Patent Baristas

Dr. Andrew von Eschenbach, the head of the Food and Drug Administration, addressed the issue of biogenerics at the annual meeting of the annual meeting of the Pharmaceutical Research and Manufacturers of America (PhRMA).  Eschenbach basically outlined that biogenerics would be considered only “similar” to brand-name drugs, not interchangeable or able to be substituted.

This is similar to the approach of the EU as used by the European Medicines Agency. “We recognize that the end point would be what could be best described as similarity,” von Eschenbach said. “Similarity in the sense that when a doctor gives you the product — delivered it to a patient — it will achieve an effect that is similar to the effect that we expected from” the brand-name drug.

The Generic Pharmaceutical Association maintains the FDA already has the scientific knowledge to approve knockoffs, just as it now can sign off on changes made by brand-name biotech companies in how they produce their drugs.

Recent approvals of follow-on biologics by the FDA have been limited to those few biotechnologically derived products such as human growth hormone and certain insulin products approved under the New Drug Approval provisions of the Food, Drug, and Cosmetic Act, such as Novartis’ Sandoz approval of a 505(b)(2) NDA for its Omnitrope® version of Pfizer’s Genotropin® human growth hormone. While not a true generic application, a 505(b)(2) NDA allowed Sandoz to submit less than a full NDA.

The problems currently faced stem from the fact that biologics are approved under the Public Health Service Act (PHSA) not under the FD&C Act like small molecule drugs. While the FD&C Act provides an abbreviated new drug application (ANDA) provision that allows for generic versions of chemical drugs, the PHSA lacks any statutory mechanism that allow filing an abbreviated license for a biologic. The agency itself has taken the position that it lacks the authority to approve generic biologics under the PHSA.

Using the existing mechanisms for approving generic versions of biogeneric drugs involves two problems: (a) proving that the generic drug is identical to the brand name active ingredient, dosage form, route of administration, conditions of use (i.e., labeling) and dosage strength; and (b) proving that it is bioequivalent to the brand-name drug. If these are proven for small molecule generic versions, the generic product can be substituted for the brand-name product.

With biogenerics, you would have to show that the two biologics, made using different processes, contain the same ingredient. Then, you would have to prove that the two products are bioequivalent, especially when analytical methodology often does not exist or is proprietary to the brand name product. This would be quite difficult absent clinical studies.

In the Omnitrope case, the European Medicines Agency (EMEA) concluded that, while Omnitrope was not identical to Genotropin, it was similar enough to warrant approval with labeling comparable to that of Genotropin. EMEA determined that the two products were comparable as to their effectiveness, it did not declare them as bioequivalent. Having reached those conclusions, EMEA was able to regard Omnitrope as a biosimilar to Genotropin.

Concurrently with endorsing Omnitrope, EMEA issued a number of guidelines on how biosimilar medicines should be regulated:

Comparability studies are required between the biosimilar and the reference brand medicine. The extent to which comparability can be proven impacts how many nonclinical and clinical studies the biosimilar applicant will be required to perform.

Nonclinical studies, usually less extensive that those for innovator applications, will be required for the biosimilar.

Clinical studies (rather than the classic bioequivalence studies used for chemical drugs) will be needed to support the biosimilar drug’s safety and effectiveness. In particular, the studies must address immunogenicity concerns.

Postmarket pharmacovigilance plans will be expected as part of approval commitments.

EMEA also issues drug-specific guidelines for developing biosimilars. EMEA has issued these annex guidelines on human growth hormone, recombinant erythropoietins, recombinant granulocyte-colony stimulating factor and recombinant human insulin.

After lots of pressure from the courts and lawmakers, the FDA approved Sandoz’s 505(b)(2) NDA for Omnitrope. In so doing, the agency made clear that the Omnitrope approval did not establish any distinct precedent for other follow-on biologics, stating:

Is this FDA’s first approval of a follow-on protein product?

No. FDA has approved other follow-on protein products under section 505 of the Food, Drug, and Cosmetic Act. These include GlucaGen (glucagon recombinant for injection), Hylenex (hyaluronidase recombinant human), Hydase and Amphadase (hyaluronidase), and Fortical (calcitonin salmon recombinant) Nasal Spray.

Does today’s approval of Omnitrope create a new pathway for follow-on versions of all protein products?

No. The approval of Omnitrope in a 505(b)(2) application does not establish a pathway for approval of follow-on products for biological products licensed under section 351 of the Public Heath Service Act, nor does it mean that more complex and/or less well-understood proteins approved as drugs under the Food, Drug, and Cosmetic Act could be approved as follow-on products.

The FDA has classified Omnitrope as “BX” (insufficient data to determine therapeutic equivalence) in FDA’s Approved Drug Products with Therapeutic Equivalence Evaluations (Orange Book).

Reps. Waxman, Clinton and Schumer have now introduced H.R. 6257, the Access to Life-Saving Medicine Act (ALMA).  The Act would establish the a path for follow-on biologic applications including:

An abbreviated process for biological licenses for products that is comparable to approved biologics by amending the PHSA

Comparability requirements based upon the follow-on product having no clinically meaningful differences from the approved reference product in terms of safety, purity or potency, based upon nonclinical or clinical studies, as needed

An approval process that includes a focus on correlating comparability to the reference product’s mechanism of action (If the mechanism of action is known, the follow-on applicant need only demonstrate comparability in one proposed condition of use. In contrast, if the mechanism is unknown, the applicant must show comparability for each proposed condition of use.)

Comparability requirements for the follow-on and reference products’ principal molecular structure features

Option for a comparable biologic product applicant to establish interchangeability with the reference product (if so established, the applicant may earn tax credits and an exclusive marketing period that would block other subsequent interchangeable versions of the reference product); to be interchangeable, a product must produce the same clinical results as the reference

Requirement that FDA approve or disapprove a follow-on biologic application at the earlier of eight months after submission or 180 days after the application is accepted for filing; this deadline would only be extendable by joint agreement of FDA and the applicant

The FDA says it will continue to develop guidelines required to consider applications on biogenerics.

A reader on Philip Brooks’ Patent Infringement Updates asked about the downstream effects of the CAFC decision invalidating Pfizer’s Norvasc® patent (U.S. Patent No. 4,879,303). In this appeal, the CAFC held that the district court erred in holding that the subject matter of claims 1-3 of the ’303 patent would not have been obvious. Pfizer, Inc. v. Apotex, Inc. (f/k/a Torpharm) (2006-1261; Decided March 22, 2007).

But, Pfizer won in three earlier district court cases, including a case against Mylan Pharmaceuticals that was handed down just last month. In that case, a federal court in the Western District of Pennsylvania (Pittsburgh) upheld the patent covering the active ingredient in Norvasc.

The judge ruled that the ‘303 patent covering amlodipine besylate was valid, enforceable and would be infringed by Mylan’s product. The decision, which has already been appealed by Mylan, handed down an order barring Mylan from launching a generic version of amlodipine until September 2007.

On a related note, a federal court in the Northern District of Illinois ruled against Apotex in January 2006; and a federal court in the Middle District of North Carolina rejected a challenge by Synthon in August 2006.

A reader posed the following questions:

Mylan is engaged in a separate appeal of Norvasc litigation involving the same patent.

Does the reversal of patent validity in one case mean that the patent is no longer valid across the board, and that the Mylan appeal is now moot and Mylan can launch?

Or does the lower court injunction barring Mylan’s launch still apply?

If a patent is held invalid, it is invalid as to all parties (see Blonder-Tongue case). Therefore, Mylan’s appeal is moot (although I don’t know the details of the appeal). The Supreme Court’s decision in Blonder-Tongue Laboratories, Inc. v. University of Illinois Foundation, 402 U.S. 313 (1971), requires that Pfizer cannot assert patents against one party which have been found to be invalid or unenforceable against another party.

In Blonder-Tongue, the Supreme Court permitted accused infringers to plead collateral estoppel, also known as issue preclusion, when facing an infringement claim on a patent already declared invalid in a proceeding against another defendant, i.e., after the above CAFC case finding that Apotex has proven invalidity or unenforceability of Pfizer’s patents based on obviousness, Pfizer is not permitted to continue to assert the patents in proceedings against Mylan.

Blonder-Tongue permitted the use of defensive collateral estoppel when the accused infringer shows 1) that a patent was found invalid in a prior case that had proceeded through final judgment and in which all procedural opportunities were available to the patentee; 2) that the issues litigated were identical; and 3) that the party against whom estoppel is applied had a full and fair opportunity to litigate.

The injunction just doesn’t go away, however, so Mylan will have to go to the judge and move to have the injunction lifted in view of the finding that the patent is invalid.

Some readers have asked why there is a pediatric exclusivity add-on for FDA approvals. These exclusivity extensions are provided under the Food and Drug Administration Modernization Act of 1997, section 505A of the Federal Food, Drug and Cosmetic Act (21 U.S.C. § 355(a)), which permits certain new drug applications to obtain an additional six months of exclusivity if the drug manufacturer submits certain FDA-requested information relating to the use of the active moiety in a pediatric population.

Section 505(A) required FDA to develop, prioritize, and publish a list of approved drugs for which additional pediatric information may produce health benefits in the pediatric populations and update it annually. As an incentive to industry to conduct studies requested by the Agency, Section 505(A) provides for a 6-month period of marketing exclusivity (pediatric exclusivity).

Pediatric exclusivity is an add-on to existing marketing exclusivity or patent protection. In general, products with no patent life or exclusivity remaining cannot qualify. Under certain conditions, however, pediatric exclusivity may be granted to a product without remaining exclusivity if the supplemental application itself qualifies for a new exclusivity period under the Drug Price Competition and Patent Term Restoration Act (Waxman-Hatch Amendments). For example, an application to extend an approved adult indication to the pediatric population for a product with no patent life or exclusivity remaining could obtain pediatric exclusivity if new clinical studies of safety and efficacy are required for approval. In that case, the pediatric supplement would earn 3 years of marketing exclusivity under the 1984 amendments, to which the additional 6 month pediatric exclusivity would be added.

Pediatric exclusivity attaches to any existing exclusivities (including orphan exclusivity) and to all patent protections listed in the Orange Book for any drug product containing the same active moiety as the drug studied. For studies conducted on an unapproved drug, pediatric exclusivity will attach to any exclusivity or patent protection that will be listed in the Orange Book upon approval of that unapproved drug.

Pediatric exclusivity adds 6 months to the exclusivities and patent protections listed of each drug product for which the party submitting the studies holds the approved new drug application. For example, if the drug product has 5-year, new chemical entity (NCE) exclusivity, the addition of pediatric exclusivity will give the applicant 5 1/2 years of NCE exclusivity.

Pediatric exclusivity does not attach to the end of a patent term extension under 35 U.S.C. § 156; rather, it extends the period during which the approval of a competitor’s ANDA or 505(b)(2) application may not be made effective by FDA. For Paragraph IV certifications, pediatric exclusivity does not attach unless an infringement suit is failed and the 30 month stay provision are triggered under Section 505.

Pediatric studies submitted in a supplemental application for a drug that has already received one period of pediatric exclusivity may qualify the drug to receive another 6-month period of pediatric exclusivity, however the second 6-month period will attach only to the 3 year exclusivity period (under sections 505(c)(3)(D)(iv)) and 505(j)(5)(D)(iv)) granted to the supplemental application for which the studies were completed.

Section 505(A) does apply to OTC drugs that are the subject of approved NDAs. But, only drug products subject to section 505 of the Food, Drug, and Cosmetic Act are eligible for pediatric exclusivity. Biological products that are subject to the Public Health Service Act are not eligible for pediatric exclusivity, even if they have orphan exclusivity or other patent protection.

The CAFC finally shot down Pfizer’s Norvasc® patent after it filed suit against Apotex alleging infringement stemming from Apotex’s filing an Abbreviated New Drug Application (“ANDA”) seeking approval to commercially sell amlodipine besylate tablets before the expiration of the term of U.S. Patent No. 4,879,303. Pfizer, Inc. v. Apotex, Inc. (f/k/a Torpharm) (2006-1261; Decided March 22, 2007).  Pfizer won in three earlier district court cases. 

The ANDA product is a generic version of Pfizer’s amlodipine besylate drug product, approved by the FDA for treating hypertension and chronic stable and vasospastic angina.  Norvasc® contains amlodipine besylate. The active ingredient found in Norvasc® is 2-[(2-aminoethoxy)methyl]-4-(2-chlorophenyl)-3-ethoxycarbonyl-5-methoxycarbonyl-6-methyl-1,4-dihydropyridine, commonly referred to as amlodipine. Amlodipine is a member of a class of compounds referred to as dihydropyridines.

The ’303 patent, entitled “Pharmaceutically Acceptable Salts,” is listed in the FDA’s Approved Drug Products with Therapeutic Equivalence Evaluations (“Orange Book”) with respect to the Norvasc®.  Apotex certified in ANDA No. 76-719 that it believed the ’303 patent was invalid and unenforceable, and sought approval to market and sell its amlodipine besylate tablets before September 25, 2007 (i.e., the expiration date of the ’303 patent plus an additional six months of pediatric exclusivity) pursuant to 21 C.F.R. § 314.94(a)(12)(i)(A)(4).

Apotex denied infringement and counterclaimed for declaratory judgments that the claims of the ’303 patent are invalid for anticipation and obviousness, and that the ’303 patent is unenforceable due to Pfizer’s alleged inequitable conduct before the United States Patent and Trademark Office (“USPTO”).

Earlier, the district court entered a judgment for Pfizer and found infringement. The district court then ordered that the effective date of any approval of Apotex’s ANDA No. 76-719 shall not be earlier than September 25, 2007, and enjoined Apotex from making, using, offering to sell, selling, or importing any product comprising amlodipine besylate covered by (or the use of which is covered by) the claims of the ’303 patent until September 25, 2007.

On appeal, the CAFC has now reversed and has held that the district court erred in holding that the subject matter of claims 1-3 of the ’303 patent would not have been obvious. By statute, a claimed invention is unpatentable if the differences between it and the prior art “are such that the subject matter as a whole would have been obvious at the time the invention was made to a person having ordinary skill in the art.”

Here, the CAFC felt that evidence of record easily satisfied that a reasonable fact-finder could only conclude that Apotex has shown by clear and convincing evidence that the skilled artisan would indeed have been so motivated to combine the prior art to produce the besylate salt of amlodipine. The court also held that a reasonable fact-finder could only conclude that the skilled artisan would have had a reasonable expectation of success with the besylate salt form of amlodipine.

Pfizer argued that (1) the earlier ’909 patent does not suggest or motivate the skilled artisan to make amlodipine besylate because none of the anions listed in the ’909 patent have a cyclic structure as does besylate, and (2) even if the ’909 patent were combined with the cited Berge refernce, the skilled artisan would not have been motivated to make amlodipine besylate because Berge shows that besylate was actually one of the most rarely used anions in the pharmaceutical industry, as only 0.25% of approved drugs as of 1974 were besylate salts. Finally, Pfizer asserts that other prior art references relied upon by Apotex are not relevant because the examples of besylate salts disclosed in these references are limited to pharmaceuticals unrelated to amlodipine.

The Court rejected this argment stating that “a suggestion, teaching, or motivation to combine the relevant prior art teachings to achieve the claimed invention does not have to be found explicitly in the prior art references sought to be combined, but rather “may be found in any number of sources, including common knowledge, the prior art as a whole, or the nature of the problem itself.”

While the district court found that the skilled artisan would have had no expectation of success in making a besylate salt of amlodipine because there was no reliable way to predict the influence of a particular salt species on the active part of the compound, the CAFC held that obviousness cannot be avoided simply by a showing of some degree of unpredictability in the art so long as there was a reasonable probability of success.

Many often complain that holdings of obviousness were based on the impermissible “obvious to try” standard. The question becomes then, when the skilled artisan must test, how far does that need for testing go toward supporting a conclusion of non-obviousness?

Citing DyStar, 464 F.3d at 1367, the court held that:

Obviousness is a complicated subject requiring sophisticated analysis, and no single case lays out all facets of the legal test. [There is] danger inherent in focusing on isolated dicta rather than gleaning the law of a particular area from careful reading of the full text of a group of related precedents for all they say that is dispositive and for what they hold. When parties . . . do not engage in such careful, candid, and complete legal analysis, much confusion about the law arises and, through time, can be compounded.

Pfizer argued that an obvious rejection would negate its “discovery” because it was obtained through the use of trial and error procedures. The CAFC differentiated this case stating that:

We find this case analogous to the optimization of a range or other variable within the claims that flows from the “normal desire of scientists or artisans to improve upon what is already generally known.” In re Peterson, 315 F.3d 1325, 1330 (Fed. Cir. 2003) (determining where in a disclosed set of percentage ranges the optimum combination of percentages lies is prima facie obvious). In In re Aller, 220 F.2d 454, 456 (C.C.P.A. 1955), our predecessor court set forth the rule that the discovery of an optimum value of a variable in a known process is usually obvious.

Thus, while patentability of an invention is not negated by the manner in which it was made, “the converse is equally true: patentability is not imparted where ‘the prior art would have suggested to one of ordinary skill in the art that this process should be carried out and would have a reasonable likelihood of success.’” Merck, 874 F.2d at 809 (quoting In re Dow Chem. Co., 837 F.2d 469, 473 (Fed. Cir. 1988)). For these reasons, we hold that Apotex introduced clear and convincing evidence that a skilled artisan would have had a reasonable expectation of success with the besylate salt form of amlodipine at the time the invention was made. Accordingly, we agree with the district court that a prima facie case of obviousness was established with regard to the claims of the ’303 patent, albeit for different reasons.

Earlier, the USPTO published an Official Gazette notice in November of 1996 providing a partial waiver of the requirements for restriction and for unity of invention determinations. The 1996 Notice permitted examination of a reasonable number (reasonable being normally up to ten, independent and distinct molecules).

Now, in their quest to reduce patent application pendency times without hiring examiners, the USPTO has reconsidered the policy “in view of changes in the complexity of applications filed” (their words), the types of inventions claimed and the state of the prior art in this technology since that time.  Apparently the changes in the complexity of searching tools does not factor into the equation.

The USPTO claims that because of these unsubstantiated changes in the art, the search and examination of up to ten molecules described by their nucleotide sequence often consumes a disproportionate amount of Office resources. Consequently, a new Notice published in the gazette rescinds the partial waiver for restriction practice in national applications and for unity of invention determinations in both PCT international applications and the resulting national stage applications.

As part of the rationale, the office claims that in 1996, polynucleotide molecules were often claimed by simple reference to a nucleotide sequence. In contrast, the USPTO contends that:

polynucleotide molecules are now often claimed in a single application in a variety of complex formats, some of which may embrace multiple inventions, such as by reference to: the amino acid sequence of the protein encoded; the ATCC number of a deposited plasmid containing the polynucleotide molecule; arbitrary laboratory designations; function of the nucleic acid alone or in combination with a partial linear nucleotide sequence; a genus described in terms of homology, percent identity, or hybridization; a genus (or subgenus) described by nucleic acid sequence with variable positions specified within the sequence listing; single nucleotide polymorphisms (SNPs); antisense; or interfering RNA.

Interestingly, a quick search of the patent database shows patents that issued in 1996 claiming multiple sequences (US 5,589,582), claiming polynucleotides by referencing ATCC numbers of plasmids (US 5,589,582), claiming a polynucleotide having a certain percent identity (US 5,556,767), claiming antisense oligonucleotides (US 5,571,903) and so forth.

This change — and the resulting immense price hike for all biotech inventions — is effective immediately and is applicable to all pending applications. Note, however, that supplemental restriction requirements will not be advanced in applications that have already received an action on their merits in the absence of extenuating circumstances.

For regular U.S. applications, claims to polynucleotide molecules will be considered for independence, relatedness, distinction and burden as for claims to any other type of molecule.

For International applications and national stage filings of international applications, unity of invention will exist when the polynucleotide molecules, as claimed, share a general inventive concept, i.e., share a technical feature which makes a contribution over the prior art.

Examination of Patent Applications Containing Nucleotide Sequences (PDF)

I have been tagged by Colin Samuels of the Infamy or Praise blog to continue a meme-tag that has been circulating about.   Actually, I was tagged a bit ago but am just catching up on some loose ends.

OK, in the interest of collegiality, here are five things you probably didn’t know about me:

1. I  have a saltwater fish tank (but I only have these two fish);
2. I bought a Taylor guitar seven years ago and still haven’t been able to teach myself how to play (owing to the fact that I have an idiot for an instructor);
3. My favorite movie is North by Northwest (and not just because of Eva Marie Saint) although Rear Window is a close second;
4. I never finished my doctorate dissertation in tropical diseases; and finally …
5. I secretly want to take up sailing and work from offshore.

To advance this circle of life, I’ll tag the RethinkIP guys (Matt/Doug/Steve) along with  the Patent Hawk (Gary) and the Orange Book blogger (Aaron)

Harvard Drug Group has filed an antitrust class action suit against Purdue Pharma alleging an unlawful scheme to maintain its monopoly in the U.S. for its brand name prescription drug OxyContin CR, the notorious opioid analgesic prescribed to treat moderate to severe pain.  OxyContin CR (oxycodone hydrochloride) is a controlled release formulation.  (Harvard Drug Group LLC v. Purdue Pharma L.P. (SDNY 07cv1937)).

Harvard alleges that Purdue engaged in a scheme involving fraud before the U.S. Patent and Trademark Office in order to obtain U.S. patents relating to OxyContin including 5,549,912; 5,508,042; and 5,656,295 stating that these wouldn’t have issued if not for Purdue’s fraud and inequitable conduct.Since these patents were then listed in the FDA’s Orange Book with Purdue filing patent infringement claims against potential generic competitors who sought FDA approval for a competing generic version of OxyContin, in order to block and delay generic competition.

Harvard claims that Purdue (1) unreasonably restrained, suppressed, and eliminated competition in the market for oxycodone CR (OxyContin and generic versions of OxyContin); (2) illegally maintained a monopoly in the market for oxycodone CR; (3) fixed, raised, maintained, and/or stabilized the price of OxyContin at supra- competitive levels; and (4) overcharged Harvard and other direct purchasers of OxyContin dollars by depriving them of the benefits of competition from lower priced generic versions of OxyContin.

Under the Federal Food, Drug, and Cosmetic Act, manufacturers who create a new, “pioneer” drug must obtain the approval of the Food and Drug Administration to sell the new drug by filing a New Drug Application. An NDA must include submission of specific data concerning the safety and effectiveness of the drug, as well as any information on applicable patents.  The Act was amended with the enactment of the Hatch-Waxman amendments, the Drug Price Competition and Patent Term Restoration Act of 1984, Pub. L. No. 98-417, 98 Stat. 1585 (1984).

Hatch-Waxman provides a brand-name manufacturer with the opportunity to obtain what is essentially a preliminary injunction, in the form of an automatic stay that may last as long as thirty months. When the FDA approves a brand-name manufacturer’s NDA, the FDA publishes, in a publication entitled “Approved Drug Products with Therapeutic Equivalence Evaluations,” known as the “Orange Book“, any patents which, according to information supplied to the FDA by the brand-name manufacturer, claim the approved drug or its approved uses, and with respect to which a claim of patent infringement could reasonably be asserted if a person not licensed by the owner engaged in the manufacture, use, or sale of the drug. 21 U.S.C. § 355(j)(7)(A)(iii).

The FDA does not check the facts supplied to it by the brand-name manufacturer, but trusts that the manufacturer will be truthful. In listing patents in the Orange Book, the FDA acts in a purely ministerial capacity. To obtain FDA approval of an ANDA (and thus the legal right to sell a generic version of a brand-name drug), a generic manufacturer must certify that the generic drug addressed in its ANDA does not infringe any patent listed in the Orange Book as claiming the brand-name drug.

Under Hatch-Waxman, a generic manufacturer’s ANDA must contain one of four certifications:

• that no patent for the brand-name drug has been filed with the FDA (a “paragraph I certification”);
• that the patent for the brand-name drug has expired (a “paragraph II certification”);
• that the patent for the brand-name drug will expire on a particular date and the generic company does not seek to market its generic product before that date (a “paragraph III certification”); or
• that the patent for the brand-name drug is invalid or will not be infringed by the generic manufacture’s proposed product (a “paragraph IV certification”).

21 U.S.C. § 355(JX2)(A)(vii).

If a generic manufacturer files a paragraph IV certification asserting that the patent is invalid or will not be infringed, the brand-name manufacturer has the opportunity to delay the generic manufacturer’s receipt of final approval, and, thus, its ability to come to market. This is because a generic manufacturer filing a paragraph IV certification must promptly give notice of this fact to both the NDA owner and the owner of the patent(s) at issue. The generic manufacturer’s act of providing notice of its paragraph IV certification triggers the time by which a patent owner may file an action for patent infringement and take advantage of a stay of FDA approval of the generic version of the NDA owner’s drug.

If the patent owner fails to initiate a patent infringement action within 45 days after receiving the generic manufacturer’s paragraph IV certification, then the FDA may finally approve the generic manufacturer’s ANDA upon satisfying itself that the generic is equivalent to the brand-name drug. If, however, the patent owner initiates an infringement action against the ANDA filer within 45 days, then the FDA may not finally approve the ANDA until the earlier of either 30 months or the issuance of a decision by a court that the patent is invalid or not infringed by the generic manufacturer’s ANDA. 21 U.S.C. § 355G)(5)(B)(iii).

Additionally, Hatch-Waxman provides a 180-day period of market exclusivity to the first generic manufacturer that files an ANDA containing a paragraph IV certification, commencing on the date the generic manufacturer begins marketing the new drug or, if there is a patent infringement claim against it, from the date the generic manufacturer receives a patent infringement decision in its favor, whichever is earlier. If neither of these conditions occur, the exclusivity period cannot expire and no other generic manufacturer may market its generic version of the affected drug.

Here, Harvard claims that Purdue repeatedly represented that it had “surprisingly discovered” that its controlled-release oxycodone formulation would control pain for “approximately 90% of patients” over a comparatively narrow, four-fold dosage range, much narrower than for other opioid analgesics. Purdue stated that, as a result of this reduced dosage range (and, hence, the simplification of the titration process), “[t]he expertise and time of physicians and nurses, as well as the duration of unacceptable pain patients must endure during the opioid analgesiac titration process is substantially reduced[.]”

However, Harvard claims that Purdue did not have any scientific proof for its key contentions concerning its controlled release oxycodone formulation, but intentionally withheld this from the PTO to get the patents to issue.

In an infringement suit against Endo Pharmaceuticals (an ANDA filer) the court held that the ‘ 912, ‘042, and ‘295 patents were unenforceable because Defendants had intentionally made material misrepresentations to the PTO. The District Court found: “Purdue made a deliberate decision to misrepresent to the PTO a ‘theoretical argument’ and an ‘expectation’ as a precisely quantified result* or ‘discovery.'” (Purdue Pharma L.P., et al, v. Endo Pharmaceuticals, et al S.D.N.Y.).

Harvard now contends that Purdue’s exclusionary conduct prevented generic entry into the relevant market and unlawfully enabled them to sell OxyContin without being subject to generic competition stating that but for their illegal conduct, Endo would have begun marketing generic versions of OxyContin on July 31, 2002, or earlier; and, subsequently, other generic competitors would have entered the market.

Harvard now wants the class members to recover payments for the higher prices for OxyContin than it would have paid for OxyContin and/or for generic oxycodone CR in the absence of anti-competitive conduct.

In 2004, Tercica, a licensee under a Genentech patent for a growth hormone, filed suit against Insmed in the U.K. alleging infringement of EP patent No. 571,417, or the ‘417 patent. The ‘417 patent has claims directed to particular uses of a combination of IGFBP-3 and IGF-1. In the complaint, Tercica asked the court for an injunction to restrain allegedly infringing activity, for a declaration that the ‘417 patent is valid and infringed, for an order requiring the delivery or destruction of allegedly infringing articles and materials and for an inquiry into possible economic damages.

In addition, Genentech and Tercica sued Insmed for infringement of U.S. Patent Nos., 5,187,151 (‘151 patent) and 6,331,414 (‘414 patent) in the U.S. District Court for the Northern District of California. These patents are directed to certain methods of using rhIGF-1/rhIGFBP-3 and methods of producing rhIGF-1, respectively.

On February 16, 2005, Tercica filed an amended complaint, adding an infringement allegation against Insmed with respect to U.S. Patent No. 5,528,287, or the ‘287 patent. The claims of the ‘287 patent are directed to DNA encoding BP53 (i.e. IGFBP-3) and recombinant constructs, transformed host cells and methods for using the same. Genentech and Tercica claimed that the production or use of IPLEX, a complex of rhIGF-1/rhIGFBP-3, would infringe these patents and that the infringement was willful.

The court found that Insmed Incorporated and Insmed Therapeutic Proteins, Inc. infringed the ‘287 patent; willfully infringed the ‘151 patent; and upheld the validity of the ‘414 patent. Tercica exclusively licensed these patents in April 2002 for use in its manufacture and sale of, among other things, Increlex. Prior to the trial, the Court had ruled that Insmed’s process for making the IGF-1 in IPLEX literally infringes three claims of the ‘414 Patent, and Insmed had stipulated that it infringes on three additional claims.

The jury verdict ordered Insmed to pay $7.5 million and 15% royalties for damages pertaining to IPLEX past sales of up to $100 million, and 20% royalties for IPLEX past sales greater than $100 million.

Genentech and Tercica have now resolved their litigation against Insmed in both the US and the UK in a settlement of the patent infringement and unfair business practices suits brought against Insmed.

In parallel, the companies announced that they have entered a license and development agreement in order to end the dispute, while Tercica and Genentech have waived the damages awarded by the jury in the US patent infringement litigation.

Under the terms of the settlement, Insmed will no longer provide Iplex to patients with severe Primary IGF-1 deficiency and other short stature indications and will withdraw its Iplex marketing application in the EU. Insmed will have freedom regarding manufacture, development and commercialisation of the drug for certain non-short stature indications, subject to opt-in rights and royalty provisions for Tercica and Genentech, the companies said.

Furthermore, the parties will form a joint-development committee to guide the development and commercialization of Iplex in non-Tercica/Genentech indications.  The Settlement, License and Development Agreement is in effect until the later of 2018 or the expiration of any subsequent Tercica/Genentech issued patents that cover IPLEX or its indications.

See the earlier note on the UK case here.