Patent Baristas » Pharmaceutical

Where In The World Is Pharmaceutical Innovation?

Stephen Jenei — Wed, 10 Nov 2010 22:10:55 +0000

In a recent paper by Yali Friedman of the BiotechBlog, Yali looks at the growth of research capabilities in emerging economies such as India and China. With a substantial increase in the outsourcing of some of the more routine activities involved in pharmaceutical research and development (R&D), such as compound synthesis and preclinical toxicity tests, a question is whether research-based companies are shifting the volume and value of innovative science research to emerging economies.

This paper focuses on the location of innovation in the pharmaceutical sector, particularly in the United States as the world’s largest pharmaceutical market, comprising roughly 40% of the world’s pharmaceutical revenues. There were 1,400 first-year patents granted to drugs approved between 2001 and 2009.

Inventorship of these patents was concentrated in a small number of countries: 60% of inventors were from the United States, and 31.5% of inventors were from just seven other countries (United Kingdom, Japan, Germany, Sweden, France, Switzerland and Belgium).

So far, the emerging markets of India and China but the substantial time lag — often ~10 years or more between the initial discovery of a potential drug and its market approval — and the recent nature of the increase in investment in innovative research in such countries, this observation is not unexpected.

Read the results here: Location of pharmaceutical innovation – 2000-2009

When It Comes to Patent Term Extensions, An Enantiomer is a Different Drug From Racemate

Stephen Jenei — Wed, 19 May 2010 17:48:59 +0000

Recently, the courts looked at the question of whether separate enantiomers can have “first commercial marketing or use” status for purposes of patent term extension under 35 U.S.C. § 156. The U.S. Patent and Trademark Office, after consulting with the FDA, had granted an extension for US Pat. No. 5,053,407, which is exclusively licensed to Ortho-McNeil Pharmaceutical and is directed to an enantiomer of a racemic compound.

Under the Hatch-Waxman Act, a patent term extension is permitted for a patent that claims a drug that required regulatory approval prior to being put on the market (the Drug Price Competition and Patent Term Restoration Act, codified in part at 35 U.S.C. § 156 et seq.).

The district court agreed with the positions of the Patent and Trademark Office and the FDA, and held that the statutory requirements for term extension were met for the ’407 patent. The court then prevented Lupin Pharmaceuticals from making and selling the drug during the extended term of the patent. Needless to say, Lupin was crestfallen and appealed but the US Court of Appeals for the Federal Circuit affirmed the district court’s judgment in Ortho-McNeil Pharma v. Lupin Pharma (09-1362).

The ’407 patent is for an antimicrobial compound having the common name levofloxacin. Levofloxacin is the levorotatory enantiomer (also designated the S(-) enantiomer) of the racemate ofloxacin, which is a known antimicrobial product. A racemate consists of equal amounts of spatial isomers called enantiomers, molecules that are mirror images of each other.

Due to their spatial orientation, enantiomers are optically active and are characterized by whether they rotate plane-polarized light clockwise (dextrorotatory) or counter-clockwise (levorotatory). Although enantiomers and their racemates have the same chemical composition, they may differ in their physical, chemical, or biological properties. It is often the case that one of the enantiomers possesses a substantially greater portion, if not all, of the biological activity of the racemic mixture. This raises the question of the status of separated enantiomers as “new drug products” and whether they can be “first commercial marketing or use” if the racemate has previously been granted market approval, pursuant to 35 U.S.C. § 156(a)(5)(A).

The inventors determined that levofloxacin has properties that are significantly superior to those of ofloxacin. The ’407 patent describes this synthesis, and presents data showing that levofloxacin is more effective as an antimicrobial agent, more rapidly available for biological effectiveness, and has lower acute toxicity and thus may be administered in higher doses than ofloxacin.

The PTO concluded that extension of the patent term was warranted, and the PTO and FDA collaborated in calculation of the applicable extension of 810 days, in accordance with §156(d)(2)(A). Lupin the tried to block the extension under 21 U.S.C. §355(j)(2)(A)(vii)(IV) (Paragraph IV certification).

The law, in 35 U.S.C. §156(a), states that:

The term of a patent which claims a product, a method of using a product, or a method of manufacturing a product shall be extended in accordance with this section . . . , if– . . . (a)(4) the product has been subject to a regulatory review period before its commercial marketing or use; (a)(5)(A) except as provided in subparagraph (B) or (C) [not here relevant], the permission for the commercial marketing or use of the product after such regulatory review period is the first permitted commercial marketing or use of the product under the provision of law under which such regulatory review period occurred; . . .

The term “drug product” means the active ingredient of (A) a new drug, antibiotic drug, or human biological product (as those terms are used in the Federal Food, Drug, and Cosmetic Act and the Public Health Service Act), . . . including any salt or ester of the active ingredient, as a single entity or in combination with another active ingredient.

The issue was whether this was the first permitted commercial marketing or use of levofloxacin, as required by 35 U.S.C. §156(a)(5)(A), for the racemate had previously been marketed. The district court held that the extension was in conformity with the practices of the PTO and the FDA with respect to enantiomers, and that the PTO’s determination that levofloxacin is a different “product” than the racemate ofloxacin must be afforded “great deference.”

Lupin argued that the PTO and the FDA incorrectly interpreted the statute as far as enantiomers are concerned. Lupin insisted that an enantiomer is half of its racemate, and thus that the enantiomer levofloxacin was an “active ingredient” or component of the previously marketed racemate ofloxacin. That is, the racemate was merely a composition containing two drugs: the R and the S enantiomers. Thus, levofloxacin is the same “drug product” as ofloxacin meaning that levofloxacin was not “the first permitted commercial marketing or use of the product” as required by §156(a)(5)(A).

Ortho countered that an enantiomer has consistently been recognized, by the FDA and the PTO, as a different “drug product” from its racemate. The FDA practices were explained by Dr. David Lin, a former acting Division Director in the FDA’s Division of New Drug Chemistry, declaring that “in each and every instance in which it has considered the question, the FDA has described a racemate as a single active ingredient, distinct from its enantiomers, and each enantiomer as a single active ingredient distinct from the other and from the racemate.”

Lupin tried arguing that the status of enantiomers with was legislatively changed in 2007, in the statute that changed the FDA policy concerning data exclusivity for new enantiomer products. 21 U.S.C. §355(u)(1) (Supp. II 2008). The new provision authorizes an applicant “for a non-racemic drug containing as an active ingredient (including any ester or salt of the active ingredient) a single enantiomer that is contained in a racemic drug approved in another application” to, under certain conditions, “elect to have the single enantiomer not be considered the same active ingredient as that contained in the approved racemic drug.” Lupin felt that by specifically allowing an applicant to “elect” this separate treatment for enantiomers, Congress expressed its understanding that enantiomers were the same active ingredient as the racemate for all other purposes, including patent term extension.

The Federal Circuit said it couldn’t find any support for this theory in the legislative record, or elsewhere and affirmed the district court’s ruling that the ’407 patent on levofloxacin was properly granted the statutory term extension, for the enantiomer is a different drug product from the racemate ofloxacin, and was subject to regulatory approval before it could be commercially marketed and used.

This case clarifies that separate enantiomers can obtain independent patent protection and be entitled to patent term extension for “first commercial marketing or use” as new drug products. However, the Federal Circuit has said that patents for separated enantiomers can be invalidated on obviousness grounds. So, pharmaceutical companies that can show (very?) good reasons that separation of enantiomers was not obvious can look forward to a much longer patent term – for now.

Jogging Pills Urge You to Compare Drug Costs

Stephen Jenei — Wed, 18 Mar 2009 14:40:20 +0000

Consumer Reports is using giant jogging pills on treadmills in order to announce its launch of a public campaign in support of comparative effectiveness research to urge policy makers to get behind the effort to provide doctors and patients with independent comparisons of different treatments for medical conditions.The interactive display is set up in Washington’s Union Station today where CU is running some medications through vigorous testing.

While patients have spent about $286 billion on prescription drugs in 2007 alone, about 75 percent of it on brand-name products, drug makers spent about $5.4 billion in 2007 on advertising medicines. The companies also spend about $15 to $20 billion annually on trade journal advertising and other outreach including in-person sales calls, professional symposia and gifts to spread their message to doctors, pharmacists, benefit managers, and others.

You can stop by and pick up a copy of their latest publication, Best Drugs for Less or learn about Best Drugs for Less online. Best Drugs for Less is supposed to provide “unbiased, independent evaluations to help people choose medicines that are safe, effective, and affordable.” The magazine is aimed at helping patients and doctors cut through the clutter of drug advertising so they can make informed decisions about their medications.

You can also check out their list of 10 ways to reduce your drug costs.

Patent Office Gives Thumbs Up to Genentech’s Cabilly Patent

Stephen Jenei — Thu, 26 Feb 2009 03:44:37 +0000

Earlier, the Supreme Court ruled that MedImmune could sue Genentech for patent infringement even though MedImmune continued to pay licensing fees to Genentech to use disputed technology to develop the drug Synagis®. At the same time, the U.S. Patent and Trademark Office decided to have a second review of the patents at issue, U.S. Pat. Nos. 4,816,567 and 6,331,415, which relate to antibodies and to non-specific immunoglobulins formed by recombinant techniques using host cell cultures.

The Patent Office has now finished those proceedings dealing with Genentech’s Cabilly patent under concurrent proceedings for an Inter Partes Reexamination (RE Appl. No. 90/007,542) and an Ex Parte Reexamination (RE Appl. No. 90/007,859). While an earlier ruling by the Office declared the the claims invalid as being anticipated under various earlier patents and references, the Patent Office has now issued a Notice of Intent to Issue a Reexamination Certificate (NIRC) confirming the patentability of all claims of the Cabilly patent. A fancy way of saying that the claims are good to go.

Note, during the reexamination process, Genentech did amend claims 21 through 32 but claims that there were amended in a way that does not affect the commercial viability of the patent. More importantly, this decision by the Patent Office is final and unappealable.

The Notice set out that the invention is for a method for producing an immunologically functional immunoglobulin molecule or an immunologically functional immunoglobulin fragment by transforming a single host cell with a first DNA sequence encoding immunoglobulin heavy chain and a second DNA sequence encoding immunoglobulin light chain and independently expressing the first DNA sequence and second DNA sequence so that said immunoglobulin heavy chain and light chain are produced as separate molecules in said transformed single host cell.

Based on the prosecution history of the patent at issue, and the interference record from Interference No. 102,572, the Examiner determined that the term “immunoglobulin molecule” in claims 1 and 33 is considered to be an immunologically functional molecule and capable of binding to a known antigen.

The following is an examiner’s statement of reasons for patentability and/or confirmation of the claims found patentable in this reexamination proceeding:

The combination of the Cabilly I patent claims and the teachings of Axel, Rice, Kaplan, Builder, Accolla, Dallas, Moore patent, Deacon and Valle and Ochi references do not suggest or contain an enabling disclosure of a method to produce an immunologically functional immunoglobulin molecule by independently expressing immunoglobulin heavy chain and light chain in a single transformed host cell.

Claims 1-20, 33-36 are confirmed and amended claims 21-32 are allowed.

Genentech’s controversial patent will not expire now until the end of 2018, an expiration date that is over 29 years after the Cabilly I patent issued. While we don’t know the details of the final settlement, I imagine that MedImmune is probably feeling pretty good right about now that they didn’t breach their license in order to bring their earlier action contesting the patents.

See the Patent Office documents here:

Notice of Intent to Issue a Reexamination Certificate
Notice of Intent to Issue a Reexamination Certificate

Earlier:

MedImmune and Genentech Settle, Lawyers Look For New Topic of Discussion
USPTO Smacks Down Genentech’s Antibody Patent
Supreme Court High-Fives MedImmune

What’s Two Extra Weeks Of Exclusivity for Evista® Worth? A Lot.

Stephen Jenei — Tue, 24 Feb 2009 22:04:54 +0000

The U.S. Court of Appeals for the Federal Circuit handed Eli Lilly a victory over that Teva Pharma in upholding an extension of the statutory thirty-month stay under the Hatch-Waxman Act, thus preventing the U.S. Food and Drug Administration from finally approving Teva’s Abbreviated New Drug Application (ANDA). Eli Lilly & Co. v. Teva Pharma (09-1071).

The Hatch-Waxman Act requires a pioneer drug manufacturer to notify the FDA of all patents that “claim[ ] the drug for which the [NDA] applicant submitted the application.” The FDA lists the patents in its Approved Drug Products With Therapeutic Equivalence Evaluations (Orange Book). Under the law, a generic manufacturer infringes a patent by filing an ANDA to obtain approval for a generic drug product claimed by a valid and unexpired patent.

In this case, Lilly holds the approved NDA for raloxifene hydrochloride tablets, which is marketed under the brand name Evista® for the treatment and prevention of postmenopausal osteoporosis. Lilly lists twelve patents that claim Evista® in the Orange Book.

Teva filed an ANDA with the FDA to get approval to manufacture and market generic raloxifene filing paragraph IV certifications, i.e., a patent is invalid or will not be infringed. Lilly sued Teva for infringement of four method patents listed in the Orange Book: U.S. Patent Nos. RE38,968, RE39,049, RE39,050, and 6,906,086. The FDA gave a 30 month stay on approval from the date that Lilly received Teva’s paragraph IV notifications, expiring on November 16, 2008.

Lilly later amended its complaint to assert that Teva infringed three additional Evista® patents—U.S. Patent Nos. 6,458,811, 6,797,719, and 6,894,064—covering raloxifene particle size and formulation.

On July 8, 2008, Teva amended its ANDA to include a new particle-size measuring methodology for the active pharmaceutical ingredient in its proposed raloxifene tablets. Teva disclosed this amendment to Lilly on July 10, 2008, and provided it three batch samples on July 28, August 19, and September 17, 2008. The district court, however, previously set a discovery deadline of August 18, 2008. Teva allegedly began changing its particle-size measuring methodology as early as November 2007 with the goal of avoiding infringement of Lilly’s asserted patents.

Lilly asked the district court to extend the statutory thirty-month stay due to Teva’s alleged discovery violations, which extended the stay from the original November 16, 2008, until the beginning of trial on March 9, 2009.

The U.S. District Court found that Teva had “recast its product more than eighteen months after it provided the original sample to Lilly and only eight months before trial is set to commence.”

Teva appealed.

The Court of Appeals upheld the extension saying that the district court acted within its discretion in this area and it has the discretion to adjust the statutory thirty-month stay of ANDAs if “either party to the action failed to reasonably cooperate in expediting the action.” Trial courts may shorten or extend the thirty-month statutory period based on the parties’ uncooperative discovery practices.

Take-Home Lesson: Don’t mess around in turning over materials in discovery. It will cost you dearly. Think two weeks is not much to fuss over? Think again. Last year, Eli Lilly reported sales of Evista® of $1,075,600,000. That works out to over $41 million for a mere two weeks of exclusive sales.

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Note that Circuit Judge Prost, disagreed with the majority saying “[t]he thirty-month stay … may be extended for one reason and one reason only: “because either party to the action failed to reasonably cooperate in expediting the action.”

Although Teva did not complete production until September 5, 2008, the court did not purport to base any finding that Teva “failed to reasonably cooperate in expediting the action” on this eighteen-day delay. … Not once in this order did the court indicate, much less unambiguously state, that it found Teva had failed to reasonably cooperate in expediting the action.