In Merck & Co. v. Hi-Tech Pharmacal (06-1401) , the Court of Appeals for the Federal Circuit looked at the question of whether a patent term extension under the Hatch-Waxman Act, 35 U.S.C. § 156, may be applied to a patent subject to a terminal disclaimer under 35 U.S.C. § 253, filed to overcome an obviousness-type double-patenting rejection.

Finding that the language of § 156 is unambiguous and fulfills a purpose unrelated to and not in conflict with that of § 253, the court held that a Hatch-Waxman term extension may be so applied.

Merck had filed a patent application covering carbonic anhydrase inhibitors, including dorzolamide, which is the active ingredient in Trusopt®, a drug used to treat glaucoma..  That patent application eventually issued as United States Patent No. 4,797,413 but during prosecution, the examiner rejected all claims on the ground of obviousness-type double patenting over the claims of an earlier patent owned by Merck, U.S. Patent No. 4,677,115.

To overcome this rejection, Merck filed a terminal disclaimer that disavowed any term of the ’413 patent that would extend beyond June 30, 2004, the original term of the ’115 patent (17 years from its date of issue).  The filing of the terminal disclaimer was accepted by the Examiner and the  patent was granted.

Later, under the Uruguay Round Agreements Act (URAA), patent term was changed to 20 years from the date of filing of the patent application with issued patents getting a term of the greater of 20 years from its earliest effective filing date or 17 years from its date of issue.  The expiration date of the ‘115 patent was reset to December 12, 2004 (twenty years from the filing date of the ’115 patent).  Because the terminal disclaimer linked the expiration date of the ’413 patent to the term of the ’115 patent, the expiration date of the ’413 patent likewise was reset to December 12, 2004.

Merck got approval to market Trusopt, listing the ‘413 patent in the Approved Drug Products with Therapeutic Equivalence Evaluation (the “Orange Book”).   Then the USPTO extended the term of the ’413 patent 1233 days based on the period of regulatory review undertaken by the FDA.

When Hi-Tech Pharmacal filed Abbreviated New Drug Applications for a generic version of a drug containing the active ingredient dorzolamide and used in drops for the treatment of ocular hypertension, it sent a paragraph iv patent certification notice to Merck, stating that Hi-Tech’s generic eye-drops do not infringe the ’413 patent.  In response, Merck sued.

Hi-Tech filed a motion to dismiss on the ground that while its products were covered by the claims of the ’413 patent, the terminal disclaimer foreclosed the patent term extension and the ’413 patent therefore expired on December 12, 2004.  Merck filed a cross-motion for judgment on the pleadings on the ground that the terminal disclaimer did not foreclose the Hatch-Waxman term extension.

The District Court sided with Merck and enjoined Hi-Tech from commercializing the drug claimed in the ’413 patent until the end of the patent term extension, i.e., until April 28, 2008.

The Hatch-Waxman Act established a patent term extension for patents relating to certain products subject to regulatory delays that could not be marketed prior to regulatory approval.  Section 156 provides an extension of up to five years if certain conditions are met as set forth in the five numbered sub-paragraphs of § 156(a):

(a) 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 from the original expiration date of the patent, which shall include any patent term adjustment granted under section 154(b), if

(1) the term of the patent has not expired before an application is submitted under subsection (d)(1) for its extension;

(2) the term of the patent has never been extended under subsection (e)(1) of this section;

(3) an application for extension is submitted by the owner of record of the patent or its agent and in accordance with the requirements of paragraphs (1) through (4) of subsection (d);

(4) the product has been subject to a regulatory review period before its commercial marketing or use;

(5)(A) except as provided in subparagraph (B) or (C) [not relevant in this case], 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.

Hi-Tech claimed that terminal disclaimers are irrevocable and final because the disclaimer is the only reason the patent issued.  Merck countered that § 156 unambiguously states that a patent term “shall be extended” where the conditions enumerated are satisfied.  Moreover, it argues that § 156 makes no mention of terminal disclaimers under 35 U.S.C. § 253 and does not prohibit them.

While § 156 states that, if the requirements are met, the patent term “shall be extended.” According to the Federal Circuit, the use of the word “shall” in a statute generally denotes the imperative.  Thus, use of the word “shall” indicates that if the enumerated list of requirements is met, the patent term is entitled to be extended. 

In addition, the court held that:

§ 156 states that the Hatch-Waxman extension shall run from the expiration date of the patent, as adjusted under section 154(b) to make up for certain PTO delays.  In turn, § 154(b)(2)(B) expressly excludes patents in which a terminal disclaimer was filed from the benefit of a term adjustment for PTO delays.  There is no similar provision that excludes patents in which a terminal disclaimer was filed from the benefits of Hatch-Waxman extensions.  The express prohibition against a term adjustment regarding PTO delays, the absence of any such prohibition regarding Hatch-Waxman extensions, and the mandate in § 156 that the patent term shall be extended if the requirements enumerated in that section are met, support the conclusion that a patent term extension under § 156 is not foreclosed by a terminal disclaimer.

Therefore, the court held that a patent term extension under § 156 may be applied to a patent subject to a terminal disclaimer. 

Posted March 30th, 2007 by Stephen Albainy-Jenei in IP Litigation
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After Teva Pharmaceuticals appealed the dismissal of its declaratory judgment action in District Court, the United States Court of Appeals for the Federal Circuit has taken a fresh new look at things in light of the Supreme Court’s decision in MedImmune, Inc. v. Genentech, Inc., 127 S. Ct. 764 (2007).

Because the district court relied on the Fed Circuit’s earlier two-part declaratory judgment test for patent non-infringement, it found that Teva failed to establish a reasonable apprehension of imminent suit and that it therefore lacked jurisdiction over the declaratory judgment action. Finding that its declaratory judgment test for non-infringement or invalidity “conflicts” with the Supreme Court, the Fed Circuit reversed.  See Teva Pharmaceuticals v. Novartis (06-1181).

Basically, Novartis has a New Drug Application for three strengths of the drug Famvir® in which Novartis listed five patents in the Orange Book, each of which covers and is directed to various aspects of Famvir®, including U.S. Patent Nos: 5,246,937; 5,840,763; 5,866,581; 5,916,893; and 6,124,304. The ’937 patent is directed to the active ingredient in Famvir®, famciclovir, while the remaining Orange Book patents are directed to methods of therapeutic use (”method patents”) of Famvir®. The ’937 patent expires in 2010, but the related therapeutic use patents do not expire until 2014-15.

In 2004, Teva filed an Abbreviated New Drug Application with the FDA for generic famciclovir tablets in which Teva certified under paragraph IV that its drug did not infringe any of the five Novartis Famvir® Orange Book patents or that the patents were invalid. Novartis brought an infringement suit against Teva on the ’937 patent alone and did not include in the action the related therapeutic use patents. The infringement suit is pending in District Court.

In light of the suit, Teva brought a declaratory judgment action on the four remaining method patents in order to settle everything at once or “patent certainty.” Title 21 U.S.C. § 355(j)(5)(C) is a 2003 amendment to the ANDA statute entitled “civil action to obtain patent certainty.” Under this provision, if the patentee or NDA holder does not bring an infringement suit within 45 days after receiving notice of a paragraph IV certification, the ANDA applicant may bring a civil action for a declaratory judgment that the patent at issue is invalid or will not be infringed by the drug for which the ANDA was submitted. Like MedImmune, Teva argued that it would have been left with the Hobson’s choice of either launching at risk of liability for patent infringement or foregoing the opportunity.

Novartis argued that Teva had no reasonable apprehension that it would be sued by Novartis for infringing the four method patents. In response, Teva argued that: (1) Novartis had already sued Teva on the underlying composition patent; (2) listing patents in the Orange Book established infringement as a matter of law; (3) Novartis had a history of aggressively suing generic drug companies; and (4) Novartis had declined to give Teva a covenant not to sue.

The district court dismissed Teva’s declaratory judgment action using the Fed Circuit’s earlier two prong “reasonable-apprehension-of-imminent-suit” test from Pfizer in stating that Teva had failed to establish a reasonable apprehension of imminent suit and that the district court therefore lacked jurisdiction over the declaratory judgment action.

The Declaratory Judgment Act requires a case of actual controversy. In MedImmune, the Court found that its precedent “did not draw the brightest of lines between those declaratory-judgment actions that satisfy the case-or-controversy requirement and those that do not.” Id. Instead of applying a bright line, the Court stated that its decisions required:

… that the dispute be “definite and concrete, touching the legal relations of the parties having adverse legal interests”; and that it be “real and substantial” and “admi[t] of specific relief through a decree of a conclusive character, as distinguished from an opinion advising what the law would be upon a hypothetical state of facts.”

In MedImmune, the Court re-affirmed the correct standard for determining a justiciable declaratory judgment action: “Basically, the question in each case is whether the facts alleged, under all the circumstances, show that there is a substantial controversy, between the parties having adverse legal interests, of sufficient immediacy and reality to warrant the issuance of a declaratory judgment.”

In reviewing this case in light of MedImmune, the Fed Circuit found that under “all the circumstances” as found in this case, Teva has an injury-in-fact and therefore has a justiciable Article III controversy.

Novartis came up with the disingenuous argument that there is no actual controversy between it and Teva on the four method patents in spite of Teva’s paragraph IV certifications of the four method patents because Novartis has not filed suit nor threatened to sue Teva on the method patents. Novartis claimed that the suit on the ’937 patent is an entirely different controversy.

The court pooh-poohed this for the following reasons:

First, Novartis listed its Famvir® patents in the Orange Book. By doing this, Novartis represented that it had an infringement claim.

Second, Teva submitted its ANDA certifying that it did not infringe Novartis’ Famvir® Orange Book patents or that the patents were invalid. The very act of submitting an ANDA is an act of infringement.

Third, an actual controversy is seen from the combination of three statutory provisions: 1) the “civil action to obtain patent certainty” under 21 U.S.C. § 355(j)(5)(C); 2) the ANDA declaratory judgment provision under 35 U.S.C § 271(e)(5); and 3) the purpose of the Hatch-Waxman Act. The “civil action to obtain patent certainty,” which was enacted in 2003 is designed to prevent patentees from “gaming” the Hatch-Waxman Act.

Fourth, Novartis’ pending infringement litigation against Teva on Teva’s submitted ANDA is an Article III controversy.

And fifth, the possibility of future litigation that Novartis created by electing to challenge Teva’s ANDA on only one of the five Orange Book listed Famvir® patents contributes to finding that Teva has a justiciable declaratory judgment controversy.

In reversing, the court held that:

By filing a lawsuit on only one its five patents certified under paragraph IV in Teva’s ANDA, Novartis has tried to simultaneously leverage the benefits provided to a patentee under the Hatch-Waxman Act and avoid the patentee’s accompanying responsibilities. Novartis’ ’937 patent suit against Teva has invoked the statutory automatic 30-month stay and is concurrently insulating the four method patents from a validity challenge. In the statute, Congress explicitly required that in exchange for the 30-month stay, patentees were to “reasonably cooperate in expediting the action” of whether the paragraph IV patents were invalid or not infringed.

Senior Circuit Judge Friedman concurred with the findings but stated:

In these unusual circumstances, where the Supreme Court went out of its way to state its disagreement with our “reasonable apprehension of imminent suit” test, which was not an issue in the case before it, it appears incumbent on us to stop using that test and hereafter to apply the general declaratory judgment standards that the Supreme Court applied in MedImmune.

Posted March 30th, 2007 by Stephen Albainy-Jenei in IP Litigation
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The guys at FedCirc.us have announced a new search feature — cleaverly named search.fedcirc.us — that gives you quick and easy access to patent caselaw and commentary. Here’s how it works:A Google-powered search box is provided on the left side of the page. Search results are presented under the box once a search is performed (it’s even pre-loaded with a search). Just enter your search string and click the button.

Posted March 30th, 2007 by Stephen Albainy-Jenei in Cool Tools
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In the reverse payment case Joblove v. Barr Labs (S.Ct. No. 06-830), the Supreme Court has now asked for the government’s views on the antitrust effects of settlement agreements between holders of drug patents and generic drug makers enjoying the 180-day market exclusivity after Food and Drug Administration approval. This case involves the same legal issue that was raised in FTC v. Schering-Plough Corp., No. 05-273 (Jun. 26, 2006; denying certiorari), as well as three other recent petitions.The issue is the appropriate antitrust standard applicable to an agreement between a brand pharmaceutical manufacturer (and patent holder) and a generic market entrant (and alleged patent infringer) whereby the patent holder shares a portion of its future profits with the alleged infringer in exchange for the latter’s agreement to not market its competitive product. The three Circuit Courts of Appeals that have addressed the issue have rendered inconsistent decisions.

These antitrust class actions involve the prescription drug tamoxifen citrate (tamoxifen), a drug for the treatment of breast cancer. Zeneca manufactures and markets tamoxifen under the brand-name Nolvadex®. Zeneca’s former parent, Imperial Chemical Industries PLC (ICI), held the patent for tamoxifen, U.S. Patent 4,536,516 (‘516 Patent). In 1987, Barr amended its ANDA for tamoxifen to include a Paragraph IV Certification, which prompted a patent infringement suit by ICI (Zeneca’s parent which was then the patent holder). In 1992, the ‘516 Patent was held invalid and unenforceable.

While an appeal from the judgment invalidating the patent was pending in the Federal Circuit, Zeneca and ICI, the patent holders, and Barr, the alleged infringer, agreed to settle the case. Zeneca and ICI agreed to: (1) pay Barr $21 million; (2) pay Barr’s supplier $35.9 million; and (3) supply Barr with Zeneca-manufactured tamoxifen for resale in the United States at a high royalty rate. In return, Barr agreed to: (1) abandon its successful challenge of the tamoxifen patent; (2) withdraw its Paragraph IV Certification to manufacture and market generic tamoxifen prior to the patent’s expiration; and, if possible, and (3) prevent competitive entry by future generic manufacturers.

Now, the plaintiffs allege that the Agreements unlawfully restrained competition in the market for tamoxifen in violation of Sections 1 and 2 of the Sherman Act, 15 U.S.C. §§ 1, 2, and analogous state statutes. The question presented being “Under what circumstances is an agreement by a brand pharmaceutical manufacturer (and patent holder) to share a portion of its future profits with a generic market entrant (and alleged patent infringer), in exchange for the generic’s agreement not to market its product, a violation of the antitrust laws?”

In FTC v. Schering-Plough Corp., the Solicitor General concluded that no conflict exists that would warrant this Court’s review of this issue, based on the same body of case law that exists today. The court of appeals, after noting the public policy favoring settlement of litigation and the statutory right of patentees to exclude competition with in the scope of their patents, rejected that this violated the Sherman Act per se by settling, instead of litigating, a legitimate dispute between them over the validity of the patent for the drug tamoxifen. The court agreed that “’simply because a brand-name pharmaceutical company holding a patent paid its generic competitor money cannot be the sole basis for a violation of antitrust law,’ unless the ‘exclusionary effects of the agreement’ exceed the ’scope of the patent’s protection.’”

To add mud to the mix, the Preserve Access to Affordable Generics Act (S. 316) has been introduced into Congress to prohibit brand name drug companies from paying off generic drug companies to delay the entry of a generic drug into the market.

This would amend the Clayton Act (15 U.S.C. 12 et seq.) adding section 28, entitled “Unlawful Interference with Generic Marketing.” This section would read:

(a) It shall be unlawful under this Act for any person, in connection with the sale of a drug product, to directly or indirectly be a party to any agreement resolving or settling a patent infringement claim which (1) an ANDA filer receives anything of value; and (2) the ANDA filer agrees not to research, develop, manufacture, market, or sell the ANDA product for any period of time.

(b) Nothing in this section shall prohibit a resolution or settlement of patent infringement claim in which the value paid by the NDA holder to the ANDA filer as a part of the resolution or settlement of the patent infringement claim includes no more than the right to market the ANDA product prior to the expiration of the patent that is the basis for the patent infringement claim.

We’ll keep you posted on developments.

Posted March 27th, 2007 by Stephen Albainy-Jenei in FTC
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As a follow-up on yesterday’s article on the road to biogenerics, Food and Drug Administration deputy commissioner Janet Woodcock testified before an Oversight Committee held to examine the prospects and need for a pathway that would allow the FDA to approve safe and affordable generic versions of biotech drugs. Witnesses included representatives of FDA, pharmaceutical manufacturers, scientists, and consumer groups.

During the House Oversight and Government Reform Committee hearing, Woodcock said that while the FDA can currently establish the safety between versions of simple protein-based drugs, it will likely “be a stepwise progression over a decade or so,” before the agency can scientifically verify that a generic version of a complex biotech drug can be substituted for the original. 

The issue comes down to a question of whether generic drug companies would have to conduct clinical trials (and to what extent) before gaining approval. Rep. Henry A. Waxman, D-Calif., along with Representatives Emerson, and Pallone and Senators Schumer and Clinton, have re-introduced H.R. 1038, the “Access to Life-Saving Medicine Act,” which would establish a process through which the FDA will be able to approve generic biologics or biopharmaceuticals.

In summary, H.R. 1038 “Amends section 351 of the Public Health Service (PHS) Act to authorize the Secretary of HHS to approve abbreviated applications for biological products that are ‘comparable’ to previously approved (reference) biological products.”

The current abbreviated pathway described in section 505(b)(2) of the FD&C Act permits an applicant to rely on published literature or on the FDA’s finding of safety and effectiveness for a referenced approved drug product to support approval of a proposed product. A 505(b)(2) applicant must demonstrate that reliance on the previous finding of safety and effectiveness is scientifically justified and must submit whatever additional nonclinical and clinical data are necessary to establish that the proposed product is safe and effective.

The FDA has used this pathway to approve some follow-on protein products including Hylenex (hyaluronidase recombinant human), Hydase (hyaluronidase), Fortical (calcitonin salmon recombinant) Nasal Spray, Amphadase (hyaluronidase), GlucaGen (glucagon recombinant for injection), and Omnitrope (somatropin [rDNA origin]).

However, Woodcock made clear that things won’t go easy absent a drastic change in the law stating that:

Because of the variability and complexity of protein molecules, current limitations of analytical methods, and the difficulties in manufacturing a consistent product, it is unlikely that, for most proteins, a manufacturer of a follow-on protein product could demonstrate that its product is identical to an already approved product. Therefore, the section 505 (j) generic drug approval pathway, which is predicated on a finding of the same active ingredient, will not ordinarily be available for protein products.

To establish that two protein products would be substitutable, the sponsor of a follow-on product would need to demonstrate through additional clinical data that repeated switches from the follow-on product to the referenced product (and vice versa) would have no negative effect on the safety and/or effectiveness of the products as a result of immunogenicity. For many follow-on protein products — and in particular, the more complex proteins – there is a significant potential for repeated switches between products to have a negative impact on the safety and/or effectiveness. Therefore, the ability to make determinations of substitutability for follow-on protein products may be limited.

Not that the FDA has been resting on it’s laurels. As evidence of progress on follow-on protein products, Woodcock noted that :

Because there are many challenging scientific and policy questions about follow-on protein products, FDA has actively promoted a public dialogue on these issues. FDA has held two public meetings (September 2004 and February 2005) and co-sponsored a workshop, in collaboration with the National Institute for Standards and Technology, and with the New York Academy of Sciences (December 2005), to gather input on scientific and technical issues related to follow-on protein products. These meetings resulted in a large number of comments and concerns from the interested parties that have informed our considerations of these issues.

Expect continued arguments over the process as well as the projects savings over current costs.

Posted March 27th, 2007 by Stephen Albainy-Jenei in Biogenerics, FDA
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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.

Posted March 26th, 2007 by Stephen Albainy-Jenei in Biogenerics, FDA
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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.

Posted March 22nd, 2007 by Stephen Albainy-Jenei in Current Affairs
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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.

Posted March 22nd, 2007 by Stephen Albainy-Jenei in FDA
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