Orange Book Blog

Patent Protection for Research Tools Remains Unclear After Federal Circuit Revisits Integra v. Merck

Integra Lifesciences v. Merck KGaA, No. 2002-1052 (Fed. Cir. 2007)

          by Robert S. Dailey

Last Friday, the Court of Appeals for the Federal Circuit decided Integra v. Merck, on remand from the Supreme Court.  Click here for the opinion.  The case has important implications for owners of "research tools" patents.

In the mid-1990s, Integra sued Merck KGaA (the German company) and Scripps for infringing five patents relating to peptides that contain the RGD sequence of amino acids.  This suite of patents included both patents directed to RGD-containing peptide compounds and patents directed to laboratory methods (i.e., research tools) using the RGD-containing peptides.

Merck and Scripps defended their conduct by relying on the FDA safe harbor of 35 USC § 271(e)(1), which precludes liability for activities "reasonably related to the development and submission of information under [the Food, Drug and Cosmetic Act]."  The FDA safe-harbor was passed as part of the Hatch-Waxman Act to permit "a limited amount of testing so that generic manufacturers can establish the bioequivalency of a generic substitute."  In this sense, the safe harbor encompasses activities that develop information that will normally find its way into an FDA submission.

At the original trial in the district court, Integra argued for a narrow reading of the FDA safe harbor in three respects.  First, Integra argued that the safe harbor includes only studies on the safety of administration to humans, and does not include experiments on mode of action (i.e., ADME and PK studies).  Second, Integra argued that the safe harbor excludes studies on related compounds that were not the subject of any FDA submission.  Third, Integra argued that the safe harbor can only include experiments complying with the FDA’s Good Laboratory Practices (GLP), since only data from GLP-compliant studies qualify for submission to the FDA.

A jury verdict and bench opinion accepted Integra's narrow reading of the safe harbor statute, and found Merck and Scripps liable for infringement.  A divided panel of the Federal Circuit affirmed.  The Supreme Court granted certiorari on the limited question of "whether uses of patented inventions in preclinical research, the results of which are not ultimately included in a submission to the [FDA], are exempted by [the FDA safe harbor]."  The term "patented inventions" presumably included both patented compounds and patented research tools that use those compounds.

Ranbaxy and GSK Reach Settlement on Launch of Generic Valtrex

          by Robert S. Dailey

Indian generic drug manufacturer Ranbaxy announced last week that the company has settled its litigation with GlaxoSmithKline over generic Valtrex.  Ranbaxy received final FDA approval for its generic drug earlier this year.  Under the agreement, the generic will launch in the second half of 2009 and Ranbaxy will retain 180-day exclusivity.

GSK's U.S. Patent No. 4,957,924 covers the composition of Valtrex, a hydrochloride salt of the L-valyl ester prodrug of acyclovir.  The generic form is referred to as valacyclovir.  Patent protection was set to expire in late June 2009.  Therefore, it does not appear that the settlement will lead to an early launch of the generic.  Details of the settlement have not been released.

The Paragraph IV action had originally been filed in May 2003 in the District of New Jersey.  A bench trial before Judge Mary Cooper was set to begin on July 18, but had been delayed until September at the parties’ request.

Ranbaxy’s stock rose 10% last week on the announcement of its 2009 entry into this lucrative product market.

RELATED READING:

• AP story
• Reuters-India article

Pharma News Briefs

• FDA Law Blog reported Monday that the proposed follow-on biologics legislation is in serious jeopardy in Congress.  Pharmalot had a similar report last Friday.
• Meanwhile, European regulators recently granted approval to three new biosimilar drugs, as Patent Docs reports today.
• The San Francisco Chronicle recently published a nice article summarizing the debate over generic biotech drugs.
• The Business Standard recently reported on incentives for Indian drug companies to develop generic biotech drugs.
• Peter Zura's 271 blog had this interesting post Wednesday on controversy caused by reaction of the Indian generic pharmaceutical industry to patent reform legislation in Congress.
• MarketWatch had this article last weekend examining the leveling off of pharmaceutical prices in America.
• Par and J&J announced they have settled their generic Ultracet patent litigation: MarketWatch; Patent Docs.
• IMPAX announced a district court ruling relating to generic Rilutek: PharmaLive; UPI.

Federal Circuit Affirms Invalidity of AstraZeneca's Toprol-XL Patent

In re Metoprolol Succinate Patent Litigation, No. 2006-1254 (Fed. Cir. 2007)

On Monday, the Federal Circuit affirmed a district court summary judgment decision that AstraZeneca's U.S. Patent No. 5,081,154 is invalid for double patenting.  The '154 patent claims metoprolol succinate, the active ingredient in Astra's blockbuster cardiovascular drug Toprol-XL.  KV Pharmaceutical, Andrx, and Eon Labs have all filed ANDAs for generic Toprol-XL and are defendants in the litigation.

The Federal Circuit explained that "non-statutory, or 'obviousness-type,' double patenting is a judicially created doctrine adopted to prevent claims in separate applications or patents that do not recite the 'same' invention, but nonetheless claim inventions so alike that granting both exclusive rights would effectively extend the life of patent protection."  The majority (Judges Gajarsa and Mayer) concluded that the '154 patent is invalid for double patenting over U.S. Patent No. 4,780,318.  The '318 patent expired in 2005 and claims pharmaceutical compositions containing one of a number of active ingredients (including metoprolol succinate), while the '154 patent has not yet expired and, as noted, claims the compound metoprolol succinate.  Judge Schall dissented.

According to the majority opinion, a 1997 Federal Circuit decision, In re Emert, 124 F.3d 1458, mandated the invalidity finding in this case:

In Emert, this court held the claims of an application unpatentable for double patenting, finding that "the '887 application's claimed invention, an oil soluble dispersant comprising B1, while not anticipated by the '624 patent due to the slight modification of three claim limitations, would have been prima facie obvious in light of the claim to the combination [A and B]" because the patentee "effectively conceded that the differences between B and B1 are not material and would have been obvious to a person having ordinary skill in the art."  Similarly, in this case, Claim 1 of the '154 Patent claiming a compound (A1) is an obvious variation of Claim 8 of the '318 Patent claiming a composition comprised of one compound of an enumerated list (A1, A2, A3, etc.), an inner layer (B), and an outer layer (C).  Specifically, it would have been an obvious variation of Claim 8 of the '318 Patent to omit the inner layer (B) and the outer layer (C).  Astra offers no convincing reason why Emert does not apply.

In dissent, Judge Schall disagreed that Emert controls this case.  According to Judge Schall, "the critical point is that, in this case, the compound metoprolol succinate has not been claimed twice."  He explained: "I believe the law is that there is no double patenting simply because a later claimed element is set forth in an earlier claim to a combination."

Besides affirming the invalidity finding, the Federal Circuit also vacated the district court's summary judgment decision of inequitable conduct and remanded the case for resolution of a factual dispute over whether Astra had the requisite intent to deceive the patent office during prosecution of the '154 patent.  The Federal Circuit explained that it reached this issue "because the parties dispute whether a patentee may reinstate the validity of a patent by filing a terminal disclaimer during litigation," and the Federal Circuit has not yet decided that question.

RELATED READING:

• The Patent Prospector
• Patent Docs
• Sandoz press release
• 10/29/06 OBB post, reporting on KV Pharma's Toprol-XL citizen petition

Pharma News Briefs

• The House of Representatives passed an omnibus FDA bill on Wednesday.  The Senate passed its own FDA bill in May.  Differences between the two bills will be hammered out in conference committee, where follow-on biologics provisions may be tacked on.  See coverage at: FDA Law Blog; Pharmalot;  PhRMA press release; WSJ Health Blog.
• Business Standard magazine had this story Monday on reaction by Indian generic drug companies to authorized generics.
• FDA Law Blog had an interesting post last week on a recent request for information on FDA's policy for Orange Book listings of patents that cover drug delivery systems but that do not recite an active ingredient or drug formulation.
• More generic Norvasc approvals: Lupin; Ranbaxy; Roxane.

Apotex Prevails Over Daiichi Sankyo in Floxin Otic Case, as Federal Circuit Invalidates Daiichi's Patent

Daiichi Sankyo Co. v. Apotex, No. 2006-1564 (Fed. Cir. 2007)

In a nonprecedential opinion released today, the Federal Circuit reversed a district court decision that held Daiichi Sankyo's U.S. Patent No. 5,401,741 not invalid for obviousness.  The '741 patent claims a method for treating bacterial ear infections by topically administering the antibiotic ofloxacin (marketed by Daiichi as Floxin Otic solution, 0.3%).  Apotex had filed an ANDA for generic Floxin Otic, certifying under Paragraph IV that the '741 patent is invalid.  The FDA tentatively approved Apotex's ANDA in November 2005.

The Federal Circuit's decision turned on its finding of clear error in the district court's determination of the level of ordinary skill in the art, one of the Graham factors.  The district court had concluded that the ordinary person skilled in the art pertaining to the '741 patent would be "a pediatrician or general practitioner--those doctors who are often the 'first line of defense' in treating ear infections."  The Federal Circuit observed that in their briefs to the district court, the parties had provided little more than conclusory arguments, and therefore the district court "looked to other decisions involving patents for a method of treating a physical condition for guidance."  According to the Federal Circuit, the district court's reliance on those decisions was improper.

The Federal Circuit suggested that the district court should have made its own factual findings regarding the level of skill in the art.  For instance, according to the Federal Circuit, "the inventors of the '741 patent were specialists in drug and ear treatments--not general practitioners or pediatricians;" "others working in the same field as the inventors of the '741 patent were of the same skill level;" and "while a general practitioner or pediatrician could (and would) prescribe the invention of the '741 patent to treat ear infections, he would not have the training or knowledge to develop the claimed compound absent some specialty training such as that possessed by the '741 patent's inventors."

The level of skill in the art matters in this case because Daiichi succeeded in convincing the district court that a key prior art reference, "Ganz," disclosed  "nothing at all" relevant because it was directed at "a highly, highly subspecialized physician . . . which would be the otologist or the ear doctor," not a primary care physician or general practitioner.  The Federal Circuit concluded, "Daiichi's evidence as to why this reference did not render the invention of the '741 patent obvious was based on an improper determination of the level of skill in the art," and therefore reversed the district court's validity finding.

RELATED READING:

• Bloomberg article

Scherago Int'l "Biosimilars 2007" Conference, Washington, D.C., September 24-25

Scherago International has announced "Biosimilars 2007," a two day conference to "air the issues" and "raise the questions" associated with biosimilars (also called follow-on biologics or biogenerics).  The conference will be held September 24-25 in the Jack Morton Auditorium on the campus of George Washington University, in Washington D.C.

Speakers include leaders in Congress working on biosimilars legislation--including Congressman Henry Waxman--as well as leaders and experts from the FDA, industry, public organizations and consumer groups.  Panel discussions will add to the presentation of the many issues and allow the audience to ask questions of the speakers.

The conference will include five main sessions:

• Legislation in the US, EU, and Japan
• Policy
• Legal/Patent
• Economic and Financial
• Regulatory/Scientific & Technical

According to the conference organizers, those who should attend include:

• Legal Affairs / Corporate Strategy / Regulatory Affairs
• Intellectual Property / Patent Attorneys / Regulatory Compliance
• New Product Development / Business Development  / Business Operations
• Project Management / Laboratory Heads/Chiefs / Scientific Affairs
• Principal Scientists / Chief Scientific Officer

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

Orange Book Blog is a media partner of this conference.

Pharma News Briefs

• Last week, the U.S. District Court for the District of Columbia denied Mylan's emergency motion for a temporary restraining order that would have forced FDA to relist Pfizer's Norvasc patent in the Orange Book.  Until June 22, when FDA delisted Pfizer's patent, Mylan and Apotex had the only approved ANDAs for generic Norvasc.
• Bloomberg reported Thursday that Pfizer and Sandoz have settled their litigation over Sandoz's ANDA for generic Zithromax.  The district court entered an order dismissing the case on June 25.
• Also Thursday, The Wall St. Journal Health Blog reported that the government of Brazil and Abbott Labs stepped back from the brink and agreed on a price for Kaletra, Abbott's AIDS drug.
• The National Law Journal had this article Friday on alleged abuse of the citizen petition process by pharmaceutical companies.
• FDA released a new final guidance document entitled "ANDAs: Pharmaceutical Solid Polymorphism -- Chemistry, Manufacturing, and Controls Information."  The guidance provides recommendations on assessing sameness when a drug substance exists in polymorphic forms.

Festo XIII: Federal Circuit Further Limits the Doctrine of Equivalents

Festo v. Shoketsu Kinzoku Kogyo Kabushiki Co., No. 2005-1492 (Fed. Cir. 2007)

In a decision that appears to diminish the value of pharmaceutical formulation patents, today the Federal Circuit held that "[a]n equivalent is foreseeable if one skilled in the art would have known that the alternative existed in the field of art as defined by the original claim scope, even if the suitability of the alternative for the particular purposes defined by the amended claim scope were unknown."  Judge Dyk wrote today's opinion; he was joined by Chief Judge Michel.  Judge Newman wrote a strong dissent.

This litigation began in August 1988 when Festo sued the defendant for infringement of U.S. Patent No. 4,354,125.  The '125 patent, entitled "Magnetically Coupled Arrangement for a Driving and a Driven Member," has nothing whatsoever to do with pharmaceuticals, but the ensuing litigation has had a dramatic effect on patent law.  The case has made two round-trips from the district court to the Federal Circuit and Supreme Court and back--and then finally back up to the Federal Circuit, which is where today's decision was made.

The case concerns the scope of the Doctrine of Equivalents, a judicial doctrine stating that although an accused product might not be literally identical to a patented invention, it still may be held to infringe the patent if it is "equivalent".  The doctrine is especially important with respect to pharmaceutical formulation patents, because generic drug companies often try to "design around" such patents by using excipients that are not identical to those used in the innovator product, but which serve the same function.

In 2002 (in "Festo VIII"), the Supreme Court held that a narrowing amendment to the claims of a patent application, made during prosecution, would preclude application of the doctrine of equivalents, with three exceptions: (1) the equivalent was "unforeseeable at the time of the application," (2) "the rationale underlying the amendment bears no more than a tangential relation to the equivalent in question," or (3) that "some other reason suggests that the patentee could not reasonably be expected to have described the insubstantial substitute in question."

Earlier this year, the Federal Circuit strictly limited the "tangential relation" exception (in Cross Medical); now the court has done something similar with the "unforeseeability" exception.  By holding that whether a scientist in the field of the invention would have in fact recognized a substitute as usable is irrelevant to the legal question of foreseeability, the court has practically eliminated the exception.

As applied to pharmaceutical formulation patents, generic drug companies will certainly argue that the case stands for the proposition that if an excipient was known to exist at the time a claim amendment was made, then as a matter of law it was not unforeseeable--even if a formulation scientist would not have recognized that the excipient could have served as an acceptable substitute.

Given the Federal Circuit's pattern of rulings in Doctrine of Equivalents cases over the last 15 years or so, today's decision is not especially surprising.  Nonetheless, it serves to remind patent owners that they should anticipate having to enforce patents by proving literal infringement.

RELATED READING:

• Patent Docs

ACI "FDA Boot Camp" Conference, Boston, July 17-18

American Conference Institute's popular "FDA Boot Camp" comes to Boston on July 17-18.  According to ACI, seats at this year's New York and last year's Chicago editions sold out.

The conference is designed to give patent lawyers, product liability lawyers, 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.

Presentations on the agenda include:

• The Basics: Understanding and Working with the FDA--Jurisdiction, Functions, Organization, and Operations
• The Nature of the Approval Process
• Understanding the Clinical Trial Process for Drugs and Biologics
• Patent and IP Overview for Drugs and Biologics: Hatch-Waxman, Trade Dress, and More
• Drugs and Biologics: Labeling
• Medical Devices: Classification and the Essentials of the Device Premarket Review Process

The chair for the conference is Michael P. Peskoe of Edwards Angell Palmer & Dodge LLP.  Additional details and registration information are available at the conference website.

Orange Book Blog is a media partner of this conference.