivatives of thienopyridines, seeking optimum anti-platelet aggregation properties with minimal undesirable effects.

They eventually selected for development the compound  “ticlopidine.”  After development, ticlopidine was approved in the US for use as an anti-thrombotic agent.  This was approved but had possible adverse effects of rarely occurring but serious blood disorders, neutropenia and thrombotic thrombocytopenic purpura, associated with prolonged usage of ticlopidine.

Sanofi then synthesized and evaluated several hundred additional thienopyridine derivatives, including a class of compounds having the following general structure, wherein one of the hydrogen atoms on the bridge carbon atom (marked with an asterisk), is replaced with an ester, carboxylic acid, or amide group.  This class is the subject of the ’596 patent (and the counterpart Canadian ’875 patent), and had good anti–platelet aggregation properties.

Focusing on the ’596 patent, the specification includes twenty-one examples of specific compounds, including a compound designated as PCR 4099.  This compound has the chemical name methyl alpha-5(4,5,6,7-tetrahydro(3,2-c)thieno pyridyl)(2-chlorophenyl)-acetate, with the acronym MATTPCA.  PCR 4099 as the hydrochloride salt was selected for commercial development as a potential replacement for ticlopidine in light of its improved platelet inhibition and toxicity profile.

However, PCR 4099 still raised toxicity concerns, for at very high doses it caused convulsions in laboratory animals.  Thus the research efforts continued, concurrently with the clinical and commercial development of PCR 4099.  Sanofi states that about 1500 compounds in this general class were synthesized, of which about 600, including PCR 4099, were chiral thienopyridines.

Enantiomers are spatial isomers, also called stereoisomers, identified and distinguished by their optical characteristics when a purified solution of the separated isomers is exposed to plane-polarized light.  Enantiomers generally are formed in equal amounts, to produce what is called a racemate; the racemate is optically neutral.

Believing that there was no advantage to separation of the enantiomers of thienopyridines, and no other racemates were separated until November 1985 when Sanofi then determined the biological properties of the enantiomers of PCR 4099, and found that they had the rare characteristic of “absolute stereoselectivity”: the dextrorotatory enantiomer provided all of the favorable antiplatelet activity but with no significant neurotoxicity, while the levorotatory enantiomer produced no antiplatelet activity but virtually all of the neurotoxicity.  This kind of stereoselectivity is rare.

Sanofi filed a patent application directed to clopidogrel and certain salts and pharmaceutical compositions.  The ’265 specification explains that the racemate of the same chemical formula was described in the earlier French ’247 patent, which corresponds to the earlier U.S. ’596 patent.  The ’265 patent discusses the unusual stereoselectivity of the biological properties as between the dextrorotatory and the levorotatory enantiomers.  The US patent examiner, who had also examined the ’596 patent, allowed the claims after requiring that the ’265 claims make clear that the dextro- and levo- enantiomers are “substantially separated.”

Apotex appealed on the issues of anticipation and obviousness.

Claimed subject matter is “anticipated” when it is not new; that is, when it was previously known.  Invalidation on this ground requires that every element and limitation of the claim was previously described in a single prior art reference, either expressly or inherently, so as to place a person of ordinary skill in possession of the invention.

Apotex argued that the reference shows the specific racemate PCR 4099 and states that the compounds in the reference have enantiomers and that the enantiomers are included in the invention.  Apotex claimed that the properties of the enantiomers of PCR 4099 are inherently and necessarily present in its known racemate, such that when the enantiomers are separated the previously observed properties are “immediately recognized” in one or the other enantiomer.

The question hinged on whether a generic disclosure necessarily anticipates everything within the genus, and recognized that the answer depends on the factual aspects of the specific disclosure and the particular products at issue.  In this case the district court said the references’ general statements that these compounds consist of enantiomers didn’t make an anticipating disclosure of the separated dextrorotatory enantiomer of PCR 4099.

Apotex also tried arguing that although the reference did not state that the disclosed compound was a racemate, it would have been known to one of ordinary skill that synthetically produced chiral compounds are racemic.

This was knocked down:

The district court did not clearly err in finding that the statements in the ’596 patent and its Canadian counterpart that the products therein consist of enantiomers are not a description of the specific dextrorotatory enantiomer clopidogrel or a suggestion of its unusual stereospecific properties.  The knowledge that enantiomers may be separated is not “anticipation” of a specific enantiomer that has not been separated, identified, and characterized.  The district court correctly held that neither the ’596 patent nor its Canadian counterpart contains an anticipating disclosure of the subject matter of claim 3 of the ’265 patent.

The court also looked at the question of obviousness.  For chemical compounds, the structure of the compound and its properties are inseparable considerations in the obviousness determination.  Previous case law established that when dealing with analytical procedures where there is a close structural similarity between a new chemical compound and prior art compounds, it is generally deemed to create a prima facie case of obviousness, shifting to the patentee the burden of coming forward with evidence of nonobviousness.

Apotex argued that the recognition in the prior art that PCR 4099 is composed of enantiomers outweighs the effect of any unexpected or unpredictable properties of the separated dextrorotatory enantiomer.

The court also shot this down:

The determination of obviousness is dependent on the facts of each case.  See Graham, 383 U.S. at 17-18.  In Forest Laboratories, 501 F.3d at 1269, this court affirmed that the (+) enantiomer of citalopram would not have been obvious in light of the known racemate, when it was shown that the therapeutic properties of the (+) enantiomer were unexpected.  In contrast, in Aventis Pharma Deutschland GmbH v. Lupin, Ltd. 499 F.3d 1293, 1302 (Fed. Cir. 2007), this court held that the ramipril isomer’s potency was “precisely what one would expect, as compared to a mixture containing other, inert or near-inert stereoisomers.”  Apotex argues that Aventis is the closer analogy, but the evidence was directly contrary to that position.  The district court entered extensive findings in this case on the unexpected and unpredictable properties of clopidogrel, and there was no contrary evidence suggesting, based on the prior art, that the stereoselective properties were “precisely what one would expect,” as in Aventis.

Update:  As noted in the comments, Teflon® is a brand of poly(tetrafluoroethylene) or poly(tetrafluoroethene) (PTFE), a synthetic fluoropolymer used as a non-stick coating for pans and other cookware, and is registered trademark of E. I. du Pont de Nemours and Company.

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