Orange Book Blog

At the intersection of Patent and FDA Law

Recent Posts

  • Novartis Wins Temporary Restraining Order Against Teva in Lotrel Case

    Novartis v. Teva, No. 04-4473 (D.N.J. 2007)

    More drama involving amlodipine–this time with Lotrel (made by Novartis), rather than Norvasc (made by Pfizer).  Lotrel contains a combination of two active ingredients–amlodipine besylate and benazepril–whereas Norvasc contains only one.  Both drugs are indicated for the treatment of high blood pressure and both are blockbusters.

    Teva announced in a press release today that the FDA granted final approval to Teva’s ANDA for generic Lotrel on Friday, Teva began shipping the product immediately, and the U.S. District Court for the District of New Jersey granted Novartis’s motion for a temporary restraining order on Saturday, halting Teva’s shipments.

    Novartis and Teva have been locked in litigation over Teva’s ANDA for generic Lotrel since 2004.  The 30-month stay expired earlier this year and, probably sensing that Teva was close to obtaining final approval (and fearing an at-risk launch), Novartis moved for a preliminary injunction in March.  The district court was set to hear arguments on that motion in July.

    Novartis’s TRO motion recounts the events leading up to the filing of the motion on Saturday, and reveals that Teva’s only invalidity defense is obviousness.  Although Novartis’s TRO motion does not detail the parties’ arguments (instead, it incorporates by reference Novartis’s motion for preliminary injunction, which was filed under seal), I suspect that if obviousness is the primary issue in the litigation, Teva was emboldened to launch at-risk by the Supreme Court’s recent decision in KSR v. Teleflex.  Still, Teva seems to be laying it all on the line–especially considering that it is the 180-day exclusivity holder and its commercial launch triggered that exclusivity period.  The clock is ticking.

    Besides temporarily enjoining Teva from selling its generic Lotrel, the Order entered by the district court on Saturday requires Teva to immediately recall any generic Lotrel already shipped to customers.  The court has scheduled a hearing on the matter for tomorrow at 11 am (eastern).

    The patent-in-suit is U.S. Patent No. 6,162,802.

    RELATED READING:

    UPDATE: Teva announced Monday that the district vacated the temporary restraining order during the hearing Monday morning.  The court ordered Teva and Novartis not to sell any generic Lotrel until at least next Tuesday, May 29, when the court holds a status conference.  Read the AP story.

  • Pharma News Briefs

    • In a May 14 Order, the district court in D.C. denied all motions for reconsideration of its April 30 decision on Norvasc pediatric and 180-day exclusivity.  FDA Law Blog has all the reconsideration briefs.  Apotex and Mylan have now appealed to the D.C. Circuit.
    • The In Vivo Blog reports that "Democratic and Republican staffers involved in the follow-on biologics debate have reported good progress on the approval pathway and safety issues for follow-on biologics."
    • According to Red Herring, generic drug companies in India are very excited about the Supreme Court’s recent KSR decision.
    • Pharmalot has this recent post on a White House trade deal favoring generic drug makers.
    • AP reports that the Phillippines government has petitioned to void Pfizer’s Norvasc patent there.

  • Eisai Defeats Dr. Reddy’s and Teva in Aciphex Patent Suit

    Eisai v. Dr. Reddy’s and Teva, Nos. 03-9053 and 03-9223 (S.D.N.Y. 2007)

    Eisai owns U.S. Patent No. 5,045,552, which claims the chemical compound rabeprazole sodium, the active ingredient in Eisai’s blockbuster proton-pump inhibitor Aciphex.  Dr. Reddy’s, Teva and Mylan filed ANDAs for generic Aciphex with paragraph IV certifications to the ‘552 patent.  Aciphex has annual U.S. sales of over $1 billion and accounts for a large percentage of Eisai’s U.S. revenue, so naturally Eisai filed suit against the generic applicants.

    Last October (as we previously reported), Judge Gerard E. Lynch of the Southern District of New York granted Eisai’s motion for summary judgment of patent validity and partially granted Eisai’s motion for summary judgment of no inequitable conduct.  Dr. Reddy’s and Teva had already stipulated to infringement.  Judge Lynch held a two-week bench trial on the remaining inequitable conduct issues in March, and last Friday he issued a 62-page opinion in favor of Eisai.

    At trial, Dr. Reddy’s and Teva offered three allegations of inequitable conduct:

    1. Eisai failed to disclose a later-filed, later-issuing co-pending patent application directed to the ethyl homolog of rabeprazole;
    2. Eisai failed to disclose an international patent publication; and
    3. Eisai omitted certain data from a Rule 132 declaration filed in the prosecution of the ‘552 patent, and therefore the declaration was misleading.

    Judge Lynch found that Dr. Reddy’s and Teva failed to prove that the co-pending application and certain rejections made during its prosecution were of such a highly material nature as to support an inference of an intent to deceive.  Moreover, he concluded that the defendants utterly failed to prove any degree of an intent to deceive–finding the Eisai witnesses to be highly credible.  Judge Lynch further found that Dr. Reddy’s and Teva failed to prove either materiality of the international patent publication or an intent to deceive the patent office by failing to disclose it.  Finally, Judge Lynch found that the Rule 132 declaration was not in fact misleading, and that Eisai had no intent to deceive the PTO by omitting certain data from it.

    Though Friday’s ruling came in the litigations involving Dr. Reddy’s and Teva, Mylan had previously agreed to be bound by the outcome in the two cases.  The ruling is an especially bitter defeat for Dr. Reddy’s–since it was the first ANDA filer and the 180-day exclusivity holder.  Dr. Reddy’s (and perhaps Teva too) is expected to appeal the decision to the Federal Circuit.

    RELATED READING:

  • Federal Circuit Affirms Validity of Janssen’s Risperdal Patent, Rejecting Mylan’s Obviousness Arguments

    Janssen Pharmaceutica et al. v. Mylan Pharms., No. 07-1021 (Fed. Cir. 2007)

    Last Thursday, the Federal Circuit heard oral arguments in Mylan’s appeal of a district court decision upholding the validity of Janssen Pharmaceutica’s patent on Risperdal (risperidone), an antipsychotic medication with over $2 billion in annual U.S. sales.  On Friday, the Federal Circuit affirmed the decision under Rule 36 without issuing an opinion.  The case is noteworthy because the central issue on appeal was obviousness and the judges asked numerous questions about the effect KSR on the case.

    Much of the oral argument focused on whether the district court erred by rigidly applying a "lead compound standard," requiring Mylan to prove at trial that one of skill in the art would have chosen a single particular starting compound from which to develop the claimed compound.  The district court had called this standard, set forth in the Federal Circuit’s Yamanouchi v. Merck decision, a "factually-specific application of the ‘motivation-suggestion-teaching’ test."

    The Federal Circuit judges specifically asked whether KSR called the lead compound standard into question.  Counsel for Janssen replied, "no," arguing that whether you call it "lead compound analysis," "motivation," "reason," or "common sense," the district court’s analysis was correct.  Janssen’s attorney further expressed his belief that the Supreme Court in KSR essentially endorsed the TSM test, so long as it is not rigidly applied.

    Judges Gajarsa, Prost, and Otero (by designation from the Central District of California) presided over the oral argument.  If you would like to listen to the argument, search for case no. 07-1021 on the oral arguments web-page of the Federal Circuit website.

    RELATED READING:

  • Does FDA Need a Statutory Path to Approve Follow-on Biologics?

            Guest Post by Prof. Christopher M. Holman, UMKC School of Law

    Much of the current discussion surrounding the proposed follow-on biologics bills assumes that a “statutory path” is necessary before FDA can implement an abbreviated biologics license application (BLA) process for biotechnology-derived therapeutic proteins.  In fact, FDA probably already has the authority to create such a process by regulation, but so far has declined to do so.

    The argument that FDA requires a statutory path is based largely on the fact that the PHSA (the statute governing the regulation of most biotechnology-derived therapeutic proteins) does not explicitly provide an abbreviated BLA approval processes analogous to the FDCA’s 505(b)(2) “paper NDA” and 505(j) abbreviated NDA (ANDA).  But the FDCA explicitly requires clinical trials for the approval of an NDA, so FDA arguably needs explicit statutory authorization to implement an abbreviated process that dispenses with the requirement of clinical trials.  As noted in the House Report published in connection with the passage of Hatch-Waxman, the only statutory difference between a NDA and an ANDA is the requirement of human clinical trials.

    The PHSA, on the other hand, does not require clinical trials for approval of a BLA, and hence no explicit statutory path should be required for biologics.  FDA’s regulations require clinical trials to show safety and efficacy of biologics approved under the BLA process, but these are regulations dating back to the mid-1970s (well before the approval of any biotechnology-derived proteins), and could be updated by FDA to dispense with such a requirement in some instances, assuming the science would support such a revision, without requiring Congress to amend the PHSA.

    In 1996, a district court specifically found that FDA has the statutory authority under the PHSA to approve a comparable biologic without requiring new clinical trials.  Berlex Labs v. FDA, 942 F.Supp. 19 (D.D.C. 1996).  Although that case dealt with a change in manufacturing process implemented by the original manufacturer, with respect to the question of statutory authority the court’s rationale should apply equally to a comparable protein produced by a different manufacturer.

    During recent Congressional testimony, FDA’s representative Dr. Woodcock was questioned on the supposed need for a statutory path.  She walked a close line, at one point indicating that a statutory path was required, but on closer questioning conceding that the PHSA does not require clinical trials, and that the only statutory requirement is that the FDA ensure the “purity, potency and safety” of biologics approved under the Act.  Members of Congress also queried whether the rationale of Berlex Labs v. FDA should not also apply to biologics, but did not receive a direct answer.  Earlier, in January 2007, Reps. Dingell and Stupak sent a letter to FDA questioning whether a statutory path was really necessary, and asking for a response from FDA no later than February.  To my knowledge, FDA has not responded.

    (more…)

  • Pharma News Briefs

    • AP published this report on yesterday’s House hearing on "reverse payment" settlements.
    • AP also recently published this article on follow-on biologics legislation, entitled "Time is Running Out for Generic Biotech."
    • Antitrust Review recently posted an update on the FTC’s authorized generics study.
    • FDA Law Blog has a new post today on the most recent developments in the generic Norvasc litigation.
    • FDA Law Blog also posted last week on a Medicis challenge to FDA’s policy regarding exclusivity for "old" antibiotics.
    • Patent Docs has two interesting recent posts–here and here–on applying TRIPS to patented drugs in developing countries.
    • Patently-O has a new post today by Cal Crary, a pharma litigation analyst: "Impact of KSR v. Teleflex on the Pharmaceutical Industry."
    • PhRMA put out this press release on the U.S. Trade Representative’s annual report on IP rights; see also this related post on Pharmalot.
    • Pharmalot also recently had this interesting post on India’s generic drug companies.

  • House Energy and Commerce Committee to Hold Hearings on Follow-on Biologics and Reverse Payments

    On Wednesday, May 2nd, two subcommittees of the House Committee on Energy and Commerce will hold hearings of importance to pharmaceutical companies: first, on legislation to establish an abbreviated pathway for FDA approval of follow-on biologics; second, on a pending bill to ban “reverse payment” settlements of Hatch-Waxman litigation.

    At 10 a.m. ET, the Subcommittee on Health will hold a hearing entitled “Assessing the Impact of a Safe and Equitable Biosimilar Policy in the United States.”  Persons scheduled to appear include Dr. Janet Woodcock, Deputy Commissioner and Chief Medical Officer of the FDA, as well as executives from Insmed, Genentech, GPhA, and others.

    At 3 p.m. ET, the Subcommittee on Commerce, Trade, and Consumer Protection will hold a hearing entitled “Protecting Consumer Access to Generic Drugs Act of 2007.”  Persons scheduled to appear include Jon Leibowitz, Commissioner of the FTC, as well as Prof. Scott Hemphill, law professor at Columbia, Dr. Barry Sherman, CEO of Apotex, and others.

    RELATED READING:

    • Pharmalot interview with Rep. Jay Inslee (D-WA) on his follow-on biologics bill
    • March 25 post on House Oversight Committee hearing on follow-on biologics
    • March 8 post on Senate Health Committee hearing on follow-on biologics
    • February 15 post on Senate Judiciary Committee passage of reverse payments bill

    UPDATES:

    • An archived video, the prepared testimony, and a transcript of the follow-on biologics hearing are available here.
    • The video, testimony, and transcript of the reverse payments hearing are here.

  • ACI “FDA Boot Camp” Conference, May 15-16, San Francisco

    American Conference Institute is planning another “FDA Boot Camp” conference for May 15-16 in San Francisco.  Prior versions of this conference in New York and Chicago were very popular.

    According to ACI, “FDA Boot Camp has been designed to give product or patent litigators, as well as patent prosecutors and life sciences investment and securities experts, a strong working knowledge of core FDA regulatory competencies.”  The conference features top FDA regulatory experts from pharmaceutical companies and outside law firms.

    Here are a few of the presentations on the agenda:

    • The Basics: Understanding and Working with the FDA–Jurisdiction, Functions, Organization, and Operations
    • The Nature of the Approval Process for Drugs, Biologics, and OTC Products
    • Patent and IP Overview for Drugs and Biologics: Hatch-Waxman, Trade Dress, and More
    • Drugs and Biologics: Labeling
    • Non-patent Exclusivity
    • Bioequivalence: What Patent Lawyers Need to Know
    • Follow-on Biologics

    The co-chairs for the conference are Peter Safir of Covington & Burling LLP and William Vodra of Arnold & Porter LLP, both of whom are well known food and drug lawyers.

    Additional details and registration information are available at the conference website.

    Orange Book Blog is a media partner of this conference.

  • District Court Denies All Challenges to FDA Decision on Norvasc Exclusivity; Generic Cos. Likely to Appeal

    Mylan Labs. et al. v. Leavitt et al., No. 07-579 (D.D.C. 2007)

    In an April 18 decision, the FDA determined that Pfizer is entitled to six months of pediatric exclusivity on Norvasc (amlodipine besylate), that Mylan may continue to sell its generic version of Norvasc, that FDA will approve Apotex’s generic Norvasc ANDA if and when the Federal Circuit issues a mandate from its March 22 decision, and that no other Norvasc generics will be approved unless Pfizer’s Norvasc patent is removed from the Orange Book.

    Last week, Mylan, Apotex, and Teva filed motions in the U.S. District Court for the District of Columbia challenging various aspects of the FDA’s decision.  This morning, in a 22-page Opinion and Order, Judge Ricardo M. Urbina denied all three motions.

    Judge Urbina noted at the outset that FDA’s decision is subject to the "arbitrary and capricious" standard of review, under which the court "must consider whether the agency’s decision was based on a consideration of the relevant factors and whether there has been a clear error of judgment."  According to the Supreme Court, "The scope of review under the arbitrary and capricious standard is narrow and a court is not to substitute its judgment for that of the agency."  With this in mind, Judge Urbina addressed each of FDA’s decisions:

    FDA’s Decision that the Effective Date of the Federal Circuit’s Ruling is the Date it Issues its Mandate

    Judge Urbina agreed with FDA’s decision that Pfizer is entitled to pediatric exclusivity, though he used different reasoning to get there.  He reasoned that because 21 USC 355a(c)(2)(B) is silent "as to the particular court which may determine the patent dispute," the January 24, 2006 Northern District of Illinois Order
    in Pfizer v. Apotex triggered Pfizer’s pediatric exclusivity.  And, moreover, that decision "is effective and remains so during the pendency of the appeal unless the district court’s judgment is stayed or until the Federal Circuit issues its mandate."

    I expect Apotex will file a motion for stay very shortly.

    FDA’s Decision that Apotex Will Cease to Be Subject to Pfizer’s Exclusivity if the Mandate Issues Before September 25, 2007

    If FDA had followed its "longstanding practice to deem paragraph IV certifications as paragraph II certifications upon patent expiration," Pfizer’s pediatric exclusivity period (which began upon patent expiration on March 25, 2007) would block final approval for Apotex’s ANDA.  However, Judge Urbina deferred to FDA’s reasoning that Section 355a "manifests a clear Congressional intent that pediatric exclusivity not block the approval of an ANDA where the ANDA applicant has prevailed in the paragraph IV litigation."  He concluded that "FDA’s decision to exempt Apotex in light of its status as a prevailing party in challenging Pfizer’s patent is reasonable and is not contrary to the language in Hatch-Waxman."

    FDA Decision that Apotex is the Sole Statutory Beneficiary of the Federal Circuit’s Apotex Ruling

    Here, the FDA ruled that because the Federal Circuit invalidated only three claims of Pfizer’s Norvasc patent and left several claims untouched, Pfizer’s patent remains valid as to the remaining claims and is presumed to be properly listed in the Orange Book.  Judge Urbina agreed, concluding: "Until Teva succeeds in its own patent litigation with Pfizer or until administrative or legal action completely de-lists Pfizer’s patent from the Orange Book, the FDA’s decision to withhold market approval for Teva’s generic drug remains in effect.

    FDA’s Decision that Mylan’s Eligibility for 180-Day Exclusivity does not Extend Beyond Patent Expiration

    This one is interesting.  It sounds like Mylan meant to hold its challenge to this decision in reserve, but mistakenly filed a brief on it now.  The court proceeded anyway.

    Mylan argued that "nothing in the text or legislative history of the Hatch-Waxman Act indicates that generic exclusivity is forfeited upon patent expiration."  Judge Urbina quickly dispensed with this argument, observing that "[u]nder Hatch-Waxman, paragraph IV certifications are no longer valid upon patent expiration" and must be changed to paragraph II certifications.  At that time, the ANDA becomes eligible for immediate final approval.

    Because there’s so much money at stake, I would be surprised if one or more of the generic companies didn’t appeal to the D.C. Circuit.

    RELATED READING:

  • Supreme Court Upholds “TSM Test” of Obviousness; Mixed Impact for Pharmaceutical Patent Owners

    KSR Int’l v. Teleflex, 550 U.S. ___ (2007)

    In a unanimous decision released this morning, the Supreme Court reversed the Federal Circuit’s decision in KSR v. Teleflex.  The Court rejected the Federal Circuit’s rigid application of its "Teaching, Suggestion or Motivation" ("TSM") test in this particular case, but stopped short of discarding the test entirely.  Justice Kennedy wrote the opinion for the Court.

    Under the TSM test, an invention is obvious (and therefore unpatentable) only if there is a teaching, suggestion or motivation to combine prior art references.  The TSM test is especially relevant to patents on "combination
    inventions," such as those on pharmaceutical formulations.  Indeed, in
    today’s decision the Supreme Court cited with approval the Federal
    Circuit’s flexible application of the TSM test in Alza v. Mylan, in which the Federal Circuit invalidated Alza’s patent on an extended-release formulation of Ditropan.

    Pharmaceutical patent owners are likely relieved that the Supreme Court did not reject the TSM test outright and replace it with a much more stringent standard, such as "Synergism" (as applied in a 1976 Supreme Court case) or "Extraordinary Level of Innovation" (as suggested by the Solicitor General).  On the other hand, today’s decision does seem to raise the bar to patentability.

    While the Court’s decision today didn’t establish a clear test of obviousness, it did suggest "predictability" as a touchstone for obviousness:

    • "The combination of familiar elements according to known methods is likely to be obvious when it does no more than yield predictable results."
    • "[W]hen a patent claims a structure already known in the prior art that is altered by the mere substitution of one element for another known in the field, the combination must do more than yield a predictable result."
    • "If a person of ordinary skill can implement a predictable variation, Section 103 likely bars its patentability."
    • "[A] court must ask whether the improvement is more than the predicatable use of prior art elements according to their established functions."

    PhRMA, BIO, and IPO all filed briefs in support of Teleflex and a flexible TSM test.  Paul Berghoff, Jeremy Noe, and I contributed to the IPO brief.

    [Incidentally, nothing seems to bring the Supreme Court together as much as a patent case.  In his confirmation hearings last year, Chief Justice Roberts spoke of his desire to bring more unity to the Court.  It seems like every Supreme Court patent decision in the past year has been unanimous or nearly so.  Maybe this explains the Court’s recent interest in patent cases!]

    RELATED READING: