Today, I gave a webinar presentation with Ken Phelps, President of Camargo Pharmaceutical Services, on the interaction of patents and exclusivity of drugs approved by the FDA under section 505(b)(2). Ken is an expert at 505(b)(2) filings so my job (covering patent issues) was pretty easy.

Ken notes that large pharma and small start-ups alike are keenly interested in these filings with no signs of letting up. It’s not hard to see why. Section section 505(b)(2) drug applications find a unique (although often neglected) place between innovative drug NDAs and and the generic ANDAs.

Section 505 of the Federal Food, Drug, and Cosmetic Act describes three basic types of new drug applications:

1. an application that contains full investigations of safety and effectiveness (section 505(b)(1));
2. an application that contains full investigations of safety and effectiveness but where at least some of the information required for approval comes from studies not conducted by or for the applicant and for which the applicant has not obtained a right of reference (section 505(b)(2)); and
3. an application that contains information to show that the proposed product is identical in active ingredient, dosage form, strength, route of administration, labeling, quality, performance characteristics, and intended use, among other things, to a previously approved product (section 505(j)).

An important benefit of 505(b)(2) applications compared to Abbreviated New Drug Applications (ANDAs) is the ability to earn market exclusivity. Like ANDAs, 505(b)(2) submissions must include all relevant patents and patent certifications and are subject to the same Paragraph IV challenges and litigation, including a 30-month stay. However, 180-day exclusivity is not granted.

So, what type of information can an applicant rely on?

1. Published literature (a literature-based 505(b)(2)). If the applicant has not obtained a right of reference to the raw data underlying the published study or studies, the application is a 505(b)(2) application; if the applicant obtains a right of reference to the raw data, the application may be a full NDA (i.e., one submitted under section 505(b)(1)).

2. The Agency’s finding of safety and effectiveness for an approved drug to the extent such reliance would be permitted under the generic drug approval provisions at section 505(j). This approach is intended to encourage innovation in drug development without requiring duplicative studies to demonstrate what is already known about a drug while protecting the patent and exclusivity rights for the approved drug.

What kind of application can be submitted as a 505(b)(2) application? The applications are for either (a) new chemical entity (NCE)/new molecular entity (NME) or (b) changes to previously approved drugs — changes of the type described immediately below may not require review of information other than BA or BE studies or data from limited confirmatory testing:

• Dosage form
• Strength
• Route of administration
• Substitution of an active ingredient in a combination product.
• Formulation
• Dosing regimen
• Active ingredient, e.g., a different salt, ester, complex, chelate, clathrate, racemate, or enantiomer of an active ingredient in a listed drug containing the same active moiety.
• New molecular entity, often a prodrug of an approved drug or the active metabolite of an approved drug
• Combination product
• Indication
• Rx/OTC switch
• OTC monograph
• Naturally derived or recombinant active ingredient
• Bioinequivalence, where absorption is different from the 505(j) standards

You cannot submit an application that is a duplicate of a listed drug and eligible for approval under section 505(j) or submit an application where the only difference is the extent to which the active ingredient(s) is absorbed or otherwise made available to the site of action is less than the listed drug.

Why is all this trouble worth it? In a word: Exclusivity. A 505(b)(2) application may obtain 3 years of Waxman-Hatch exclusivity if one or more of the clinical investigations, other than BA/BE studies, was essential to approval of the application and was conducted or sponsored by the applicant.  An applicant can get 5 years of exclusivity if it is for a new chemical entity.  A 505(b)(2) application may also be eligible for orphan drug exclusivity or pediatric exclusivity.

Approval or filing of a 505(b)(2) application, like a 505(j) application, may be delayed because of patent and exclusivity rights that apply to the listed drug.  This is the case even if the application also includes clinical investigations supporting approval of the application.

The 505(b)(2) application requires applicant to file patent certifications with application and serve notice on NDA holder and patent owner. This patent information will be published in the Orange Book when the application is approved. The types of filings include:

1. Paragraph (I): no patent was listed in Orange Book
2. Paragraph (II): listed patent has expired
3. Paragraph (III): listed patent will expire before requestedapproval
4. Paragraph (IV): listed patent is invalid or will not be infringed

The great thing about this is, if approved, is that the applicant will enjoy complete exclusivity. If the approval is for a new chemical entity (NCE), the exclusivity prohibits a generic manufacturer from submitting an ANDA for 5 years from date of NDA approval. Although, if an ANDA includes a paragraph IV certification, an ANDA can be filed after 4 years, but any 30-month stay is extended by up to 1 year (to expire 7-1/2 years after NDA approval).

An application for new clinical indications for approved products receive three years of exlusivity. This exclusivity prohibits FDA approval (but not submission) of an ANDA for 3 years after NDA/sNDA approval. Therefore, ANDA approval can come exactly 3 years later.

The period of time of exclusive marketing rights is granted by FDA at the time of approval and cannot be challenged or voided. The time runs from the date of approval, except for pediatric exclusivity, which attaches to an existing exclusivity or patent period.

All this and patent protection may apply also. What’s not to love?

Posted April 22nd, 2008 by Stephen Albainy-Jenei in Generic drugs, FDA
| | 1 Comment »

Forest Labs had a bit of a reversal of fortune in its patent dispute with Caraco Pharmaceutical Labs over its drug Lexapro®, which is used to treat depression and generalized anxiety disorder.

The U.S. Court of Appeals for the Federal Circuit reversed and remanded the case back to the U.S. District Court, which had dismissed Caraco’s request for a declaratory judgment of noninfringement. Caraco Pharmaceutical Labs v. Forest Labs (07-1404).

Caraco’s action was dismissed for lack of Article III jurisdiction on the grounds that it had been rendered moot when Forest unilaterally granted Caraco a covenant not to sue for infringement of the patent-in-suit, U.S. Patent No. 6,916,941.

What’s interesting is that Forest’s covenant not to sue did not eliminate the controversy between the parties. So, the court held that Caraco’s declaratory judgment action presents a continuing Article III controversy.

In filing its Lexapro® NDA, Forest listed two patents in the FDA’s Orange Book, namely: U.S. Patent Nos. Re. 34,712 and 6,916,941. The ’712 patent includes claims covering substantially pure forms of escitalopram, the active ingredient of Lexapro®. The ’941 patent generally covers crystalline particles of escitalopram oxate of a particular size range, as well as dosage forms containing particles of this size range, and methods of manufacturing particles in this size range. The ’712 patent expires in 2012; the ’941 patent expires in 2023.

The first ANDA applicant to file a Paragraph IV certification for Forest’s ’712 and ’941 patents was Ivax Pharmaceuticals. Therefore, Ivax is entitled to 180 days of generic market exclusivity, which will begin either on the day it begins marketing its generic drug, or on the date a court determines that the ’712 and ’941 patents are invalid or not infringed—whichever comes first.

Forest thanked Ivax by suing them for infringement of the ’712 patent, the earlier of the two patents to expire. Ivax counterclaimed that the ’712 patent was invalid. Despite suing Ivax on the ’712 patent, Forest did not sue Ivax for infringement of the ’941 patent.

By holding the ’941 patent card, Forest kept it from an invalidity or noninfringement challenge by Ivax. Forest won and obtained a judgment that the drug described in Ivax’s ANDA infringed the ’712 patent. Because Ivax didn’t obtain a judgment that both of Forest’s Orange-Book-listed patents are invalid or not infringed it didn’t get its 180-day exclusivity period.

The court said that only two pathways remain open to subsequent Paragraph IV ANDA filers who seek to trigger Ivax’s exclusivity period before the ’712 patent expires in 2012.

First, a subsequent Paragraph IV ANDA filer could obtain a court judgment invalidating the ’712 patent, which would allow the FDA to approve Ivax’s drug. With FDA approval, Ivax would be legally free to sell its generic drug, and its exclusivity period would be triggered on the day of its first commercial marketing.

Second, a subsequent Paragraph IV ANDA filer could trigger Ivax’s exclusivity period immediately—regardless of when Ivax begins marketing its drug—via the court-judgment trigger. However, because Ivax was the first Paragraph IV ANDA filer with respect to both the ’712 and ’941 patents, a subsequent Paragraph IV ANDA filer can only activate Ivax’s exclusivity period via the court-judgment trigger by obtaining a judgment that both the ’712 and ’941 patents are invalid or not infringed.

If a subsequent Paragraph IV ANDA filer is not able to pursue either of these two pathways to triggering Ivax’s exclusivity period, then Ivax’s exclusivity period cannot begin until the ’712 patent expires in 2012. Ivax’s exclusivity period will not be triggered on the date the ’712 patent expires unless Ivax actually begins marketing its generic drug on that date. Even if Ivax does so, the FDA will still be restricted from approving any subsequent Paragraph IV ANDA until 181 days after the date the ’712 patent expires.

In short, absent an event triggering Ivax’s exclusivity, all subsequent Paragraph IV ANDA filers, including Caraco, will be denied entry to the drug market for a significant time. These subsequent Paragraph IV ANDA filers will be precluded from the market regardless of whether the generic drugs described in their ANDAs infringe Forest’s Orange-Book-listed patents and regardless of whether Forest’s patents are valid.

Got that?

So, when Caraco filed an ANDA for generic escitalopram that included a Paragraph IV certification for Forest’s ’712 and ’941 patents, Forest sued Caraco for infringement of the ’712 patent — Forest did not sue Caraco on the ’941 patent.

Since Caraco has an economic interest in determining whether the ’941 patent is invalid or not infringed by the drug described in its ANDA — because only a judgment of invalidity or noninfringement with respect to both the ’712 and ’941 patents can trigger Ivax’s exclusivity period.

Forest filed a motion to dismiss Caraco’s action on the grounds that the action did not present a “case” or “controversy” as required by Article III of the Constitution. In its motion, Forest argued that there was no controversy because Caraco did not have a reasonable apprehension of suit on the ’941 patent. Forest hinged its entire argument for dismissal on the covenant not to sue, stating: “There is no controversy because we gave a covenant not to sue.” The district court agreed, stating from the bench that “[t]here’s a covenant not to sue on the ’941 so there’s not going to be any loss, there’s no threat of lawsuit.”

In overturning the decision, the court found that the district court failed to take into account the more recent cases:

(1) In, MedImmune v Genentech, the Supreme Court said that whether a declaratory judgment action presents an Article III controversy must be determined based on “all the circumstances,” not merely on whether the declaratory judgment plaintiff is under a reasonable apprehension of suit.

(2) In Novartis v. Teva, the CAFC held that where an NDA holder brings an infringement suit against a Paragraph IV ANDA filer on only one of several Orange-Book-listed patents covering its NDA, the ANDA filer has standing to seek a declaratory judgment on any of the NDA holder’s remaining Orange-Book-listed patents for that NDA. However, Novartis had not been decided at the time so Ivax never sought a declaratory judgment that Forest’s ’941 patent was invalid or not infringed by its generic drug. Even though Novartis only sued Teva on one of its Orange-Book-listed patents, this was sufficient to trigger a 30-month stay barring Teva’s ANDA from approval under 21 U.S.C. § 355(j)(5)(B)(iii).

In reversing and remanding, the CAFC pointed out that:

First, the dissent states that there is “no basis to conclude that the first-filing generic manufacturer will, or is likely to, delay bringing its product to market after the ’712 patent expires.” We agree. What the dissent fails to recognize, however, is that the injury upon which Caraco’s suit is premised is the delay (in triggering Ivax’s exclusivity period) between now and when the ’712 patent expires in 2012, not any delay (in triggering Ivax’s exclusivity period) after the ’712 patent expires. Thus, the dissent is in error when it notes that our analysis requires speculating as to when Ivax decides to market its drug after the ’712 patent expires.

Second, the dissent states that we assume that a first Paragraph IV ANDA filer who unreasonably delays in marketing its drug cannot lose its right to exclusivity. The dissent is incorrect. Our conclusion that the first filer in this case, i.e. Ivax, cannot forfeit its exclusivity period is not based on an assumption, but rather the texts of the Hatch-Waxman Act and the MMA. A s discussed, the MMA amendments to the Hatch-Waxman Act include a grandfather provision that specifically exempts a certain class of Paragraph IV ANDA filers, including Ivax, from being subject to the MMA’s 180-day exclusivity forfeiture provisions. Accordingly, it cannot plausibly be argued that Ivax may nevertheless forfeit its exclusivity period.

Third, the dissent states that our analysis “assumes that [Caraco] will prevail in its non-infringement claim—an uncertain assumption at best.” We make no such assumption, nor need we. A plaintiff need not prove it will prevail on the merits of its case in order to prove that it has standing to bring the case. Steel Co., 523 U.S. at 89 (”It is firmly established in our cases that the absence of a valid (as opposed to arguable) cause of action does not implicate subject-matter jurisdiction, i.e., the courts’ statutory or constitutional power to adjudicate the case.”).

Expect to see more on this issue. Forest had Lexapro sales of about $2.5 billion last year.

More at the Orange Book blog and IPBiz.

Posted April 9th, 2008 by Stephen Albainy-Jenei in Generic drugs, IP Litigation
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Eighteen states and the District of Columbia have filed suit against Abbott Laboratories and Solvay’s Fournier Industrie et Santé and Laboratories Fournier for allegedly entering into a scheme to block the generic version of the cholesterol lowering drug TriCor®  (fenofibrate), indicated for the treatment of hypercholesterolemia and hypertriglyceridemia.

According to the AGs in the states, the companies made trivial changes to the formulations of TriCor, and marketed those while withdrawing the original drug from the market. The companies deleted references to the original forms of the drug from national drug databases, according to prosecutors, making it more difficult for a generic version of TriCor to obtain generic status

The states filed their lawsuit in federal court in Wilmington, Delaware, accusing Abbott and of undermining efforts to bring generic drugs to market by patenting new formulations of TriCor with only minor changes to the drug.

TriCor, which costs more than $3 a pill, generated sales of $1.2 billion for Abbott in 2007, but the company, according to the lawsuit, has tried to maintain a monopoly on the market by obtaining term-extending patents. Abbott denies the allegations saying it has not prevented other fenofibrate drugs from being marketed.

The prosecutors say Fournier obtained patents covering the variations of TriCor and then filed patent infringement lawsuits against generic companies that tried to compete. The litigation meant that the Food and Drug Administration could not approve generic versions of TriCor.

In a long-running battle with Teva Pharmaceutical, Abbott has tried to stay one step ahead of the generic entry. Originally, Teva filed an ANDA for ANDA for a TriCor capsule formulation and made a Paragraph IV certification that U.S. Pat. No. 4,895,726 was invalid so not infringed. A bbott sued and initiated a 30-month stay of FDA approval.

While the capsule battle was continuing, Abbott filed a new NDA for 54 mg and 160 mg TriCor in a tablet formulation arguing that the tablet was bioequivalent to the capsule. After this was approved, Abbott stop selling the capsules and bought back all the capsules from the market.

The Abbott, in a move that was probably too smart for their own good, changed the code for TriCor capsules in the National Drug Data File (NDDF) to “obsolete.” The NDDF is a private database that provides information about FDA-approved drugs. Changing the code to obsolete then removed the TriCor capsule drug formulation from the NDDF, which prevented pharmacies from filling TriCor prescriptions with a generic capsule formulation.

Needless to say, Teva took it kind of hard and added antitrust counterclaims to its suit against Abbott. Abbott is no longer marketing the 54 mg and 160 mg strength tablets because it has now changed its Tricor product to 48 mg and 145 mg strength tablets. Abbott even filed a new NDA for 48 mg and 145 mg TriCor tablets looking to change the label to state that the new tablets do not need to be taken with food (the dissolvable version).

Teva claims that Abbott’s actions have frustrated generic competition in Fenofibrate products through a combination of two market conversions and the gaming of the Hatch-Waxman Act, denying consumers access to a generic alternative to Abbott’s products.

The dissolvable version of TriCor retains patent protection until 2018.

In the current suit by various AGs, the states involved are Arizona, Arkansas, California, Connecticut, the District of Columbia, Florida, Iowa, Kansas, Maine, Maryland, Minnesota, Missouri, Nevada, New York, Oregon, Pennsylvania, South Carolina, Washington, and West Virginia.

No word yet on when Abbott’s new magic orange-colored TriCor comes out.

See a timeline at the Orange Book blog.

Posted March 21st, 2008 by Stephen Albainy-Jenei in Generic drugs, FDA, IP Litigation
| | 5 Comments »

What happens when a brand name drug company asserts that a patent covers its drug and then pulls it out from the Orange Book? You fight to get it back in, that’s what.

In August, Teva Pharmaceuticals USA submitted a Citizen Petition pursuant to section 505 of the Food, Drug, and Cosmetic Act (FDCA) asking the FDA to do just that.

The FDA’s official Approved Drug Products with Therapeutic Equivalence Evaluations (the “Orange Book“) listed two patents as claiming Risperdal® tablets: U.S. Patent No. 4,804,663, which was set to expire on December 29, 2007, and U.S. Patent No. 5,158,952 (”the ‘952 patent”), which will expire on October 27, 2009.  Risperidone is an antipsychotic medication sold by Janssen Pharmaceutica (a subsidiary of Johnson & Johnson) under the trade-name Risperdal®.

Teva submitted an original Abbreviated New Drug Application (ANDA) seeking approval to market generic risperidone tablets. Because the Orange Book listed both the ‘663 and ‘952 patents for Risperdal® tablets, Teva was required to certify as to both patents.

Teva filed a certification under § 355(j)(2)(A)(vii)(III) (”Paragraph III certification”) as to the ‘663 patent, which is set to expire on December 29, 2007, and a certification under § 355(j)(2)(A)(vii)(IV) (”Paragraph IV certification”) as to the ‘952 patent, asserting that the patent was invalid or would not be infringed by Teva’s generic risperidone tablets.

Ordinarily, Teva would be entitled to 180 days of marketing exclusivity for its generic risperidone tablets as a result of its paragraph IV certification to the ‘952 patent. That’s because the ‘952 patent appeared in the official Orange Book when it originally filed – that meant that Teva was required to submit a certification to that patent at the time it submitted its ANDA for generic risperidone drug products. Teva then became the first company to submit a paragraph IV certification to any of the listed patents claiming Risperdal®.

On October 12, 2001, FDA notified Teva that it had “delisted” the ‘952 patent from the Orange Book (even though it continued to appear in the official Orange Book at that time) It also informed Teva that it would not accept Teva’s ANDA for filing unless Teva modified its patent certification to reflect that the ‘952 patent was no longer listed as claiming the reference drug product.

In November 2006, the D.C. Circuit ruled that the plain text of the FDCA prevented the FDA from effectuating the delisting of a patent following the submission of a paragraph IV certification as to that patent. Ranbaxy Laboratories Ltd. v. Leavitt, 469 F.3d 120, 125-26 (D.C. Cir. 2006). The court struck down the FDA’s practice because it “changed the incentive structure adopted by Congress,” by “depriving the generic applicant of a period of marketing exclusivity” after the generic manufacturer had expended significant resources in developing a non-infringing generic substitute and undertaken the risk of infringing the patent by filing a paragraph IV certification.

Teva then filed a Citizen’s Petition with the FDA arguing that the FDCA entitles Teva to a 180-day period of first-filer exclusivity for generic Risperdal® tablets since it was the first generic manufacturer to file an ANDA for generic risperidone tablets containing a paragraph IV certification as to the ‘952 patent.

Under 21 U.S.C. § 355(j)(5)(B)(iv) (2002), the earliest any subsequently-filed paragraph IV ANDA can be approved is “one hundred and eighty days after” Teva first commercially markets its generic risperidone tablets or the date of a court decision holding the ‘952 patent to be invalid or not infringed.

Teva argued that both FDA regulations and case law make clear that the agency does not adjudicate questions of patent law; instead, it plays only a ministerial role in maintaining the Orange Book. As a result, where a patent remains listed for a particular drug in the official Orange Book, a generic applicant has no choice but to believe that the NDA holder is continuing to assert that patent as claiming the listed drug.

Thus, at the time of its ANDA submission in August 2001, Teva was required to submit a certification to the ‘952 patent. Teva now wants its 180-exclusivity for these drug products.

The question here is whether or not a brand manufacturer can game the system by delisting a patent after the submission of a paragraph IV certification and without notice, forcing generic manufacturers to invest resources and assume the risk of patent litigation without any guarantee of the 180-day exclusivity reward.

The FDA wrote back a nice note to Teva:

We have carefully reviewed your Petition and have concluded that the ‘952 patent was delisted before Teva submitted ANDA 76-228 to FDA. For the reasons described in further detail in this Response, we deny your request that FDA relist the ‘952 patent. As Teva’s ANDA did not contain a paragraph IV certification for a listed patent, and Teva did not provide the required notice of such certification to the holder of the NDA for the reference listed drug and each owner of the listed patent, Teva would not be eligible for 180-day exclusivity pursuant to section 505(j)(5)(B)(iv) of the Act for its pending ANDA 76-228.

Like a game of Calvinball*, since the FDA had itself forced Teva to remove the paragraph IV certification or it wouldn’t accept the ANDA, the FDA now claims that Teva’s out of luck because it did, in fact, take out the certification.

Nice.

It probably wouldn’t take a law degree to guess that Teva has filed a lawsuit in federal court to try to get the Petition granted. Johnson & Johnson’s sales of antipsychotics in the U.S. were more than $2.7 billion last year with Risperdal accounting for a large part of that amount. A generic can make quite a bit in just 180 days.

Stay tuned.

Teva vs. FDA Complaint

[*Note: Under the Official Rules of Calvinball, Rule 1.2. states: “Any player may declare a new rule at any point in the game (Figure 1.2). The player may do this audibly or silently depending on what zone (Refer to Rule 1.5) the player is in.”]

Posted March 7th, 2008 by Stephen Albainy-Jenei in Pharmaceutical, Generic drugs, FDA, IP Litigation
| | 3 Comments »

The U.S. Court of Appeals for the Federal Circuit smacked Apotex with a contempt judgment after finding it filed a repetitive Abbreviated New Drug Application (ANDA) with the Food and Drug Administration (FDA). Abbott Labs v. Torpharm and Apotex (07-1019).

This involves an ongoing dispute with TorPharm and Apotex in trying to market a generic version of Depakote®, an anti-seizure medication containing divalproex sodium patented, produced, and sold by Abbott

The U.S. District Court held Apotex in contempt for violating an injunction barring it from commercially manufacturing, using, selling, offering to sell, or importing into the United States generic divalproex sodium infringing Abbott’s U.S. Patent Nos. 4,988,731 and 5,212,326 until their expiration.

The CAFC upheld the district court’s decision to entertain a contempt proceeding as well within its discretionary authority. However, because the district court erred in finding Apotex in contempt when the conduct at issue was not within the express terms of the injunction, we reverse the district court’s judgment of contempt.

Earlier, Apotex filed an ANDA under the Hatch-Waxman Act to get FDA approval to manufacture and sell a generic version of Depakote®. The active ingredient of Depakote® is divalproex sodium. In its paragraph IV certification, Apotex certified that the Abbott patents were invalid.

Abbott sued and the district court granted summary judgment in favor of Abbott on both validity and infringement. On appeal, the CAFC affirmed the ruling on validity but remanded for a trial on infringement.

On remand, the court concluded that Apotex’s filing of the ANDA infringed the claims of the Abbott patents because Abbott’s claims read on the product that was the subject of the Apotex ANDA. The district court entered the following injunction:

TorPharm, Inc., Apotex, Inc., Apotex Corp., and their respective affiliates, successors in interest, and assigns are enjoined from commercially manufacturing, using, selling, or offering to sell generic divalproex sodium which the Court has found to be infringing within the United States, or from importing such product into the United States, until Abbott’s U.S. Patent Nos. 4,988,731 and 5,212,326 expire and defendants have received final approval from FDA to market generic divalproex sodium.

The effective date of any approval by FDA of ANDA No. 75-112, or any other application concerning defendants’ generic divalproex sodium which the Court has found to be infringing, shall be no earlier than January 29, 2008, the date of expiration of Abbott’s patents.

Apotex tried to design around Abbott’s patent claims and allegedly developed divalproex sodium in the form of a polymer which differs from an oligomer in that the polymer is made up of much more than about 4 to 6 repeating units of divalproex sodium.

But, rather than file a new ANDA itself, Apotex entered into an agreement with Nu-Pharm where Apotex would pay costs but Nu-Pharm would take on the “litigation risks” from the filing. Nu-Pharm then filed the second ANDA with a paragraph IV certification that its product did not infringe the claims of the Abbott patents.

The court found Apotex in contempt for violating the injunction characterizing the injunction as extending to “any ‘generic divalproex sodium’ manufactured by Apotex that has been ‘found to be infringing.’” The court found that there was no difference between Apotex’s old product and its new product. So, the district court “extend[ed] the injunction to embrace” the Nu-Pharm ANDA. Specifically, the expanded injunction prohibited Apotex from:

commercially manufacturing, using, selling, or offering to sell generic divalproex sodium … until Abbott’s U.S. Patent Nos. 4,988,731 and 5,212,326 expire and defendants have received final approval from FDA to market generic divalproex sodium.

The district court stated that should the violation continue, Apotex “will be risking heavy sanctions for its willful disobedience of the injunction.”

On appeal, Apotex argued that the contempt proceeding was beyond the district court’s statutory authority because the Hatch-Waxman Act does not itself grant a district court subject matter jurisdiction to conduct such contempt proceedings. The court agreed stating:

While the Supreme Court has characterized infringement as defined in the Hatch-Waxman Act as “highly artificial,” see Eli Lilly & Co. v. Medtronic, Inc., 496 U.S. 661, 678 (1990), by statutory command it is infringement nonetheless. Apotex has failed to provide any authority, be it statute, case law, or legislative history of the Hatch-Waxman Act, suggesting that suits commenced under the provisions of the Act are to be treated any differently than patent infringement suits under 35 U.S.C. § 271(a).

The district court found that “Apotex’s choice of Nu-Pharm to file the ANDA was a subterfuge intended to give Apotex a crack at another district judge” who might find that Nu-Pharm ANDA drug noninfringing. Abbott V, 455 F. Supp. 2d at 835. We do not disturb that finding, and conclude that the district court did not abuse its discretion in electing to try issues relating to the Nu-Pharm ANDA in a contempt proceeding.

Notwithstanding the above, we have held that before entering a judgment of contempt of an injunction in a patent infringement case, a district court must address two separate questions. … First, the district court must address whether a contempt hearing is an appropriate forum for adjudging whether an allegedly redesigned product is infringing. … Second, if contempt proceedings are appropriate, the district court must address whether the accused product infringes the claims of the asserted patent.

Where, as here, a party files a second ANDA to a drug having no more than a colorable difference from the first, the district court is well within its discretion to entertain contempt proceedings.

In looking at the finding of contempt, the Federal Circuit held that:

We hold that the district court made an error of law in interpreting its original injunction to preclude the conduct of which Abbott complains, namely the filing of the Nu-Pharm ANDA, and thereby abused its discretion in holding Apotex in contempt.

By its plain language, the injunction issued in Abbott III only (1) enjoined Apotex from commercially manufacturing, using, selling, or offering to sell generic divalproex sodium which the Court has found to be infringing within the United States and importing such product into the United States until expiration of the Abbott patents, and (2) prohibited the FDA from approving the Apotex ANDA as well as any other ANDA application filed by Apotex directed to generic divalproex sodium which the Court has found to be infringing until expiration of the Abbott patents.

In other words, while contemplating the filing of new and/or amended ANDAs, the injunction only provided the FDA with the necessary “explicit notice” that it was prohibited from approving the Apotex ANDA or any other ANDA concerning Apotex’s generic divalproex sodium which a court found to be infringing prior to expiration of the Abbott patents. The injunction contains no “explicit notice” to Apotex that the filing of a new ANDA, by itself or a straw party, was forbidden.

Posted October 14th, 2007 by Stephen Albainy-Jenei in Generic drugs, IP Litigation
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The US Food and Drug Administration (FDA) today announced a new program aimed at speeding up the approval process for generic drugs.

FDA predicts that the program, aptly called GIVE the Generic Initiative for Value and Efficiency, would give a gift to generic companies by helping the FDA approve generic drugs more quickly. FDA approved 682 generic drugs in fiscal year 2007, 30 pct more than it did the prior year, although an increasing number of generic applications are submitted each year.

Under the program, FDA will immediately review applications for generic drugs that face no blocking patents or exclusivity provisions. The FDA said this change will let these generic drugs reach consumers more quickly. In plain English, GIVE aims to increase the number and variety of generic drug products available to drive down the costs of drugs.

The program will focus staff efforts on program goals and provide background and impetus for development of additional review efficiencies. Additional changes anticipated include, but are not limited to:

• A continued focused hiring plan, using currently available resources, to address critical review staff needs.
• Using the Office of Pharmaceutical Science to augment review capability in microbiology (critical need area).
• Identification of supplements for low-risk manufacturing changes that may qualify for a less intense level of review.
• Base risk decisions on manufacturer’s product and process understanding and the robustness of their internal quality system to control their processes.
• Enhanced use of electronic programs for handling submissions and internal documents.
• Supplement reduction for low-risk products.
• Consideration of additional changes to application procedures to increase the availability of more lower-cost generic alternatives to the public.

FDA said it would increase its current review staff of 215, increase the use of electronic submissions, and use other resources from within FDA to review applications.

A generic drug is identical, or bioequivalent to, a brand name drug in dosage form, safety, strength, route of administration, quality, performance characteristics and intended use. Drug companies must submit an abbreviated new drug application (ANDA) for approval to market a generic product.

The Drug Price Competition and Patent Term Restoration Act of 1984, more commonly known as the Hatch-Waxman Act, made ANDAs possible by creating a compromise wherein generic drug companies gained greater access to the market for prescription drugs, and innovator companies gained restoration of patent life of their products lost during FDA’s approval process.

Posted October 5th, 2007 by Stephen Albainy-Jenei in Generic drugs, FDA
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Several readers recently asked if there is a good (free) site that lists the expiration dates of pharmaceutical patents. The Generic Pharmaceutical Association (GPhA) has a chart listing Upcoming Patent Expirations for 2007-09.  One fee-based service I know of is Drug Patent Watch. 

One can also do the reviewing themselves, of course, but determining if a patent has truly expired can be a tricky business full of pitfalls.  For those who want to get look into a patent’s status, there are a number of steps to perform.

First, if the patent application was filed after June 7, 1995, the expiration date is 20 years from the date it was filed. If the application was filed by June 7, 1995 and issued before June 8, 1978, the expiration date is 17 years from issuance. But, if the application was filed by June 7, 1995 and issued after June 7, 1978, the term is the later of 17 years from issuance or 20 years from filing.

However, keep in mind that a patent term may be extended for various reasons.  Some patents have had their terms extended based on extreme delays in government approvals outside the Patent Office. This is very unusual, and applies almost always to pharmaceuticals (for example, Claritin® or Prozac®), food products (Aspartame) or medical devices or procedures, where FDA approval can sometimes eat up most of the patent term before the drug can be brought to market.

For a list of patents with term extensions, see the Patent and Trademark Office’s Extended Term List.

Some patents have less than the normal life span because their terms are limited to the terms of earlier-issued patents through the use of a terminal disclaimer, which is a result of filing two applications which claimed essentially the same invention. Terminal disclaimers will be marked on the later-issued patent. Sometimes these are flagged by an asterisk after the patent issue date, but sometimes they only appear in the text of the patent or with the related application data on the face of the patent.

Even after issuance, there are various ways a patent can expire early. For example, if the maintenance fees are not paid, the patent expires at the end of the surcharge period (4.5, 8.5 or 12.5 years after issue). However, the caveat to this is that expired patents may be revived up to 24 months after they expire, so long as the failure to pay the fee was unintentional. If the expiration date was more than two years in the past, the patent cannot be revived.

You can use the USPTO’s Patent Application Information Retrieval (PAIR) system to determine if maintenance fees have been paid.

In addition, you must determine if there has been any reexamination or voluntary disclaimer which resulted in a loss of some or all of the claim scope. This should be noted on a certificate attached to the patent image on the USPTO database, usually as the last page in the image file.  It is possible that an issued patent can be withdrawn from issue on the order of the Commissioner of Patents.

Finally, you must also check to see if the patent been declared invalid by a court.  Unfortunately, this can also be a tedious task to search through court records.

If you are genuinely concerned about a particular patent, it may be advisable to have a patent attorney (for example, one of the attorneys here at Frost Brown Todd) do a validity study and opinion on the patent. The attorney can perform a search to find prior art which might invalidate the patent, and will review the patent’s file at the USPTO to see if there is anything which might affect the validity or scope of the patent.

If you know of other sources for expired patent information, drop me a line and I will provide updated information here.

Posted July 26th, 2007 by Stephen Albainy-Jenei in Practice Tips, Pharmaceutical, Generic drugs, Due Diligence
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While not as fundamentally important as Bong Hits 4 Jesus, the U.S. Supreme Court declined to hear a case profoundly important to the pharmaceutical industry. For the second time, the Court rebuffed a challenge to a “reverse payments” deal — this one where an AstraZeneca company paid off a Barr Pharmaceuticals company to delay marketing of generic tamoxifen.

Earlier, the Solicitor General’s Office submitted a brief to the Supreme Court urging the Court to deny certiorari in the reverse payment case Joblove v. Barr Labs (S.Ct. No. 06-830). The Supreme Court had asked for the government’s views on the antitrust effects of settlement agreements between holders of drug patents and generic drug makers enjoying the 180-day market exclusivity after Food and Drug Administration approval. This case involves the same legal issue that was raised in FTC v. Schering-Plough Corp., No. 05-273 (Jun. 26, 2006; denying certiorari).

The issue is the appropriate antitrust standard applicable to an agreement between a brand pharmaceutical manufacturer (and patent holder) and a generic market entrant (and alleged patent infringer) whereby the patent holder shares a portion of its future profits with the alleged infringer in exchange for the latter’s agreement to not market its competitive product. The three Circuit Courts of Appeals that have addressed the issue have rendered inconsistent decisions.

Zeneca manufactures and markets tamoxifen citrate (tamoxifen), a drug for the treatment of breast cancer, under the brand-name Nolvadex®. Zeneca’s former parent, Imperial Chemical Industries PLC (ICI), held the patent for tamoxifen, U.S. Patent 4,536,516. In 1987, Barr amended its ANDA for tamoxifen to include a Paragraph IV Certification, which prompted a patent infringement suit by ICI (Zeneca’s parent). In 1992, the ‘516 Patent was held invalid and unenforceable.

While an appeal from the judgment invalidating the patent was pending in the Federal Circuit, Zeneca and ICI, the patent holders, and Barr, the alleged infringer, agreed to settle the case. Zeneca and ICI agreed to: (1) pay Barr $21 million; (2) pay Barr’s supplier $35.9 million; and (3) supply Barr with Zeneca-manufactured tamoxifen for resale in the United States at a high royalty rate. In return, Barr agreed to: (1) abandon its successful challenge of the tamoxifen patent; (2) withdraw its Paragraph IV Certification to manufacture and market generic tamoxifen prior to the patent’s expiration; and, if possible, and (3) prevent competitive entry by future generic manufacturers.

Now, the FTC alleges that the agreements unlawfully restrained competition in the market for tamoxifen in violation of Sections 1 and 2 of the Sherman Act, 15 U.S.C. §§ 1, 2, and analogous state statutes. The question presented being:

“Under what circumstances is an agreement by a brand pharmaceutical manufacturer (and patent holder) to share a portion of its future profits with a generic market entrant (and alleged patent infringer), in exchange for the generic’s agreement not to market its product, a violation of the antitrust laws?”

In FTC v. Schering-Plough, the Solicitor General urged that no conflict existed that would warrant the Court’s review of this issue, based on the same body of case law that exists today.

Oddly, while stating up-front that this case “raises important and complex issues“:

There may be particular reason to be concerned about the competitive consequences of a settlement that includes a substantial payment from the patent holder to the alleged infringer. Such a “reverse payment” can be a device for the sharing of the monopoly rents that are preserved when the alleged infringer is induced to stay out of the relevant market and drop its challenge to the validity of the patent.

and while noting that “the court of appeals adopted an insufficiently stringent standard for scrutinizing patent settlements that include reverse payments”:

The dissenting opinion below correctly suggested that a court reviewing an antitrust challenge to a settlement of a patent infringement claim that includes a reverse payment should apply the rule of reason—and that, in doing so, a court should consider “the strength of the patent as it appeared at the time at which the parties settled.” Pet. App. 125a-126a. The panel majority, however, rejected that approach and instead held that such a settlement would be valid unless (1) the settlement “extend[ed] * * * the monopoly beyond the pat-ent’s scope”; (2) the settlement involved fraud; or (3) the underlying lawsuit was “objectively baseless in the sense that no reasonable litigant could realistically expect success on the merits.” Id. at 52a (internal quotation marks and citation omitted). That standard is erroneous.

The SG turned around and pleaded that “this case does not present a good vehicle for addressing the question presented”:

Although the court of appeals applied an erroneous standard for scrutinizing patent infringement settlements that include reverse payments, this case is not an attractive vehicle for the Court’s consideration of the difficult and context-sensitive questions involved in assessing the legality of such settlements. The federal antitrust claims in this case appear to be moot, the factual setting is atypical and unlikely to recur, and subsequent regulatory changes may undercut one of the theories of competitive harm advanced by petitioners. For those reasons, the petition should be denied.

An official at the U.S. Federal Trade Commission said the FTC remains committed to pursuing cases against reverse payments by pharmaceutical companies that it deems to be anti-competitive. The FTC had filed an appeal but did not file a brief in this case.

See the Solicitor General’s Office Brief.

Posted June 27th, 2007 by Stephen Albainy-Jenei in Generic drugs, FTC
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