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An Overview Of ANDA Litigation In The United States

2018-01-24 12:41 · 作者:Christopher J. Sorenson   阅读:979

Christopher J. Sorenson

Partner, Merchant & Gould P.C.


(本文系知产力国际获得独家首发授权的稿件,转载须征得作者本人同意,并在显要位置注明文章来源。)




【编者按】


本文作者Christopher J. Sorenson系Merchant & Gould P.C.合伙人,生命科学诉讼业务团队的诉讼律师及前任主席,主要从事基于Hatch-Waxman法案的专利诉讼。他曾参与数次争辩性仲裁审理,还出庭过联邦法院和州立法院的审判。目前,他的工作重心是代表仿制药企业进行ANDA诉讼。


本文中文版稍后将在知产力微信订阅号(ID: zhichanli)上发表,敬请期待。





In the United States, the Food and Drug Administration (“FDA”) regulates the pharmaceutical industry, including the approval of generic drug products.   In order to facilitate greater availability of generic products in the market, while also encouraging brand company investments in research and development, Congress enacted a statutory framework commonly referred to as the Hatch-Waxman Act (21 U.S.C. § 355(j), 35 U.S.C. §§156, 271(e)).  This framework facilitates the interplay in the United States between regulatory exclusivities and the adjudication of patent exclusivities that may apply to any particular drug product.    



I.    Overview of the Hatch-Waxman Framework.



At a high level, under the Hatch-Waxman framework, entities seeking approval for a new drug (NDA applicants) must identify the patents that apply to the active ingredient, the formulation, and the methods of use relating to that product, which are then listed by the FDA in the Orange Book.[1]  Upon approval of a drug pursuant to an NDA application, the FDA will grant marketing rights to that drug that run independently of any patent term.  There are several different marketing (or “regulatory”) exclusivity periods that may apply – including NCE (New Chemical Entity) exclusivity, Orphan Drug Exclusivity (ODE), as well as other exclusivity periods.

Any patent exclusivities are adjudicated between the NDA holder and a generic manufacturer in a United States District Court.  Beginning one year before the expiration of NCE exclusivity, a generic manufacturer may submit an Abbreviated New Drug Application (“ANDA”) for FDA approval of the generic product.  The ANDA applicant must demonstrate to the FDA that its generic drug product: (1) has the same active ingredient and basic pharmacokinetics as the branded drug; (2) is bioequivalent; and (3) the dosage form and strength are the same as the branded product.  Caraco Pharm. Labs., Ltd. v. Forest Labs., Ltd., 527 F.3d 1278, 1282 (Fed. Cir. 2008). The ANDA applicant can rely on the clinical data from the branded drug to demonstrate safety and efficacy of its product, and thus, may receive expedited FDA approval at a lower cost than was incurred by the NDA holder to obtain its original drug approval.  Id.

To resolve any patent issues raised by the proposed generic product, the generic company must include a “Paragraph IV” certification to at least one of any of patents listed in the FDA Orange Book.  Id. at 1283.  This certification is one of four available,[2] but is the only one that provokes a corresponding litigation.  AstraZeneca LP v. Apotex, Inc., 633 F.3d 1042, 1046 (Fed. Cir. 2010).  A “Paragraph IV” ANDA certification is deemed an artificial act of patent infringement. Acorda Therapeutics, Inc. v. Mylan Pharm., Inc., 817 F.3d 755, 760 (Fed. Cir. 2016).  Thus, courts are allowed to determine whether the generic drug product would (if approved) infringe a valid patent, even though no actual sales of the ANDA product have occurred.  Eli Lilly & Co. v. Medtronic, Inc., 496 U.S. 661, 678 (1990).  And the NDA holder (if successful in patent litigation) can obtain a permanent injunction that will prohibit final FDA approval of the product until after the patent(s) at issue expire.  Acorda Therapeutics, Inc., 817 F.3d at 760.  Conversely, an ANDA applicant who is a first-to-file applicant, and is successful, receives a valuable 180-day marketing exclusivity period as the only approved generic product.  Apotex Inc. v. Daiichi Sankyo, Inc., 781 F.3d 1356, 1360 (Fed. Cir. 2015).

Although the exact procedures are beyond the scope of this article, if the brand company complies with certain protocols within the timeframes established by the Hatch-Waxman act, an automatic stay of approval of the ANDA application for a period of thirty months will apply.  Ortho-McNeil Pharm., Inc. v. Mylan Labs., Inc., 520 F.3d 1358, 1366 (Fed. Cir. 2008).  The patent litigation is thus on a relatively short timeline, as resolution of the case at the district court level should (at the latest) occur within 30 months of receipt by the NDA holder of notice that an Orange Book patent is the subject of a Paragraph IV notice.   This generally means that most United States District Courts will impose a case schedule that mandates a trial occur within 18-24 months from the date the notice letter is sent to the NDA holder, as reflected in the following table:

图表180124.PNG

The Hatch-Waxman framework thus offers the means to resolve patent disputes associated with the ANDA product prior to final FDA approval of the generic drug.   This, in principle, provides a means to avoid damage to the branded product’s market share, and eliminates large monetary awards against the generic manufacturer that would otherwise arise out of making, and using, the patented invention during preparation of an ANDA application.



II.   Tranexamic Acid – A Case Study.



Hatch-Waxman litigation can be complicated, and has the potential to raise many potential issues of patent law, civil procedure, science, and FDA regulation.  One case in particular offers a cogent case study that demonstrates the many overlapping considerations that may come into play during the course of an ANDA litigation in the United States.    Ferring B.V. v. Watson Labs., Inc., 764 F.3d 1401 (Fed. Cir. 2014) demonstrates the competing principles of regulatory exclusivity and the limits of patent protection available for a new formulation of a very old active ingredient.   In this case, the Hatch-Waxman framework facilitated the prompt introduction of a generic version of a drug product, while maintaining a reasonable period of market exclusivity for the brand company that had developed the product. 

Lysteda® was approved by the FDA in November of 2009.  It was approved as an immediate release tablet formulation of tranexamic acid, an active ingredient that had (for decades) been used in Europe to treat menorrhagia.  Ferring B.V. v. Watson Labs, Inc., 764 F.3d 1382, 1384 (Fed. Cir. 2014).   The FDA granted Lysteda several years of market exclusivity, which expired in 2012.  Before any patent was listed in the Orange Book for this product, and shortly after Lysteda® was originally approved, Watson filed its ANDA, seeking approval of a generic version of the Lysteda® product.  Ferring B.V. v. Watson Labs., Inc., 764 F.3d 1401, 1404 (Fed. Cir. 2014).  Ferring subsequently[3] listed three patents, each directed to a modified release formulations of tranexamic acid.  Id. at 1403.  After Watson filed Paragraph IV certifications to each patent with the FDA and gave Ferring notice of those certifications, Ferring filed a patent infringement suit in the district of Nevada in July of 2011.  The case proceeded through discovery, and a trial was held beginning in January of 2014, more than 12 months after Watson’s generic product was commercially sold in the United States, as Ferring’s regulatory exclusivity had expired and Watson’s product had been approved by the FDA. 

Among the patent claims asserted by Ferring were claims drawn to the dissolution of tranexamic acid from the drug product in water.  Id.  Watson’s ANDA specification did not include any information on the dissolution characteristics of the final product in water, but Ferring argued that some experimental testing done to support the ANDA application showed that an uncoated, intermediate form of the ANDA tablets had exhibited a dissolution profile in water within the scope of the patent claims.  Id. at 1410-11.  Ferring also noted that dissolution testing done by Watson during the litigation identified at least some final products demonstrated an infringing dissolution profile in water.  Id. at 1410.

After an eight-day bench trial, the Nevada District Court concluded the ANDA product infringed the patents, and an immediate appeal was filed.  On appeal, the Federal Circuit reversed, and noted that the filing of an ANDA was “constructive” infringement only for jurisdictional purposes, but that it was Ferring’s burden to demonstrate that the proposed ANDA product would actually infringe.  Id. at 1408.  The Federal Circuit found that Ferring had failed to meet its burden of proof, noting that only the final, approved, form of the ANDA product was relevant.  Id. at 1410.  And the Federal Circuit found that evidence of a few anomalous dissolution results among hundreds of other results showing non-infringement was not sufficient to sustain Ferring’s burden of proof.  Id.at 1409-10.  Of the hundreds of samples actually tested by Ferring’s experts, only four tablets dissolved within the claimed dissolution parameters.  Id. at 1405.  Watson’s expert offered evidence that those outliers were inadequately coated and were not representative of Watson’s ANDA product.  Id. at 1409.  The Federal Circuit found that the four anomalous tablets did not prove infringement by a preponderance of the evidence. 

The Federal Circuit also discounted experimental dissolution data of Watson’s intermediates that did not reflect the finished, coated commercial tablets.  Id. at 1410.  The uncoated intermediate cores with a measured harness of less than 17 kp were found to dissolve outside the claimed dissolution profile, and the amended ANDA required a core hardness less than 17 kp in Watson’s FDA-approved tranexamic tablets.  Id.  Accordingly, the Federal Circuit concluded that dissolution testing of intermediates outside of FDA-approved specifications did not satisfy Ferring’s burden in demonstrating infringement.  Id.  In summary, the thorough knowledge and application of patent law, scientific, and regulatory concepts led to Watson’s successful defense against patent infringement, and to its successful generic product launch.



III.  Conclusion.



As demonstrated above, experienced counsel can develop effective strategies to navigate through the complex Hatch-Waxman framework.  Brand companies often obtain valuable regulatory exclusivities, whose length depends on whether they have achieved new formulations, discovered new chemical entities, or patented strong inventions.  In turn, generic companies can obtain valuable 180-day generic exclusivities if they successfully challenge brand product patents.  And while patent disputes can get complicated in the United States, the fact that they can be litigated during FDA evaluation and before a generic product enters the marketplace benefits all parties. 

Moreover, the case study discussed above demonstrates the importance of a thorough analysis of an ANDA’s specifications, and the importance of considering pending and issued patent claims in the United States during development—especially if the ultimate strategy is to design-around the brand company’s patents.  And in the United States, anomalies will not necessarily prove infringement. 


[1] Generally speaking, the NDA holder is not allowed to list patents pertaining to the process, or manufacturing of the active pharmaceutical ingredient, but any generic manufacturer should nonetheless identify (to the extent possible) any such patents as part of their due diligence associated with deciding whether to pursue a generic product.  Patents that are not listed in the Orange Book could, in theory, be asserted against a generic product independently of the Hatch-Waxman framework upon FDA approval and commercial sale of the product in the United States. 


[2]  An applicant may proceed with its ANDA application without challenging the listed patents as well.  The certifications available in Section 355(j)(2)(A)(vii) are as follows: (I) the reference drug is not listed with any applicable patents; (II) the patent has expired; (III) the generic drug will not go onto market until the listed patent expires; or (IV) that the patent is invalid or will not be infringed by the manufacture, use, or sale of the drug.


[3] Since no patent had issued at the time, no patents were listed in the Orange Book when Watson’s ANDA was filed.  As a result, there was no automatic 30-month stay of FDA approval in this case.  See 35 U.S.C. § 355(j)(5)(B).



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