Orange Book Blog

Federal Circuit Affirms Invalidity of Par Pharma's Patents on Megestrol Acetate Formulations

Par Pharmaceuticals v. Roxane Labs, No. 2007-1093 (Fed. Cir. 2007)

In the early 1990s, Bristol-Myers Squibb developed and patented Megace, a liquid pharmaceutical composition of megestrol acetate indicated for the treatment of anorexia, cachexia, or an unexplained weight loss.  Par Pharmaceuticals sought to design around the claims of BMS's patent and introduce a generic version of Megace.  In developing its product, Par discovered that flocculated suspensions of megestrol acetate could be formed using a much wider range of excipients and concentrations than those known to BMS.  Through those efforts, Par obtained a series of patents on its flocculated suspensions, including U.S. Patent Nos. 6,593,318 and 6,593,320, the two patents-in-suit in this case.

Par won its paragraph IV challenge of BMS's patent in 2001 and, as the first ANDA applicant to file a paragraph IV certification, earned 180 days of market exclusivity for megestrol acetate oral suspension.  In 2003, Par brought suit against Roxane Laboratories, a subsequent ANDA filer for megestrol acetate oral suspension, asserting that Roxane's formulation infringes the '318 and '320 patents.  The district court granted Roxane's motion for summary judgment of invalidity for lack of enablement under section 112, paragraph 1.  Last Friday, the Court of Appeals for the Federal Circuit affirmed that decision.

The test of enablement is whether one of ordinary skill in the art can make and use the claimed invention without undue experimentation.  Furthermore, under In re Wands (Fed. Cir. 1988), eight factors are relevant to the enablement analysis: (1) the quantity of experimentation necessary, (2) the amount of direction or guidance presented, (3) the presence or absence of working examples, (4) the nature of the invention, (5) the state of the prior art, (6) the relative skill of those in the art, (7) the predictability or unpredictability of the art, and (8) the breadth of the claims.

The Federal Circuit cited two factors that were particularly relevant to the enablement analysis in this case: the unpredictability of the art and the breadth of the claims.  According to the court, "all the record evidence establishes that the art of making stable flocculated suspensions of megestrol acetate is highly unpredictable."  Moreover, the court concluded that the claims at issue "have an extraordinarily broad scope," allowing, for example, "the choice of any surfactant in any concentration."  The court observed: "In this case, Par sought extremely broad claims in a field of art that it acknowledged was highly unpredictable, therefore, Par has set a high burden that its patent disclosure must meet to satisfy the requisite quid pro quo of patent enablement."

In reviewing Par's evidence of enablement, the Federal Circuit noted that the specification of Par's patents discloses only three working examples, utilizing only one new surfactant.  Moreover, the court found the two declarations submitted by Par's expert witness to be conclusory and lacking "specifics as to the experimentation that would be needed to practice the entire scope of the claims."  Additionally, the court characterized Par's evidence that Par's inventor was able to formulate the claimed composition with seven different surfactants as "merely colorable" evidence, failing to create a genuine issue of material fact as to enablement of the full scope of the claims.

Thus, the Federal Circuit concluded that each of the asserted claims of Par's patents is invalid for lack of enablement, and therefore affirmed the district court's grant of summary judgment.

Pharma News Briefs

• Last Friday, FDA Law Blog wrote about yet another 180-day exclusivity letter from the FDA, this one requesting comment on the "failure to market" forfeiture provisions of the MMA.
• FDA Law Blog also posted a very nice summary of the FDA Amendments Act, which, among other changes, revises the citizen petition process.
• GSK sued the U.S. Patent & Trademark Office last Tuesday to block implementation of the PTO's new rules restricting patent claims and continuation applications.  Read more here: Patent Docs; Patently-O; Pharmalot; WSJ Health Blog.
• The Wall St. Journal had an interesting article last week on China's generic drug industry.  In case you're not a subscriber to the Journal, you can read the WSJ Health Blog's summary here or Pharmalot's here.
• On October 4, the FDA announced an initiative to streamline the generic drug approval process.  GPhA reacted with skepticism.

Paddock Labs Prevails Over Schwarz Pharma in Univasc Case at Federal Circuit

Schwarz Pharma v. Paddock Labs, No. 2007-1074 (Fed. Cir. 2007)

In a decision released this morning, the Federal Circuit affirmed a 2006 district court decision granting summary judgment of noninfringement of U.S. Patent No. 4,743,450 in favor of Paddock Labs.  The '450 patent, owned by Warner-Lambert and exclusively licensed by Schwarz Pharma, covers pharmaceutical compositions containing Angiotensin Converting Enzyme ("ACE") inhibitors, including Schwarz Pharma's Univasc (moexipril hydrochloride).  ACE inhibitors are popular drugs for the treatment of hypertension and congestive heart failure.  The Federal Circuit affirmed the district court decision "because the district court did not err in its conclusion that prosecution history estoppel bars resort to the doctrine of equivalents in this case."

Claim 1 of the '450 patent is directed to a pharmaceutical composition comprising an ACE inhibitor; "an alkali or alkaline earth metal carbonate"; and a saccharide.  Claim 16, the only other independent claim of the '450 patent, is directed to a process for stabilizing an ACE inhibitor comprising contacting the drug with "an alkali or alkaline earth metal carbonate"; and a saccharide.  Originally, the independent claims recited a "metal containing stabilizer" and "an alkali or alkaline earth-metal salt," respectively.  However, following an obviousness rejection during prosecution, each was amended to recite "an alkali or alkaline earth metal salt carbonate."  Paddock's ANDA products comprise an ACE inhibitor (moexipril chloride) and magnesium oxide (MgO).

As a preliminary matter, the Federal Circuit decided an issue concerning jurisdiction: whether Schwarz Pharma lacked standing to bring the appeal because Warner-Lambert, the patent owner, did not appeal the district court's judgment.  Paddock argued that Schwarz was "merely an exclusive licensee of the '450 patent who does not possess 'all substantial rights' in the patent."  While it is well established that a patent owner must be joined in an action for infringement brought by an exclusive licensee, the issue concerning appeals was one of first impression for the Federal Circuit.  The court determined that "when a patentee joins an exclusive licensee in bringing a patent infringement suit in a district court, the licensee does not lose standing to appeal even though the patentee does not join in the appeal," explaining that the reason for requiring joinder in the district court (to avoid subjecting the alleged infringer to multiple actions) does not exist on appeal.

With regard to the patent issues, the Federal Circuit agreed with the district court that amendment-based prosecution history estoppel precluded Schwarz Pharma from resorting to the doctrine of equivalents to prove infringement.  The court noted that the original claims recited a metal containing stabilizer and an alkaline earth metal salt, and therefore the subject matter encompassed by those terms was presumptively surrendered when the claims were amended.  Schwarz Pharma argued, however, that the term "stabilizer" was defined in the specification more narrowly, to exclude MgO.  But the Federal Circuit didn't buy it, since the "definition" in the specification wasn't so clear, and the ordinary meaning of "alkaline earth metal salt" encompasses MgO.  The Federal Circuit further found that Schwarz failed to rebut the presumption of surrender because MgO was not an unforseeable equivalent and the narrowing amendment was not merely tangentially related to the use of MgO.

Paddock (and Teva, incidentally) is already on the market with its generic Univasc products, so as a practical matter, today's decision simply means that Paddock won't have to pay damages for past infringement and may continue to sell its products.

Federal Circuit Affirms Injunction Against Apotex in Depakote Case, But Finds Apotex Was Not in Contempt

Abbott Labs v. Torpharm and Apotex, No. 2007-1019 (Fed. Cir. 2007)

In 1997, Apotex filed an ANDA for generic Depakote (divalproex sodium), Abbott's blockbuster treatment for bipolar disorder, migraine headaches, and epilepsy.  Abbott responded by filing suit against Apotex for infringement of U.S. Patent Nos. 4,988,731 and 5,212,326, which claim an oligomer containing about 4 to 6 repeating units of divalproex sodium.  In 2001, the district court granted summary judgment of validity and infringement.  However, in 2002, the Federal Circuit remanded for a trial on infringement.  On remand in 2004, Judge Posner, sitting by designation in the Northern District of Illinois, found that Apotex infringed Abbott's patents and enjoined Apotex from making, using or selling "divalproex sodium which the Court has found to be infringing" until Abbott's patents expire (January 29, 2008).

Not content to sit around and wait four years, Apotex attempted to design around Abbott's patents, and allegedly developed divalproex sodium in the form of a polymer that is composed of much more than about 4 to 6 repeating units of divalproex sodium.  Rather than file a new ANDA, however, Apotex struck a deal with Nu-Pharm, Inc. (a former sister company of Apotex) whereby Apotex would pay for the costs of preparing the ANDA and Nu-Pharm would take on the "litigation risks" arising from the filing.

Nu-Pharm filed the ANDA in 2005 and Abbott responded by filing suit against Nu-Pharm.  In March 2006, Nu-Pharm filed an amended ANDA, seeking approval for additional dosage strengths of the product, and Apotex filed a second lawsuit--this time naming both Nu-Pharm and Apotex as defendants.  The two cases were consolidated before Judge Pallmeyer in the Northern District of Illinois.  On August 15, 2006, Abbott filed a "Motion to Enforce Its Injunction Order" before Judge Posner and a motion to stay the proceedings before Judge Pallmeyer.

On October 6, 2006, Judge Posner found Apotex in contempt for violating the injunction he issued two years earlier.  He characterized the injunction as extending to "any generic divalproex sodium manufactured by Apotex that has been found to be infringing."  He then found that there was no difference between Apotex's old product and its new product, and that, based upon the evidence presented by the parties, Apotex's new product would infringe Abbott's patents.  Accordingly, Judge Posner extended the injunction to cover Nu-Pharm's ANDA.  Apotex then appealed to the Federal Circuit.

Apotex raised two issues on appeal: (1) whether 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; and (2) whether the contempt proceeding was improper in any event because the infringement inquiry was amenable only to trial under the Federal Rules of Civil Procedure.

In a decision released today, the Federal Circuit upheld the district court's decision to hold a contempt proceeding as well within its discretionary authority, notwithstanding any provisions in (or not in) the Hatch-Waxman Act, and affirmed the revised injunction against Apotex.  The Federal Circuit observed that "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)."  Moreover, the Federal Circuit affirmed Judge Posner's finding that clear and convincing evidence proved that the Nu-Pharm drug would infringe the claims of Abbott's patents.  Such evidence was found in documents showing no difference between the new drug and the old, and expert testimony showing the Nu-Pharm drug is in fact an oligomer.  Accordingly, the Federal Circuit affirmed that Judge Posner acted entirely within his authority to extend the injunction to prohibit the FDA from approving the Nu-Pharm ANDA, and refused to vacate the revised injunction.  Thus, it appears that Apotex will have to wait until 2008, after all, before it can market its generic version of Depakote.

As minor consolation to Apotex, the Federal Circuit also held that the district court erred in finding Apotex in contempt.  Here, the Federal Circuit held that the district court made an error of law in interpreting its original injunction to preclude the filing of the Nu-Pharm ANDA.  It was undisputed that Apotex's actions in attempting to design around Abbott's patents occurred outside the United States.  Thus, since Apotex did not make, use, sell, offer to sell in the U.S. or import into the U.S. generic divalproex sodium, the Federal Circuit found that Apotex did not violate the original injunction.

iiBIG "New Directions for Drug Delivery" Conference, Las Vegas, October 29-30

The International Institute for Business Information & Growth will hold a conference entitled "New Directions for Drug Delivery," October 29-30 in Las Vegas, Nevada.  The conference is designed for pharmaceutical scientists and specialty pharma, biopharmaceutical, and nanotechnology licensing and business development team leaders.  According to iiBIG, attendees will learn "how new scientific technologies are driving investments, alliances and clinical trials to bring novel drug delivery technologies to market."

The agenda includes several interesting sessions, including:

• "Rapid Evaluation of Drug Delivery Technologies"
• "FDA & Patents -- Case Study of Transdermal Patches"
• "Innovations and Success Strategies: Learning and Un-learning from Key Players" (a panel on which I'll be speaking)
• "Eye on the Future -- Breakthrough Scientific and Partnership Strategies"
• "Converting from Drug Delivery to Specialty Pharma -- The Road More Traveled"

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

Orange Book Blog is a media partner of this conference.

FDA Requests Comments on 180-Day Exclusivity for Generic Altace (Ramipril)

For the second time in as many weeks, FDA has asked interested parties to submit comments regarding 180-day generic drug exclusivity issues.  On September 26, as FDA Law Blog reported, FDA requested comments on exclusivity for generic Precose (acarbose) tablets; last week, FDA asked for comments on exclusivity for generic Altace (ramipril) capsules.  Two letters have been submitted so far.

Hyman, Phelps & McNamara, P.C. submitted a letter on behalf of an unnamed company that has a tentatively approved ANDA for ramipril capsules.  Their letter explains: Cobalt Pharmaceuticals was the first ANDA filer and, as such, was eligible for 180-day exclusivity; Cobalt's ANDA was submitted prior to enactment of the 2003 Medicare Modernization Act, and therefore pre-MMA exclusivity provisions apply; Cobalt's ANDA contained a paragraph IV certification with respect to U.S. Patent No. 5,061,722, a composition of matter patent set to expire in 2008; King and Aventis sued Cobalt for infringing the '722 patent, and later settled the litigation, with Cobalt stipulating to infringement; then, on September 11, 2007, the Federal Circuit invalidated the '722 patent.  According to Hyman, Phelps' letter, "Thus, Cobalt's 180-day exclusivity is 'parked' to the detriment of subsequent ANDA applicants with tentative approval (unless and until a court decision triggers exclusivity)."

Hyman, Phelps argues that FDA should determine that Cobalt's ANDA no longer contains a paragraph IV certification, but contains a paragraph III certification instead (based on the fact that Cobalt has stipulated to infringement and therefore is no longer challenging the '722 patent), and so is ineligible for 180-day exclusivity.  Moreover, they argue that as soon as the Federal Circuit issues the mandate from its September 11 decision, FDA should remove the '722 patent from the Orange Book (because it will have been formally declared invalid) and grant final approval to any tentatively approved ANDAs for ramipril capsules.

In the other letter, Buc & Beardsley wrote to FDA on behalf of its client, Lupin Pharmaceuticals, to request immediate approval of Lupin's ANDA for ramipril capsules.  Lupin is the party that prevailed over King and Aventis in the Federal Circuit on September 11.  Like Hyman, Phelps' letter, Buc & Beardsley's letter argues that Cobalt's ANDA no longer contains a valid paragraph IV certification, because Cobalt stipulated to infringement.  But unlike Hyman, Phelps', Buc & Beardsley argues that final approval of other ANDAs need not await issuance of a mandate.  Instead, based on a fine distinction from the amlodipine case, Buc & Beardsley argues that Lupin's ANDA must be finally approved immediately.

The last point may become moot, since the Federal Circuit may in fact issue a mandate from its September 11 decision before FDA decides all the exclusivity issues raised in these letters.

ACI "Maximizing Pharmaceutical Patent Life Cycles" Conference, New York, October 24-25

American Conference Institute will hold its eighth annual "Maximizing Pharmaceutical Patent Life Cycles" conference October 24-25 in New York.  According to ACI, this is the "one and only event that has consistently allowed brand name and generic drug makers to benchmark their companies' current strategies and tactics against competitors in both camps."

The agenda includes many topics covered on Orange Book Blog.  Specific talks include:

• "KSR and the New Standard for Obviousness: Exploring Its Impact on Primary and Secondary Pharmaceutical Patents"
• "Brand Name and Generic Pharmaceutical Patent Settlements: Pending Legislation, Key Cases and Strategies to Employ"
• "Patent and Non-Patent Exclusivity--New Developments Affecting the Basics and Beyond"
• "Orange Book Listings and Delistings: New Controversies, Concerns and Considerations" (I'll be speaking on this panel)
• "Update on FDA Activities Relative to Pharmaceutical Patent Life Cycles" (by Elizabeth Dickinson, Assoc. Chief Counsel for Drugs, FDA)

In addition, two optional post-conference workshops are offered on October 26: a brand name master class entitled "New Strategies for Obtaining Pharmaceutical Patent Extensions Post-KSR" and a generics master class entitled "Updated Drafting Guidelines for Paragraph IV Certifications and Notice Letters."

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

Orange Book Blog is a media partner of this conference.

Pharma News Briefs

• The Supreme Court this morning denied Pfizer's cert petition in the Norvasc case (AP story).  Although the Federal Circuit's March 22 decision is controversial, the denial of Pfizer's cert petition is not surprising, given that the Court had previously denied Pfizer's motions for an emergency stay and for an expedited appeal.
• Late last Friday the Court of Appeals for the Federal Circuit denied Novartis's emergency motion to enjoin Teva from selling generic Famvir (Teva press release; Globes article).  Three weeks ago, the Federal Circuit temporarily enjoined Teva, apparently costing Teva three weeks of its 180-day exclusivity.
• President Bush signed the FDA Amendments Act of 2007 into law last Thursday (AP story).  FDA put out this press release.  PhRMA released this statement.
• Also Thursday, the Federal Circuit denied Alphapharm's petition for rehearing en banc of Takeda v. Alphapharm, in which the court previously upheld Takeda's patent on Actos.  No opinion was issued.
• The Federal Trade Commission announced in a press release Thursday that it is challenging Mylan's proposed acquisition of E. Merck oHG, which is Merck KgAA's generic subsidiary.  See also this Reuters article.
• FDA Law Blog had a very interesting post last Wednesday on FDA's recent letter requesting comment on certain 180-day exclusivity forfeiture and Orange Book patent delisting issues.