GlaxoSmithKline's most recent Paxil patent illustrates the latest wrinkle in patent infringement defense: "product by process" patents, attorney Robert Green (Leydig, Voit & Mayer, Chicago) told the National Association of Pharmaceutical Manufacturers bulk workshop March 20 in New York City.

GSK's most recently listed patent for paroxetine, patent No. 6,172,233, was issued Jan. 9. The patent "is not yet in litigation," Green observed, but "I bet you...in a matter of weeks it will show up in litigation."

The '233 patent appears to be eligible for "Orange Book" listing only by virtue of its "product by process" claims.

While FDA does not list process patents in the Orange Book, companies can list a "product by process" claim, Green explained. "This is a claim that identifies a product by the means by which it's manufactured."

"A company like SmithKline can bring into the litigation the issue of the process by issuing a 'product by process' claim and putting it in the Orange Book," Green said. Introducing issues of process into Orange Book litigation represents a backdoor approach for brand companies to name bulk drug manufacturers in patent infringement lawsuits, Green suggested.

The '233 patent describes a "process for making paroxetine," which is detailed in the first 10 claims of the patent. Claims 11 to 13 then claim "paroxetine when prepared according to the process" described in the patent. Claim 11 "in fact is a process claim that's hiding under the auspices of a product claim," Green maintained. "But this is Orange Book listable because it is an actual product claim."

Patent '233 is the tenth patent listed in the Orange Book for Paxil. Generic firms Apotex, Genpharm, Zenith, Pentech, Synthon and Alphapharm are currently involved in paroxetine litigation with GSK.

Apotex filed the first ANDA for paroxetine in March 1998. GSK has sued Apotex for patent infringement three separate times, most recently in September. While the 30-month stay from the first lawsuit expired Nov. 18, the latest stay will not expire until March 2003 (¹ Also see "SB Paxil Exclusivity Defense: Synthon Files NDA For Paroxetine Mesylate" - Pink Sheet, 6 November, 2000.).

If GSK enforces the '233 patent, an additional 30-month stay could extend until the end of 2003.

Brand firms are also finding ways to indirectly involve process patents in Orange Book litigation, Green said. GSK predecessor Glaxo Wellcome established declaratory relief as a means to bring process patents into ongoing Orange Book suits during the Zantac litigation against Novopharm, Green pointed out. He worked on the case as counsel for Novopharm.

In that case, Glaxo sought a declaratory judgment that Novopharm, after receiving FDA approval for its ranitidine ANDA, would violate a Glaxo process patent. Glaxo alleged that Novopharm, by communicating to Glaxo that it intended to market ranitidine via a Paragraph IV certification, had created a reasonable apprehension of imminent and irreparable harm sufficient to justify declaratory judgment.

GSK has "ongoing litigation under the declaratory judgment act in order to bring the issues of process, manufacturing that material, into a lawsuit" involving paroxetine.

Patent No. 6,080,759, issued in June 2000, claims "paroxetine anhydrate form A. In the patent, claim 10 is a process for making that," Green explained.

GSK alleges that "if the generic company's ANDA is approved, the commercial manufacture, use and so forth will infringe the process patent." In order to support its argument, GSK refers to "the Paragraph IV notification letter that was required, not for the process claim, but in order to institute the litigation...dealing with the other dozen or so patents that are in the Orange Book."

Bulk drug companies are not immune to patent litigation, Green warned the NAPM group. Active pharmaceutical ingredient sources are being charged with infringement for "inducing" the finished drug manufacturer to infringe.

A company that imports, sells, offers to sell or uses within the U.S. a product made by a process claimed in a U.S. patent is liable as an infringer, attorney Christopher Griffith (Leydig, Voit & Mayer, Chicago) said. "The court can grant an injunction to prevent the violation of process patent rights to stop importing the product into the U.S."

Griffith emphasized that the burden of proof shifts to the generic company. If the court finds a substantial likelihood that the product is made by a patented process - "that could be a declaration by the originator that they are aware of no other process by which the product can be made" - the product is presumed to be made by the patented process.

API manufacturers should "try to identify the relevant process patents before you start ramping up your manufacturing," Griffith said. The request for disclosure of process patents should be made "early and often," prior to importation.

The move to include API sources in patent infringement litigation under a charge of "inducement to infringe" is becoming "a trend that I think we will start to see pick up a lot of momentum in the ongoing litigation," Green predicted.

Brand companies argue that "if it were not for the API source, the finished dose manufacturer would not have filed the ANDA in the first instance," Green explained. GSK used the argument in paroxetine litigation with Pentech, which Green's law firm represents.

On Feb. 16, Chicago District Court Judge Nan Nolan granted GSK's motion to add Pentech's bulk drug supplier Asahi Glass to its patent infringement suit against the finished dose manufacturer.

GSK alleges that Tokyo-based Asahi infringed its paroxetine patents by collaborating with Pentech in the research and development of generic Paxil and providing the drug for use in the clinical studies supporting Pentech's ANDA.

AstraZeneca appears to be using "product by process" patent claims as part of its defense of the Prilosec franchise.

While several newly listed omeprazole patents include composition of matter claims that are not strictly tied to process claims, one patent - No. 6,166,213 - appears to only be eligible for Orange Book listing by virtue of its "product by process" claims.

On March 16, AstraZeneca submitted its most recent Prilosec patent for listing in the Orange Book, patent No. 6,191,148. The currently-published Orange Book includes seven patents for Prilosec; AstraZeneca has identified four additional patents (including '148) which have been submitted for listing, but not yet published (² Also see "AstraZeneca Awaits "Orange Book" Listing For Three Prilosec Patents" - Pink Sheet, 19 March, 2001.).

The most recent Orange Book submission, patent '148, claims "an improved process for the preparation, isolation, and purification of the anti-ulcer agent omeprazole." The patent also describes "compositions of omeprazole containing no chromatographically detectable levels of residual non-alcoholic organic reaction solvent."

The '148 patent, which expires Oct. 9, 2018, was granted Feb. 20. The patent is similar to recently-issued omeprazole process and composition patents, Nos. 6,166,213 and 6,147,103.

All three patents were issued to Merck, which manufactures Prilosec under the breakup agreement for the Astra-Merck joint venture in June 1998. Merck receives 32% of Prilosec sales, or roughly $1.3 bil. in 2000.

Merck will also receive royalties on Nexium, the single isomer version of the active ingredient in Prilosec, approved Feb. 20. AstraZeneca may need a delay in generic entrants for omeprazole to give the company time to convert patients to Nexium (³ Also see "AstraZeneca Nexium Relying On Healing Rate, Symptom Maintenance" - Pink Sheet, 26 February, 2001.).

Merck has taken a high-road public position regarding patent expirations, pointing out that it is not using lawsuits and patent disputes to lengthen the first expiring patents. In September, Merck Senior Director-Government Relations Ian Spatz pointed to the launch of multiple generic versions of Merck's Vasotec (enalapril) as an example of how the system should work (⁴ Also see "Waxman/Hatch Reform Should Clarify Rules, Not Change System - Merck" - Pink Sheet, 2 October, 2000.).

Spatz suggested that reforms to the Waxman/Hatch patent extension program should focus on "clarification" of patent life, rather than fundamental changes to the generic drug approval and extension process. "It is very important [for] a generic company [to have] certainty about when a product will be available to make a copy," Spatz declared. It is "also important for an innovator company to have that certainty that we will have that period of exclusivity."

Merck maintains that the law requires the listing of its omeprazole patents in the Orange Book. The company says that AstraZeneca is responsible for deciding whether and how to defend the patents.

GSK Paxil, AstraZeneca Prilosec Have New "Product By Process" Patents

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