Orange Book Blog

Federal Circuit Affirms Topamax Decision in Favor of Ortho-McNeil and Against Mylan and Cobalt

Ortho-McNeil v. Mylan, No. 2007-1223 (Fed. Cir. 2008); Ortho-McNeil v. Cobalt, Nos. 2007-1258, -1259 (Fed. Cir. 2008)

U.S. Patent No. 4,513,006 is listed in the Orange Book as protecting Topamax (topiramate), Ortho-McNeil's blockbuster anticonvulsant for the treatment of migraines and epilepsy.  Mylan and Cobalt seek to market generic versions of Topamax before the '006 patent expires in September.  Last year, a district court construed the claims of the '006 patent and, on summary judgment, rejected Mylan's inequitable conduct, obviousness, and non-enablement arguments.  The Federal Circuit affirmed those decisions today.

Claim 1 of the '066 patent is drafted in a form typical of chemical compound claims.  Specifically, it is directed to a "sulfamate of formula (I) . . . wherein . . . R2, R3, R4 and R5 are independently hydrogen or lower alkyl and R2 and R3 and/or R4 and R5 together may be a group of formula (II) . . . ."  Mylan argued that the district court improperly construed the term "and" to mean "or" and, under the proper construction, the claim does not cover topiramate.  The Federal Circuit disagreed, reasoning, among other things, that "and appears in conjunction with the adverbs independently and together . . . [signaling] that and links alternatives that occur under the different conditions of independence or togetherness."

With respect to invalidity, the district court decision, released last February (before KSR), relied fairly heavily on the "teaching-suggestion-motivation" ("TSM") test to find the claims of the '066 patent invalid as obvious.  Accordingly, one might think this decision would be ripe for reversal.  Nevertheless, the Federal Circuit affirmed the decision, noting that "a flexible TSM test remains the primary guarantor against a non-statutory hindsight analysis such as occurred in this case."

According to the court's opinion, Ortho-McNeil scientist Dr. Bruce Maryanoff invented topiramate during a search for new antidiabetic drugs, when he "unexpectedly" . . . discovered that the compound had "powerful anticonvulsant properties."  In support of its obviousness position, Mylan argued "that a person of ordinary skill in the art faced with finding a diabetes drug (as Dr. Maryanoff was) would necessarily design an FBPase inhibitor."  The Federal Circuit found, however, that "even if an ordinarly skilled artisan sought an FBPase inhibitor, that person would not have chosen topiramate."  According to the court, "Mylan's expert, Dr. Anderson, simply retraced the path of the inventor with hindsight, discounted the number and complexity of the alternatives, and concluded that the invention of topiramate was obvious."

The Federal Circuit also affirmed the district court court's conclusion of no inequitable conduct, finding that Ortho-McNeil did not misrepresent certain prior art references to the patent office, as Mylan argued, but instead "accurately characterize[d] the references."  In addition, the court affirmed the district court's conclusion that the '066 patent is not invalid for lack of enablement, finding that the claim term "anticonvulsively effective amount" is not unclear and its determination would not require undue experimentation.

In a separate decision, released concurrently, the Federal Circuit affirmed the district court's decision against Cobalt, another ANDA filer for generic Topamax, who stipulated that it would be bound by the district court's decision in the litigation against Mylan.  Cobalt retained its rights to appeal to the Federal Circuit, but stipulated that such an appeal would be based on the record in the Mylan case.  Accordingly, the Federal Circuit rejected Cobalt's "indefiniteness" argument, raised in its appeal brief, because it was not presented to the district court.

RELATED READING:

• Reuters article

Eisai Wins Preliminary Injunction Against Teva's Generic Aricept

Eisai Co. v. Teva Pharms. USA, No. 05-5727 (D.N.J. 2008)

Eisai Co., Ltd., the Japanese manufacturer of Aricept (donepezil hydrochloride), has won a preliminary injunction against Teva Pharmaceuticals USA, Inc., keeping Teva's generic version of Aricept off the market for the time being.  Aricept, which accounts for $1.6 billion in annual U.S. sales, is reportedly the world's most prescribed treatment for Alzheimer's disease.

In the decision, released Friday, the district court found that Eisai is likely to succeed on its claim of infringement because Teva's sole defense, that U.S. Patent No. 4,895,841 is unenforceable for inequitable conduct, lacks substantial merit.  Initially, Teva also asserted that the '841 patent is invalid for obviousness.  However, in December, Teva acknowledged that it had dropped its obviousness defense.  Teva stipulated to infringement of claims 8, 10 and 13 of the '841 patent, which are directed to the active ingredient in Aricept, donepezil hydrochloride, pharmaceutical compositions thereof, and a method for treating Alzheimer's disease by administering the compound.

Teva asserted that the '841 patent is unenforceable for inequitable conduct due to Eisai's failure to disclose two references during prosecution: a co-pending patent application owned by Eisai, now known as the '431 patent; and a 1984 article in the Journal of Medicinal Chemistry, authored by Richard A. Kenley.  According to Teva, had Eisai informed the Examiner of the '431 patent application and the Kenley article, the Examiner likely would have rejected the '841 patent application for obviousness-type double patenting over the '431 patent.  Donepezil is an acetylcholinesterase ("AChE") inhibitor.  The '431 patent is directed to AChE inhibitor compounds that are structurally related to donepezil, while the Kenley article focuses on restoring activity to already-inhibited AChE enzymes.

The court determined that "Eisai's co-pending '431 patent was material enough that it should have been disclosed," noting that "both patent applications were largely aimed at treating the same disease, Alzheimer's, and both patent applications stemmed from research by at least nine common inventors at Eisai."  However, after carefully comparing the chemical structures of donepezil and the compounds disclosed by the '431 patent, the court concluded that the materiality of the '431 patent is "very low."  Meanwhile, the court concluded that the materiality of the Kenley article is "almost non-existent."  Dr. Kenley himself submitted a declaration in support of Eisai.

With respect to the other prong inequitable conduct, the court stated: "there can be no punishable intent to deceive where there is no substantial likelihood that a reasonable patent examiner would have considered the undisclosed information important to deciding whether to allow the application to issue as a patent."  Accordingly, the court concluded that Eisai is likely to succeed on the merits of its case at trial.  The court treated the remaining elements of the preliminary injunction analysis in summary fashion.

A trial date in the case has not been set.  The '841 patent is set to expire November 25, 2010.  Assuming that Teva holds the 180-day exclusivity rights for generic Aricept, Teva will likely proceed to trial (and appeal, if necessary), hoping for a decision declaring the '841 patent unenforceable at least six months prior to then.

RELATED READING:

• Bloomberg article
• Eisai press release
• Teva press release

OBB News Briefs

• Earlier this week, FDA Law Blog provided an update on Teva's suit against the FDA, seeking relisting of Janssen's patent on Risperdal (risperidone) and confirmation of Teva's 180-day exclusivity on a generic version of the drug.
• Last week, FDA Law Blog reported on a recent FDA determination that Watson Labs forfeited its 180-day exclusivity on generic Camptosar (irinotecan HCl) because it failed to obtain tentative approval of its ANDA within 30 months of filing, as required by the MMA.
• Pharmalot and the WSJ Health Blog recently ran posts on a series of articles in the Los Angeles Times examining whether generic drugs are as good as brand-name drugs.
• Eighteen states recently sued Abbott Labs for antitrust violations, alleging that Abbott made trivial changes to the formulation of its TriCor cholesterol drug, thereby delaying generic competition.  Statements were released by the Attorneys General from Florida and Iowa.
• William Kovacic was appointed the new Chairman of the Federal Trade Commission this week, succeeding Deborah Platt Majoris.  The Wall St. Journal reported that Mr. Kovacic has been a strong proponent of FTC action against "reverse payment" settlements.

IQPC "Optimising Pharmaceutical Patent Lifecycles" Conference, London, April 29-30

Legal IQ, a division of IQPC, will be holding a highly interactive two-day conference, "Optimising Pharmaceutical Patent Lifecycles," in London, April 29-30.  The conference will focus on how to maximize product revenues and yet avoid anti-competitive issues through strategic patent lifecycle management.

Featuring seventeen international experts, the conference will cover hot topics such as how to maintain a competitive advantage by integrating legal and commercial strategies to extend product lifecycles, how to update patent strategies by assessing the implications of current U.S. and European case law, how to prevent competition law violations and how to maximize the commercial value of patents by strategically managing the interplay between generics and innovators.

The conference features two practical tutorials ("P.I.T. Stop" sessions), led by experts from Bristows and Simmons & Simmons, which will allow attendees to discuss and work through common industry problems guided by the experts' perspectives.  The main focus will be on building a commercially sound patent lifecycle management strategy and reassessing the impact that patent practices have on competition law positions in Europe and the U.S.

The conference is specifically designed to answer pressing questions from top figures at EPO, UK IPO, Indian PO and USPTO, provide practical lessons in how to apply the key patent lifecycle extension strategies, and ensure that attendees maximize the efficiency of potential collaborations between innovators and generics.

For more information or the register, please visit the conference website.

Federal Circuit Addresses Effect of 271(e)(1) "Safe Harbor" in ITC Actions

Amgen v. Int'l Trade Comm'n and Roche, No. 2007-1014 (Fed. Cir. 2008)

Amgen holds at least six US patents that relate to erythropoeitin and its derivatives (EPO) and processes for making EPO, protecting the Amgen drugs Aranesp and Epogen.  Sales of Aranesp alone topped $3.6 million last year.  Roche produces EPO in Europe and has been seeking FDA approval for its own EPO drug, Mircera, in the US.

Roche began importing EPO as part of its effort to generate data for its regulatory submissions to the FDA.  Amgen did not object to these acts of importation.  However, Roche continued importing EPO even after its FDA application was complete (though Roche has not yet sold or contracted to sell any of its EPO in the US).  Amgen responded by filing a Section 337 action with the International Trace Commission (ITC), asking the ITC to enjoin Roches further importation and future sale in the US of its European-produced EPO.

The ITC denied Amgens injunction request because (1) the ITC determined that Roches importation of EPO was protected by the FDA safe harbor provision of Section 271(e)(1), which provides that conduct cannot infringe a patent when it is reasonably related to securing FDA approval; and (2) the ITC has no jurisdiction absent a sale or contract for sale of EPO in the US.  In a decision Wednesday, the Federal Circuit affirmed in part, reversed in part, and remanded the case to the ITC.

Amgen made three arguments on appeal: (1) Section 271(e)(1) provides no exemption for the importation of articles made overseas by patented processes in Section 337 actions before the ITC; (2) Section 271(e)(1) does not provide blanket protection for all pre-FDA-approval conduct; and (3) the ITC has jurisdiction whenever sale of the accused article is imminent.  All three Federal Circuit panelists sided with Amgen on the second and third points.  On the first point, however, Judges Newman and Lourie agreed with the ITC, while Judge Linn dissented to express his agreement with Amgen’s argument.

On Amgen’s first point, the majority accepted the ITC’s argument, i.e., that the Section 271(e)(1) safe harbor should operate identically in ITC litigation as in federal district court litigation.  The importation of an article made by an infringing process constitutes an act of infringement under Section 271(g).  But the safe harbor of Section 271(e)(1) holds that certain acts related to gaining regulatory approval are not acts of infringement.  Therefore, 271(e)(1) cuts back on 271(g) by declaring that certain types of conduct do not constitute infringement.  The ITC, however, does not look to Section 271(g) for its authority.  Instead the ITC looks to 19 USC § 337(a)(1)(B)(ii), which declares unlawful the importation of any article “made . . . by means of a process covered by the claims of a valid and enforceable United States patent.”  In contrast, Section 271(g) only forbids the importation of articles made by means of a process that infringes the claims of a valid and enforceable US patent.  Because the safe harbor of Section 271(e)(1) only addresses infringement, Judge Linn (in dissent) argues that the safe harbor applies to infringement liability under Section 271(g) but not to unlawful trade practices under Section 337(a)(1)(B)(ii).  The majority’s holding elects to gloss over these key differences between Section 271(g) and Section 337.

On the other hand, the majority’s holding probably does comport more closely with the policy rationales that support having the regulatory safe harbor.  As the majority notes, the legislative history supports this proposition that the 271(e)(1) safe harbor applies identically to importation under Section 271(g) and to importation under Section 337(a)(1)(B)(ii).  Moreover, the Supreme Court’s broad reading of the scope of the regulatory safe harbor in Integra v. Merck and Eli Lilly v. Medtronic lends further support for the majority’s policy judgment.  Judge Linn even agrees that the majority reaches the policy outcome that makes the most sense.  Nevertheless, the text of Section 337(a)(1)(B)(ii) is clearly at odds with such a policy outcome.

On Amgen’s second point, the Court agreed with Amgen.  The safe harbor of Section 271(e)(1) does not provide blanket protection for all pre-FDA-approval conduct.  For each separate act, the accused party must demonstrate that each act is reasonably related to gaining regulatory approval.  Amgen asserted that Roche continued importing EPO after its FDA application was complete and used the imported EPO to conduct marketing studies.  The Court remanded the case to the ITC for an act-by-act evaluation of whether Roche’s conduct was indeed within the ambit of Section 271(e)(1).

On Amgen’s third point, the Federal Circuit held that the ITC jurisdiction is invoked “[w]hen it has been shown that infringing acts are reasonably likely to occur . . . .”  The court went to great lengths to point out that this standard is not new, and is, in fact, consistent with nearly three decades of ITC precedent.  Because Section 337 provides for a prospective remedy, it makes no sense for the complainant to wait for an actual sale to occur, so long as an actual sale is imminent.

RELATED READING:

• Patent Docs
• Patently-O
• Reuters

OBB News Briefs

• Last Friday, Rep. Anna G. Eshoo (D-CA) announced that she and Rep. Joe Barton (R-TX) introduced H.R. 5629, the "Pathway for Biosimilars Act" (click here for summary; click here for text of bill).  BIO immediately applauded the bill, while GPhA immediately denounced it.  For more, visit FDA Law Blog; Pharmalot; or the WSJ Health Blog.
• Barr Labs and Teva are two of the world's largest, and most litigious, generic drug companies.  Their CEO's gave extensive interviews to separate newspapers last week: Barr's CEO Bruce Downey to Investor's Business Daily and Teva's CEO Shlomo Yanai to Globes.
• We reported in January that Teva filed a citizen petition asking FDA to relist J&J's patent on Risperdal and to grant it 180-day exclusivity on the generic.  Recently, FDA law blog and Patent Baristas reported that FDA denied Teva's petition on February 26, and Teva responded by filing suit against FDA on March 4.  Also see: Reuters and Teva press release.
• The Wall St. Journal reported last week that Thailand is poised to disregard patents on several cancer drugs.  The WSJ Health Blog has a summary of the article.
• Teva announced last month that it received approval for the first biosimilar G-CSF in Europe.

District Court Upholds Validity of P&G's Actonel Patent, Rejecting Teva's Obviousness Arguments

Proctor & Gamble v. Teva Pharms. USA, No. 04-940 (D. Del. 2008)

Late last month, the U.S. District Court for the District of Delaware (J. Farnan) upheld the validity of Proctor & Gamble's U.S. Patent No. 5,583,122, which claims risedronate sodium, the active ingredient in Actonel.  Teva had challenged the '122 patent in a paragraph IV certification in its ANDA.  P&G's U.S. sales of Actonel, which is indicated for the prevention and treatment of osteoporosis, were approximately $1 billion last year.

Teva alleged that the '122 patent is invalid as obvious in light of U.S. Patent No. 4,761,406, entitled "Regimen for Treating Osteoporosis."  Alternatively, Teva alleged that the '122 patent is invalid for obviousness-type double patenting in view of the '406 patent.  Specifically, Teva argued that the structural similarities between risedronate, claimed in the '122 patent, and 2-pyr EHDP, disclosed and claimed in the '406 patent, render claims 4, 16 and 23 of the '122 patent obvious.

The district court's opinion relies heavily on the Federal Circuit's decision last year in Takeda v. Alphapharm:

The Federal Circuit has held that "structural similarity between claimed and prior art subject matter, proved by combining references or otherwise, where the prior art gives reason or motivation to make the claimed compositions, creates a prima facie case of obviousness."  Takeda.  In addition to structural similarities, the Federal Circuit has also required a showing of "adequate support in the prior art" for the change in structure.  Id.  Clarifying these principals further, the Federal Circuit has held that a prima facie case of unpatentability requires a "showing that the prior art would have suggested making the specific molecular modifications necessary to achieve the claimed invention."  Id.

Reviewing the evidence adduced at trial in light of these legal principles, the Court concludes that Teva has not established by clear and convincing evidence that "the prior art would have suggested making the specific molecular modifications necessary" to achieve risedronate.  To begin, the Court is unpersuaded that a person of ordinary skill in the art would have selected 2-pyr EHDP as the "lead compound" out of the numerous compounds disclosed in the '406 patent.

The court further concluded, "even if Teva can establish a prima facie case of obviousness, Proctor & Gamble has demonstrated sufficient evidence of unexpected results regarding resedronate's potency and toxicity to rebut such a prima facie showing."  Finally, the court determined that Teva had not proven double patenting, as "the same type of analysis is used for an obviousness-type double patenting inquiry as for a Section 103 obviousness inquiry."

The '122 patent won't expire until December 2013.  Teva immediately announced its intention to appeal the district court's decision to the Federal Circuit.

RELATED READING:

• Business Week
• P&G press release
• Teva press release

Federal Circuit Invalidates Pfizer's Latest-Expiring Patent on Celebrex, for Double Patenting

Pfizer v. Teva Pharms. USA, No. 2007-1271 (Fed. Cir. 2008)

Pfizer owns three Orange Book-listed patents protecting its blockbuster arthritis drug Celebrex (celecoxib): U.S. Patent Nos. 5,466,823; 5,563,165; and 5,760,068.  As we previously reported, last year a district court held that Teva's ANDA infringes all three patents, and enjoined Teva from marketing its generic version of Celebrex until 2015, when the '068 patent expires.  (There is also a fourth, later-expiring, patent listed in the Orange Book for Celebrex, No. 5,972,986, but presumably Teva filed a section viii statement on it).

On Friday, the Court of Appeals for the Federal Circuit held that the '068 patent, claiming methods of use, is invalid for double patenting in view of the '165 patent, claiming compositions.  The decision effectively results in a loss of one and a half years of patent protection on Celebrex.

The primary issue in the case appears to be one of first impression: whether 35 U.S.C. § 121 applies not only to divisional patent applications, but also to continuation-in-part ("CIP") applications.  35 U.S.C. § 121 provides, in part, as follows:

A patent issuing on an application with respect to which a requirement for restriction under this section has been made, or on an application filed as a result of such a requirement, shall not be used as a reference either in the Patent and Trademark Office or in the courts against a divisional application or against the original application or any patent issued on either of them, if the divisional application is filed before the issuance of the patent on the other application.

Thus, section 121 provides a "safe harbor" to divisional applications from obviousness-type double patenting rejections.  Teva contended that section 121 applies exclusively to divisional applications, and that because the '068 patent issued on a CIP rather than a divisional application, the '068 patent is not entitled to the protections of the statute.  According to the Federal Circuit's opinion, Pfizer argued "that the terms 'divisional' and 'continuation-in-part' are merely labels used for the administrative convenience, and that accordingly, although the '068 is termed a CIP, it is in effect a divisional for purposes of section 121."

The Federal Circuit sided with Teva.  The court reviewed the text of section 121 (which refers exclusively to divisional applications), the statute's legislative history, and case law, concluding that "the protection afforded by section 121 to applications (or patents issued therefrom) filed as a result of a restriction requirement is limited to divisional applications."  Moreover, because "[t]he claims at issue of the '068 merely recite methods of administering a 'therapeutically-effective amount' of the compositions found in claim 5 of the '165 patent," the court found them not patentably distinct over the claims of the '165 patent, and therefore invalid for obviousness-type double patenting.

Although the Federal Circuit invalidated the '068 patent, the court upheld the validity of the '823 and '165 patents, rejecting Teva's arguments that they are invalid for failure to disclose the best mode and unenforceable for inequitable conduct.  Thus, Celebrex will remain protected until at least May 30, 2014, when pediatric exclusivity attached to the '165 patent expires.

RELATED READING:

• Patent Docs
• Pfizer press release
• Reuters
• Wall St. Journal

Barr Labs Prevails in Yasmin Case; Bayer's Patent Held Invalid for Obviousness

Bayer Schering Pharma AG v. Barr Labs., No. 05-2308 (D.N.J. 2008)

On Monday, the U.S. District Court for the District of New Jersey invalidated Bayer's U.S. Patent No. 6,787,531 on grounds of obviousness, relying heavily on KSR.  The '531 patent, claiming pharmaceutical formulations of micronized drospirenone and ethinylestradiol, protects Bayer's Yasmin birth control pill.  Barr Labs had challenged the '531 patent in a paragraph IV certification with its ANDA filing.

The court's opinion follows a bench trial held over a two-week period late last year.  The main issues in the case were whether it would have been obvious "to (1) micronize drospirenone so as to increase its bioavailability, and (2) not protect the drospirenone from the gastric environment with an enteric coating."  Drospirenone is a relatively difficult molecule to formulate due to its poor water solubility and sensitivity to acid.

While Bayer argued that the prior art taught away from micronizing acid-sensitive drugs like drospirenone, the court concluded: "Undoubtably, there would be some concern about dissolution of a poorly water soluble acid sensitive drug, but the person of ordinary skill in the art could conclude that micronization is a viable option."  Similarly, while Bayer asserted that the prior art taught that acid sensitive drugs must be enteric coated, the court credited Barr's argument, finding that "inter- and intra-subject variability is a major disadvantage" of enteric coating, and concluding therefore that one "could not rule out formulating a micronized drospirenone without enteric coating."  Furthermore, the court concluded that a prior art reference teaching that drospirenone isomerzies when exposed to hydrochloric acid in vitro (Nickisch) should be discounted because its results were not corroborated by in vivo studies.

In addition to concluding that the invention claimed in the '531 patent would have been obvious, the court concluded that the invention was obvious to try:

As noted, in KSR the Supreme Court ruled that a patent claim may be obvious if the combination of elements was "obvious to try."  In this case, the testimony was limited to discussion about whether or not to employ to common formulation techniques -- micronization and enteric coating.  As in KSR "there are a finite number of identified predictable solutions."  In this case, based on the prior art as a whole, micronizing and immediately releasing drospirenone was obvious to try.

The '531 patent, which would expire in 2020, is one of three Orange Book-listed patents for Yasmin.  The others are U.S. Patent No. 5,569,652, claiming methods of use and expiring in 2013; and U.S. Patent No. 6,933,395, claiming compositions and expiring in 2017.  Although Barr is the first ANDA filer for a generic version of Yasmin, if Barr filed paragraph III certifications with respect to the '652 and '395 patents, then it must wait at least until those patents expire before it launches its generic product.

The U.S. market for Yasmin is approximately $500 million annually.  Bayer is expected to appeal Monday's decision to the U.S. Court of Appeals for the Federal Circuit.

RELATED READING:

• Bayer press release
• Patent Docs
• Pharmalot
• Wall St. Journal Health Blog (with interview of Barr Labs' CEO)