Orange Book Blog

OBB News Briefs

• Apotex and an anonymous ANDA filer recently submitted new comments to FDA on ramipril 180-day exclusivity issues.  Earlier this month, we summarized previous comments on the ramipril docket.
• Roxane Labs recently submitted new comments to FDA on acarbose 180-day exclusivity, and Impax indicated that it intends to do the same.  Their submissions are available on FDA's acarbose docket.
• The FTC announced Thursday that it has settled its antitrust complaint against Barr Labs concerning Warner Chilcott's Ovcon birth control pill.  According to FTC's press release, the settlement provides that "Barr must refrain from entering into anticompetitive supply agreements with branded companies similar to Barr's agreement with Warner Chilcott regarding Ovcon."
• Via SpicyIP and Pharmalot, Sun Pharma has filed a paragraph IV challenge of Novartis's polymorph patent on Gleevec (imatinib mesylate), which expires in 2019.  The compound patent on imatinib expires in 2015.
• FDA Law Blog had an interesting post last week about a lawsuit by two pharmacy associations against the Center for Medicaid Services, charging that the new "AMP rule," which CMS uses to calculate how much it reimburses states for generic drugs, is unlawful.  Some believe that the new Medicaid reimbursement rules make it cost-prohibitive for brand name drug companies to sell authorized generics in many cases.
• Pharmalot reported recently that legislation that would have banned "reverse payment" settlements of Hatch-Waxman litigation has stalled in the Senate.  For background, see this OBB post from last February.

Lovenox Patent Case Back at Federal Circuit; Generic Versions Still Not Yet Approved

The Lovenox patent infringement litigation between Aventis and Teva/Amphastar is making its second trip to the Federal Circuit.  In February, following remand from the Federal Circuit last year, a federal district court in California held that the Lovenox patent is unenforceable due to inequitable conduct.  The appeal may emerge as a litmus test of how far the CAFC is willing to go in lowering the bar on inequitable conduct, especially in terms of what it takes to prove deceptive intent.  In general, the party asserting inequitable conduct must prove each prong of inequitable conduct (i.e., materiality and deceptive intent) by clear and convincing evidence.

In recent cases, the CAFC has expanded the scope of what counts as a material omission, including the omission of information that would have had no bearing on patentability.  Thus, a practitioner may even comply with Rule 56 (37 CFR 1.56), and still be found to have withheld material information.  This bar-lowering has occurred primarily via the emergence of the “reasonable examiner” standard.  Hence, materiality is judged not by the PTO’s rules, but by a post hoc litigation-induced evaluation of what information a hypothetical “reasonable examiner” would (or should) have wanted during the ex parte prosecution of the patent application.

Moreover, defendants may no longer need to prove deceptive intent by clear and convincing evidence.  Instead, a “guilt by omission” standard seems to have emerged.  If the omitted information is “highly material” and if the patentee cannot proffer a reasonable explanation for the omission, then a court is permitted to infer deceptive intent.  (Of course, the line between ordinary materiality and “high materiality” is a bit fuzzy, especially if an omission can be highly material even when it would have had no effect on patentability.)

In the Lovenox district court case, the district court went one step further:  The court appeared to have shifted the burden to Aventis to disprove deceptive intent (e.g., after finding that Teva/Amphastar had made out a prima facie case of deceptive intent).  It will be interesting to see where the CAFC goes with this one.

The parties appear reluctant to tread into the legal issues surrounding the CAFC’s recent inequitable conduct jurisprudence.  After all, a sizeable portion of the judges have not yet bought into the recent trend of making it easier to prove inequitable conduct.  Instead, the parties have elected to focus on several alleged clear errors in the district court’s fact-finding.  Perhaps that’s the best approach, anyway.  By their very nature, inquires into an individual’s intent must be fact-intensive. 

Of course, the CAFC may do well to pay more heed to the post-1978 developments in antitrust law, where scholars of all stripes have generally rejected the value of intent-based evidence.  Inequitable conduct arose in 1945 and came of age during that era of legal moralism that emerged from antitrust cases like Standard Oil.  Antitrust law has now largely unburdened itself of Standard Oil and its progeny.  To the degree that inequitable conduct is a relic of that bygone age, why must we retain it in patent law?

Meanwhile, the FDA has still not yet approved any generic versions of Lovenox (enoxaparin sodium).  Lovenox consists of a complex mixture of oligosaccharides that has been shown to have improved anticoagulant effects over other low-molecular-weight heparins (LMWHs).

Earlier this month, Momenta Pharmaceuticals announced that the FDA rejected its ANDA for M-enoxaparin, apparently based on concerns about the generic drug’s immunogenicity.  In other words, the FDA was concerned that it may provoke an unwanted immune response in humans.  Moreover, according to Momenta's press release, "the FDA clarified that all applications for enoxaparin products must address the potential for immunogenicity of the drug product."

Momenta is working with Swiss generic manufacturer Sandoz to develop its generic product.  The news of the rejection caused Momenta’s stock to lose nearly 60% of its value in a single day.  In the intervening weeks, Momenta’s stock value has continued to tumble another 4-5%.

APPEAL BRIEFS:

• Aventis opening brief
• Amphastar opposition brief
• Teva opposition brief
• Aventis reply brief
• Sandoz amicus brief

RELATED READING ON FDA ACTION:

• Bloomberg article
• Pharmalot post
• WSJ Health Blog post

Dismissal of Invalidity Counterclaims Thwarts Apotex's Attempt to Trigger 180-Day Exclusivity on Cosopt

Merck v. Apotex, No. 06-5789 (D.N.J. 2007)

Merck has sold Cosopt (dorzolamide hydrochloride/timolol maleate), an opthalmic drug indicated for the treatment of ocular hypertension and open-angle glaucoma, since 1998.  In October 2005, Hi-Tech Pharmacal filed the first ANDA for a generic version of Cosopt with paragraph IV certifications to the Orange Book-listed patents: U.S. Patent Nos. 4,797,413; 6,248,735; and 6,316,443.

In January 2006, Merck sued Hi-Tech, asserting infringement of the '413 patent but not the '735 or '443 patents.  On April 18, 2006, Merck filed a statutory disclaimer of the '735 and '443 patents with the USPTO, effectively dedicating its rights under the patents to the public.  Shortly thereafter, on April 25, Merck wrote to the FDA and requested that the agency delist those two patents from the Orange Book.  The FDA, however, did not delist the patents--indeed the patents remain listed today.

In October 2006, Apotex sent Merck a letter notifying it that Apotex had filed an ANDA for a generic version of Cosopt with paragraph IV certifications to all three Orange Book-listed patents.  In response, Merck sued Apotex in December 2006, again asserting infringement of the '413 patent but not the '735 or '443 patents.  Apotex agreed to be bound by the court decision on the '413 patent in the Hi-Tech case, but pursued declaratory judgment counterclaims of invalidity of the disclaimed patents.  On March 29, 2007, the Federal Circuit affirmed the patent term of the '413 patent, leaving only Apotex's counterclaims on the disclaimed '735 and '443 patents in the case.  The '413 patent will expire in April 2008, with pediatric exclusivity extending to October 2008.

Shortly after the Federal Circuit decision on the '413 patent, Merck moved under Fed. R. Civ. P. 12(b)(1) to dismiss Apotex's counterclaims of invalidity of the '735 and '443 patents for lack of subject matter jurisdiction.  In an opinion released earlier this month, the district court granted Merck's motion to dismiss, concluding: "because Merck has formally disclaimed the '735 and '443 patents, and can no longer enforce any claims as to these patents, there is no justiciable case or controversy to support jurisdiction in an action for a declaratory judgment here."  Apotex has appealed the decision to the Federal Circuit.

BRIEFS:

• Merck brief in support of motion to dismiss
• Apotex brief in opposition to motion
• Merck reply brief

ADDENDUM:
In a separate case, relating to Precose (acarbose), Cobalt Pharmaceuticals recently filed a complaint seeking a declaratory judgment of invalidity or noninfringement with respect to another statutorily-disclaimed patent, U.S. Patent No. 4,904,769.  In that case, Cobalt is the first ANDA filer, and the '769 patent is the only Orange Book-listed patent for Precose.  For more information, see this FDA Law Blog post.

Pharma News Briefs

• King Pharmaceuticals filed its 10-Q statement with the SEC on Friday, revealing that Cobalt Pharmaceuticals, the first ANDA filer for Altace (ramipril), recently notified King of its intent to launch its generic ramipril product, notwithstanding the settlement agreement between the two parties (see pages 12 and 20 of King's 10-Q filing).
• Ranbaxy submitted new comments to FDA regarding granisetron 180-day exclusivity, largely supporting Teva's interpretation of the post-MMA "failure to market" forfeiture provisions.
• Teva and Upsher-Smith recently submitted new comments to FDA regarding acarbose 180-day exclusivity (see FDA Law Blog).
• Ranbaxy announced Thursday that it and Astellas/Boehringer Ingelheim settled their Hatch-Waxman case concerning generic Flomax (tamsulosin), and that it believes it is the first ANDA filer.
• In other settlement news, GSK and Mylan recently announced settlement of their Hatch-Waxman case concerning generic Paxil CR (see this AP story).  Mylan is the first ANDA filer for a generic version of Paxil CR.
• Momenta Pharmaceuticals announced Tuesday that FDA rejected its ANDA for a generic version of Lovenox (enoxaparin sodium injection), adding that "FDA clarified that all applications for enoxaparin products must address the potential for immunogenicity of the drug product" (see also Bloomberg.com).
• Pharmalot posted a couple interesting stories this past week about a feud between Big Pharma and FDA over who's to blame for the recent decline in new drug approvals (see Nov. 5 post; Nov. 9 post).
• There was more talk of replacing patents with prizes, this time at the World Health Organization meeting in Geneva (see WSJ Health Blog).
• Eli Lilly & Co. created a buzz last week when it announced a deal with India's Glenmark Pharmaceuticals to acquire rights to a portfolio of TRPV1 antagonists (see also MarketWatch; Spicy IP).  Lilly also recently said it plans to ramp up its R&D spending in China (see Reuters).

FDA's Request for Comments on Ramipril 180-day Exclusivity Draws Letters from Eight Generic Companies

King Pharmaceuticals markets Altace (ramipril), a treatment for high blood pressure with nearly $1 billion in annual U.S. sales.  U.S. Patent No. 5,061,722, owned by Aventis and licensed to King, is listed in the Orange Book for Altace.

Cobalt Pharmaceuticals submitted the first ANDA with a paragraph IV certification to the '722 patent in 2002, thereby earning 180-day exclusivity for ramipril (and thereby establishing this as a "pre-MMA" case).  In 2005, Lupin Pharmaceuticals submitted the second ANDA with a paragraph IV certification to the '722 patent.  Aventis and King sued both companies.  In 2006, Aventis and King settled with Cobalt.  On September 11, 2007, the Federal Circuit reversed a district court decision in the Lupin case and invalidated the claims of the '722 patent (see this post).

According to the FDA website, five companies have received tentative approval to market generic ramipril: Dr. Reddy's; Purepac; Roxane; Sandoz; and Teva (see this web page).  Shortly after the Federal Circuit decision, one of those five companies and Lupin submitted letters to FDA urging that final approval of their ANDAs should not be held up by Cobalt's 180-day exclusivity (see this post).  In response, FDA requested comments from other interested parties.  To date, FDA has received comments from eight generic drug companies and three PBM companies (all may be found here).  The comments fall into three categories.

Lupin (with support from the three PBMs)

Besides accusing King of settling with the first ANDA filer to deliberately create a "bottleneck" to generic competition from subsequent ANDA filers, Lupin presents three main arguments : (1) Cobalt is no longer entitled to 180-day exclusivity because Cobalt stipulated to infringement of the '722 patent in its settlement with King, which caused Cobalt's paragraph IV certification to be converted into a paragraph III certification; (2) Lupin should be permitted to amend its ANDA to remove its paragraph IV certification because the '722 patent was invalidated (such an amendment would mean Lupin's approval would not be affected by any exclusivity Cobalt might have); and (3) Lupin is entitled to immediate approval of its ANDA--without waiting for the Federal Circuit to issue a mandate from its Sept. 11 decision (such immediate approval would give Lupin a head start in marketing ramipril before other generic competitors).

Anonymous tentatively approved filer (with support from Sandoz and Apotex)

The law firm of Hyman, Phelps & McNamara ("HPM") submitted a letter "on behalf of a company with a tentatively approved ANDA" for ramipril.  The letters from Sandoz and Apotex essentially mirror HPM's letter.  The letters make two main arguments: (1) Cobalt is no longer eligible for 180-day exclusivity, for the same reasons as those put forward by Lupin; and (2) once the Federal Circuit issues its mandate, FDA should deem the '722 patent to be de-listed from the Orange Book, which will then free FDA to grant final approval to all tentatively approved ramipril ANDAs.  In support of the second argument, Sandoz cites FDA's April 18, 2007 amlodipine decision.

Cobalt (with support from Barr, Ranbaxy, and URL Mutual)

Cobalt's letter makes three main points: (1) contrary to the allegations of Lupin, HPM and others, this is not a case where 180-day exclusivity has been "parked" indefinitely--rather, Cobalt's exclusivity period will be triggered when the Federal Circuit issues its mandate, and will terminate 180 days later; (2) the statute is unambiguous--no subsequent ANDA may be approved until the expiration of Cobalt's 180-day exclusivity; (3) there is no statute, regulation or case under which Cobalt may be found to have forfeited its exclusivity.  Cobalt makes what seems to be a very important point in that last argument: the admission of infringement that Cobalt made in the settlement of its litigation with King was made "without prejudice to Cobalt's allegations that the claims of the '722 patent are invalid and unenforceable."  Thus, Cobalt argues that it has not admitted the validity or enforceability of the '722 patent, and therefore its paragraph IV certification with respect to the '722 patent remains valid.  Barr and Ranbaxy echo this point in their letters.

Finally, Cobalt correctly notes that the impact of FDA's decision in this case will likely be limited, since there are only a handful of remaining cases governed by the pre-MMA version of the statute.  Nonetheless, it will be interesting to see how the FDA resolves this situation.

Pharma News Briefs

• FDA recently posted numerous comments from industry regarding Ramipril 180-day exclusivity issues on its website.  The comments come in response to FDA's request last month.  A summary of the new comments is in the works.
• FDA also established a docket for comments on Granisetron HCl 180-day exclusivity issues.  This too follows an FDA request made last month.
• Yesterday, the WSJ Health Blog had two pessimistic reports on the pharmaceutical industry: "Drug Drought Deepens as FDA Approvals Lag" and "Pharma Woes Won't Let Up Soon."
• Also on Halloween, the New York Time published a spooky article entitled "Chinese Chemicals Flow Unchecked Onto World Drug Market."  Reuters published a similar article the next day.  This can't be good publicity for pharmaceutical companies--both innovators and generics alike--who are increasingly outsourcing production of key ingredients to China.
• On Tuesday, the Federal Circuit denied rehearing of BIO and PhRMA v. District of Columbia, in which the court previously found Washington, D.C.'s drug price control law to be unconstitutional (see Patently-O).
• Last week, Sen. Bernie Sanders (D-VT) introduced a new bill that would scrap patent and market exclusivity for drugs and replace it with a "medical innovation prize fund" (see FDA Law Blog and Pharmalot).  I suspect that this bill is DOA, and therefore nothing to fear.
• Also last week, the WSJ Health Blog reported on Amgen's big win in its patent infringement suit against Roche's Mircera drug.
• A couple weeks ago, BioPharma Reporter published an interesting article, "U.S. Dragging its Heels on Biosimilars, Report Says."

Bayer Prevails Over Dr. Reddy's at Trial in Avelox Case

Bayer AG v. Dr. Reddy's Laboratories, Ltd., No. 04-179 (D. Del. 2007)

Last Thursday, the U.S. District Court for the District of Delaware held that two Bayer patents on Avelox (moxifloxacin hydrochloride) are valid and enforceable, and infringed by Dr. Reddy's ANDA for a generic version of Avelox.  The Opinion and Order follow a week-long bench trial held in August 2006.  Avelox is an antibiotic commonly used for the treatment of respiratory tract and other infections, with annual U.S. sales of $340 million.

The first of the two patents-in-suit, U.S. Patent No. 4,990,517, generically claims millions of quinolone compounds.  Moxifloxacin is one of many compounds listed in the '517 specification; it had not yet been synthesized at the time the application was filed.  The second patent-in-suit, U.S. Patent No. 5,607,942, claims a specific quinolone and its four stereoisomers, one of which is moxifloxacin.

Dr. Reddy's asserted that the '517 and '942 patents are invalid for obviousness and unenforceable due to inequitable conduct, and that the '942 patent is invalid for double patenting over the '517 patent.  With respect to obviousness, Dr. Reddy's asserted that one would have been motivated to modify a prior art compound at the 7-position; one would have been motivated to use a diazabicyclo octane (DBO) substituent at the 7-position; and through routine experimentation, one would have made compounds covered by the asserted claims.  Quoting KSR, the district court stated that "Reddy must identify some reason that would have prompted a person of ordinary skill in the relevant field to combine these elements to yield the claimed compounds."  Moreover, according to the district court, "Reddy must demonstrate that such a person would have had a reasonable expectation of success in doing so."

The parties disputed whether Dr. Reddy's was required to demonstrate why a person of ordinary skill in the art would have selected a particular lead compound to modify in the first place.  The district court sided with Bayer, citing the Federal Circuit's recent decision in Takeda v. Alphapharm as "affirming the district court's finding that defendant failed to prove a prima facie case of obviousness where the prior art disclosed a broad selection of compounds, any one of which could have been selected as a lead compound for further investigation, and defendant did not prove that the prior art would have led to the selection of the particular compound singled out by defendant."  The district court further found that Dr. Reddy's failed to demonstrate a motivation to modify a lead compound with DBO, or a reasonable expectation of success in making the proffered combination of prior art.

According to Bayer's press release announcing last Thursday's court decision, Teva has also challenged the validity of the same Bayer patents at issue in the Dr. Reddy's case.  Bayer's case against Teva is also pending in the District of Delaware, with trial currently scheduled to begin on February 25, 2008.

In addition to the '517 and '942 patents, the Orange Book lists two other Bayer patents for Avelox: U.S. Patent No. 5,849,752, directed to a crystal form of moxifloxacin; and U.S. Patent No. 6,610,327, claiming pharmaceutical formulations of moxifloxacin.  It is unclear how Dr. Reddy's and Teva intend to deal with those patents.