By Kurt R. Karst –   

The U.S. District Court for the District of Delaware’s recent decision in Millennium Pharmaceuticals, Inc. v. Teva Parenteral Medicines, Inc., denying a stay of patent infringement proceedings concerning generic versions of Schering’s INTEGRILIN (eptifibatide) Injection is (to our knowledge) the latest case in which a court has been asked to “toll” the 30-month stay of ANDA approval provided under FDC Act § 505(j)(5)(B)(iii) in an effort to preserve 180-day exclusivity eligibility.  As we previously reported, last year the U.S. District Court for the Northern District of Illinois (Eastern Division) in Abbott Labs. v. Matrix Labs., Inc., No. 09-cv-1586 (N.D. Ill. Nov. 5, 2009) ordered the tolling of the 30-month stay in the context of patent infringement litigation over generic KALETRA (lopinavir; ritonavir) Tablets. 

Under FDC Act § 505(j)(5)(B)(iii), the 30-month stay may be “for such shorter or longer period as the court may order because either party to the action failed to reasonably cooperate in expediting the action . . . .”  FDA commented in the preamble to the Agency’s 1994 final regulations implementing the Hatch-Waxman Amendments that “[t]he statute leaves the issue of extending the 30-month period (based on a lack of cooperation between the parties in patent litigation) to the discretion of the trial court.  The agency believes that the trial court should make determinations of cooperation on a case-by-case basis.”  FDA also commented, without qualification, that “[u]nder the statute, the reduction or enlargement of the 30-month period is left to the trial court’s discretion.” 

In the latest case, Teva filed a Motion to Stay requesting an order from the court “(1) staying the present actions until May 11, 2012 (subject to a showing of good cause by any party that the stay should be lifted earlier), and (2) tolling the [FDA] thirty-month stays of approval of Teva's [ANDAs] for the drug at issue here, eptifibatide.” 

INTEGRILIN is covered by five Orange Book-listed patents.  Two of the patents, to which one of Teva’s ANDAs reportedly contains Paragraph III certifications, are scheduled to expire in 2014.  The three other patents, to which one of Teva’s ANDAs reportedly contains Paragraph IV certifications, are scheduled to expire in 2015.  As we previously discussed, this sets up a scenario whereby an early court decision on the Paragraph IV certification patents – that is, a decision well before the Paragraph III certification patents expire – could trigger the 75-day period under FDC Act § 505(j)(5)(D)(i)(I)(bb)(AA), such that, if Teva is a first applicant eligible for 180-day exclusivity, that eligibility could be forfeited under the “failure-to-market” forfeiture provisions.  Those provisions provide that 180-day exclusivity is forfeited based on the “later of” two events – (aa) the earlier of “75 days after the date on which the approval of the application of the first applicant is made effective under [FDC Act § 505(j)(5)(B)(iii)]” or “30 months after the date of submission of the application of the first applicant,” and (bb) 75 days after a final court decision finding certain patents invalid or not infringed with respect to a “first applicant or any other applicant (which other applicant has received tentative approval)” or patent delisting.   

Citing the court’s three-factor stay standard articulated in In re Brimonidine Patent Litig., No. 07-md-1866 (D. Del. Oct. 31, 2008), in which an NDA sponsor requested (and was denied) a stay and tolling of the 30-month stay, Teva argued that: (1) the company would be “greatly prejudiced if the requested stay is not granted;” (2) a “stay could simplify the issues or render litigation unnecessary;” and (3) although the INTEGRILIN patent infringement litigation is in its infancy, case law supports granting a stay at this early stage of litigation.  

Schering and Millennium opposed Teva’s motion arguing that the three factors in In re Brimonidine Patent Litig. are not met.  Most significantly, they argued that:

Teva’s motion is grounded in the incorrect assertion that this Court has complete discretion to extend the FDA’s thirty-month stay.  Although a district court often has broad discretion to stay litigation to control its own docket, there is no such discretion here because Teva is asking this Court to extend the FDA’s statutory thirty-month stay. [(italics in original)]

. . . Congress has expressly provided that the thirty-month stay can not be altered unless a “party to the action failed to reasonably cooperate in expediting the action.” 21 U.S.C. § 355(j)(5)(B)(iii).  The Federal Circuit has made it clear [in Eli Lilly & Co. v. Teva Pharm. USA, Inc., 557 F.3d 1346 (Fed. Cir. 2009) and Andrx Pharm., Inc. v. Biovail Corp., 276 F.3d 1368, 1376 (Fed. Cir. 2002)] that failure to reasonably cooperate in expediting litigation is the sole ground for which a court may extend the thirty-month stay in an ANDA litigation.

And with respect to the decision in Abbott Labs. v. Matrix Labs., Inc., Schering and Millennium commented that:

Even apart from the fact that a decision from a district court in Illinois is not binding in the District of Delaware, Abbott Labs does not justify Teva’s proposed stay. Most critically, the Abbott Labs court improperly did not recognize that the “failed to reasonably cooperate” restriction in section 355(j)(5)(B)(iii) limits the court’s discretion to enlarge the thirty-month period. . . .  As such, the Abbott Labs decision plainly runs afoul of the Federal Circuit’s holdings in Eli Lilly and Andrx and Chief Judge Sleet’s decision in Brimonidine.

Teva replied that the court does, in fact, have the authority to toll the 30-month stay, and that the patent infringement actions “should be stayed regardless of whether the Court also tolls the stays at the FDA.  Tolling at the FDA is not a prerequisite to a stay here” (italics in original).  

Finding, among other things, that “Plaintiffs would be prejudiced in not being able to timely ‘clear the cloud’ that has been cast over the validity of their patents,” Judge Joyner ruled in his brief opinion that:

Although it would be permissible to grant a stay at this stage of the proceedings, given the balancing of the other factors discussed above, we do not believe that it would be appropriate to exercise our discretion to do so at this time.  Granting a stay would cause a hardship to Plaintiffs and any hardship caused to Defendants was the foreseeable result of Defendants’ choice to file their ANDAs when they did.

With respect to the court’s ability to toll the 30-month stay of ANDA approval, Judge Joyner decided to sidestep the issue, commenting that “we do not find it necessary to address these arguments as we have decided against staying the present action, and, therefore, there is no reason to extend the FDA’s stay.”

The March/April 2010 issue of FDLI Update contains an article by Hyman, Phelps & McNamara, P.C.’s Peter M. Jaensch and John R. Fleder that addresses the increasing number of cases brought under the federal Lanham Act law where plaintiffs have arguably sought to privately enforce the FDC Act.  In particular, the article analyzes Schering-Plough Healthcare Products, Inc., v. Schwarz Pharma, Inc. et al., 586 F.3d 500 (7th Cir. 2009).  The Court of Appeals ruled that the plaintiff was improperly seeking to enforce the FDC Act, and was treading on FDA’s primary jurisdiction over drug labeling issues.

Just after this article was published, the Ninth Circuit issued a similar ruling on April 14, 2010, in PhotoMedex, Inc. v. Irwin. The plaintiff commenced a Lanham Act case based on allegations of misrepresentations made by defendants regarding: (1) clearance by FDA to market their laser device, (2) the anticipated date their laser would be available for purchase, and (3) Irwin’s role as inventor of the device. 

The Court ruled that the first alleged misrepresentation would have required the Court to address whether a medical device manufacturer which is not permitted to bring a private action to enforce the FDC Act may nevertheless maintain a suit under the Lanham Act based on a claim that a competitor misrepresented that its product had received FDA clearance, when the FDA had declined to make such a finding or bring an enforcement action. The Court concluded that because the FDA permits Defendants to determine in the first instance whether their laser device was covered by an FDA clearance previously given to a similar device and to market their device without an affirmative statement of approval by the FDA, the Lanham Act claim could not proceed.  The Court did, however, allow the other two alleged misrepresentations.

The Court of Appeals cautioned that it was not suggesting that the Lanham Act can never support a claim involving FDA approval or clearance of drugs or medical devices.  It stated that if a company makes “an affirmative statement of approval by the FDA was required before a given product could be marketed and that no such FDA approval had been granted,” a Lanham Act claim could be pursued.

By Kurt R. Karst –   

Earlier this week, the U.S. Court of Appeals for the Federal Circuit issued its decision in Novo Nordisk A/S v. Caraco Pharmaceutical Laboratories, Ltd., No. 2010-1001, interpreting the patent delisting counterclaim provisions at FDC Act §505(j)(5)(C)(ii)(I), as added by the Medicare Modernization Act (“MMA”) – and specifically addressing whether the counterclaim provisions may be used to correct or delete an Orange Book-listed patent use code.  As we previously reported, last year the U.S. District Court for the Eastern District of Michigan (Southern Division) ruled and issued an Order and Injunction requiring Novo Nordisk, Inc. (“Novo”) to change an Orange Book-listed patent use code for a patent (U.S. Patent No. 6,677,358 (“the ’358 patent”)) on its drug product, PRANDIN (repaglinide) Tablets.  Novo appealed and the Federal Circuit reversed and vacated the district court’s judgment in a 2-1 decision. 

As we noted in our previous post, this case stems from a patent infringement action Novo brought against Caraco Pharmaceutical Laboratories, Ltd. (“Caraco”) and Sun Pharmaceutical Laboratories, Ltd with respect to the ’358 patent, and two related citizen petitions Novo and Caraco initially submitted to FDA in 2008 concerning generic drug labeling carve-out and split patent certification issues.  Novo submitted a  petition to FDA after the Agency required the company to amend PRANDIN’s labeling to reflect a new Indications and Usage statement.  Specifically, FDA required a unitary indication statement stating: “PRANDIN is indicated as an adjunct to diet and exercise to improve glycemic control in adults with type 2 diabetes mellitus.”  (Previously, the PRANDIN Indications and Usage labeling statement discussed both monotherapy and combination therapy.)  Novo ultimately amended its Orange Book patent listing for the ’358 patent with a new use code: “U-968,” which is defined as “A METHOD FOR IMPROVING GLYCEMIC CONTROL IN ADULTS WITH TYPE 2 DIABETES MELLITUS.”   (Previously, the ’358 patent was listed in the Orange Book with a “U-546” code, which is defined as “USE OF REPAGLINIDE IN COMBINATION WITH METFORMIN TO LOWER BLOOD GLUCOSE.”)

The district court deciding the patent infringement action stated that “[a]s a result of the revised use code, the FDA will no longer permit Caraco to file a ‘section viii statement’ carving out the patented repaglinide-metformin combination therapy as a predicate for securing approval of Caraco’s ANDA to market its generic repaglinide for non-infringing uses.”  That is, FDA is apparently requiring a “full” Paragraph IV Certification from Caraco as to the ‘358 patent as a result of the use code change.

Caraco challenged Novo’s use code change in an FDC Act §505(j)(5)(C)(ii)(I)  counterclaim seeking an order from the court requiring Novo to amend the ‘358 Orange Book patent listing to revert back to the U-546 use code.  FDC Act §505(j)(5)(C)(ii)(I) states:

If an owner of the patent or the holder of the approved application under [FDC Act § 505(b)] for the drug that is claimed by the patent or a use of which is claimed by the patent brings a patent infringement action against the applicant, the applicant may assert a counterclaim seeking an order requiring the holder to correct or delete the patent information submitted by the holder under [FDC Act § 505(b)] or (c) on the ground that the patent does not claim either – (aa) the drug for which the application was approved; or (bb) an approved method of using the drug.

Under FDC Act §§ 505(b) and (c), an NDA holder must submit with its application and after NDA approval “the patent number and the expiration date of any patent which claims the drug for which the applicant submitted the application or which claims a method of using such drug 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.”

The district court issued an Order and Injunction requiring Novo to submit to FDA a revised Form FDA 3542 reinstating the former U-546 listing for PRANDIN within twenty days from the date of the Order and Injunction.  Novo promptly appealed the decision to the Federal Circuit, which stayed the district court’s Order and Injunction.

In (soon-to-be Chief) Judge Rader’s April 14th majority opinion, the Court ruled that Caraco “does not have a statutory basis to assert a counterclaim requesting” a court to enter an order to replace Novo’s U-968 patent use with the former U-546 use code.  First, “the Hatch-Waxman Act authorizes a counterclaim only if the listed patent does not claim any approved methods of using the listed drug” (emphasis added).  Second, “the terms of the counterclaim provision do not authorize an order compelling the patent holder to change its use code narrative.” 

Judge Rader sets up the dispute in the case as follows:

Novo and Caraco agree that the ’358 patent claims only one of the three approved methods of using PRANDIN (i.e., repaglinide in combination with metformin).  Novo asserts that the counterclaim is available only if the ’358 patent does not claim any approved methods.  Caraco argues that it is entitled to the counterclaim because the ’358 patent does not claim two of the approved methods of PRANDIN use.  In other words, Novo reads “an approved method” in the counterclaim statute as “any approved method” while Caraco reads it as “all approved methods.”

Detecting “no ambiguity in the statutory language,” Judge Rader notes that “when an indefinite article is preceded and qualified by a negative, standard grammar generally provides that ‘a’ means ‘any.’”  As such, for a counterclaim to be available, the Orange Book-listed patent cannot claim any approved methods of using the drug.  Judge Rader goes on to note that:

a broad use code covering all uses of a pharmaceutical could require generic manufacturers to prove specifically that their use will not overlap with and infringe the patented use.  This proof, under Hatch-Waxman procedures, will take the form of a Paragraph IV lawsuit.  In that context, the generic may provide proof that their use will not cause infringement of the patented use.  This court perceives that the Hatch-Waxman Act will thus ensure that a generic drug for non-patented purposes will not be used for patented purposes via a simple section viii certification.  Instead, the generic manufacturer will need to alleviate the risk of infringement or induced infringement in a proceeding that fully tests for infringement and its implications, including potential health and safety risks.  Thus, the Act again facilitates efficient resolution of disputes concerning potential overlapping of protected and unprotected uses.  The Act seeks to strike a balance of the pioneering and generic manufacturers’ interests.

To be sure, Judge Rader states that “the terms of the counterclaim provision do not authorize an order compelling the patent holder to change its use code narrative.”  The counterclaim provision refers to “patent information” submitted by the NDA holder under FDC Act § 505(b) or § 505(c).  And both of these provisions refer only to “the patent number and the expiration date of any patent . . . which claims a method of using such drug” (emphasis added).  Thus, “the counterclaim provision only authorizes suits to correct or delete an erroneous patent number or expiration date.  The authorization does not extend to the use code narrative.”  This “careful use of language” suggests to Judge Rader that the Hatch-Waxman Act “facilitates efficient resolution of disputes over the potential overlap of patented and unpatented uses in the form of a Paragraph IV suit.”

Judge Clevenger, who agreed with Judge Rader’s analysis, filed a concurring opinion expressing skepticism that “the ongoing Paragraph IV litigation will cleanly resolve the dispute between the parties.”  He also fingered FDA as the culprit for for complicating the PRANDIN patent infringement litigation:

If not for FDA’s request that Novo change its labeling to the present broad indication, everything would have worked properly under the relevant statutes. . . .  Caraco was [] set to get FDA approval to bring its generic drug to market and to defend itself in Novo's Paragraph IV suit.

But FDA, acting independently, gummed up the works.  By requiring a single broad indication for repaglinide as part of the approved labeling, FDA created a situation where Caraco can no longer assert that its proposed labeling does not infringe the '358 patent.  It remains to be seen what impact FDA's action will have on Caraco's ability to defend itself in the ongoing Paragraph IV litigation, but FDA's regulatory action threatens to impair Caraco's ability to disprove infringement.  FDA thus may have inadvertently upset the careful balance of interests represented by the efficient dispute resolution mechanism Congress created in the Hatch-Waxman Act.

According to Judge Dyk, who lodged a 28-page dissent, “the majority’s crabbed view of the statute sanctions an unjustified manipulation of the Orange Book.” 

The statute does not require the listing of patent numbers and expiration dates in the abstract.  It contemplates the description of the scope of the patent and of the relationship between the patent and the drug or the method of use; the description of that scope and relationship is itself “patent information” . . . .  Other provisions of the statute also contemplate that the ANDA filer will be able to understand the scope of the patent and to relate the patent information to the drug or drugs being claimed and the method or methods of use being claimed. [(emphasis in original)]

The statute thus must allow correction of a misdescription of patent scope that includes a drug not covered by the patent and erroneous information about the relationship between the patent and the drug, even if the patent is properly listed elsewhere in the Orange Book.  In other words the scope of the patent and its relationship to the drug must be “patent information” . . . .

There is no basis in the statutory language or statutory purpose for distinguishing between drug information and method of use information. Either both must be “patent information,” or neither must be patent information.  In my view, all Orange Book information is “patent information.”

Judge Dyk’s dissent harkens back to the recent decision in Teva Pharms USA, Inc. v. Sebelius, 595 F.3d 1303 (D.C. Cir. 2010), in which the D.C. Circuit was convinced by Teva’s structural argument that the patent delisting counterclaim provision at FDC Act § 505(j)(5)(C)(ii)(I) must be read together with the patent delisting 180-day exclusivity forfeiture provision at FDC Act § 505(j)(5)(D)(i)(I)(bb)(CC).  In Teva, the Court stated that FDA was unable to offer “a single cogent reason why Congress might have permitted brand manufacturers to trigger [FDC Act § 505(j)(5)(D)(i)(I)(bb)(CC)] by withdrawing a challenged patent, outside the counterclaim scenario identified by Teva,” and ruled that there is “no reason to conclude that the 2003 addition of forfeiture provisions meant to give the brand manufacturer a right to unilaterally vitiate a generic’s exclusivity.” 

The import of the Teva decision is no lost on Judge Dyk:

In holding that the counterclaim provision is unavailable, the majority’s approach is notably inconsistent with the approach adopted by our sister circuit in another recent Hatch-Waxman Act case, [Teva]. . . .  Here the majority reaches a result that is unsupported by any cogent reason for leaving an ANDA applicant without a remedy to correct an erroneous Orange Book listing with respect to a method of use patent, and is directly contrary to the congressional purpose.

It is unclear whether Caraco will seek a review of the decision.  In the meantime, it will be interesting to see what effects the Federal Circuit’s decision might have on other related litigation – namely, in another patent infringement action concerning PRANDIN, and with respect to a patent delisting counterclaim recently filed in patent infringement litigation concerning ACTOS (pioglitazone) (here and here), but that does not concern patent use codes – and whether Congress will take interest in the issue and further amend the Hatch-Waxman Amendments. 

By Kurt R. Karst –

It seems to be a popular headline these days: “FDA Sued Over [take your pick].”  Following the frenetic losartan 180-day litigation – which is still not over, as FDA has filed a petition for panel rehearing and rehearing en banc of the D.C. Circuit's March 2, 2010 decision in Teva Pharms USA, Inc. v. Sebelius, 595 F.3d 1303 (D.C. Cir. 2010), and Roxane Laboratories, Inc. has appealed to the D.C. Circuit the D.C. District Court’s April 2, 2010 ruling denying Roxane’s preliminary injunction motion – FDA has been hit with two new lawsuits. 

First, on April 6, 2010, a coalition of animal rights advocates filed a complaint in the U.S. District Court for the District of Columbia seeking declaratory and injunctive relief to require FDA to substantively respond to a November 2007 citizen petition.  That petition posits that “FDA has the authority to mandate the use of nonanimal alternatives and to restrict the use of animal test methods for purposes of FDA approval,” and “requests that the FDA exercise this authority to promulgate a regulation mandating that investigators and testing facilities use scientifically satisfactory non-animal replacements for animal-based methods when meeting the requirements of the Federal Food, Drug and Cosmetic Act.” 

According to the petitioners, the requested regulation is needed to eliminate or greatly reduce the use of “ineffective and costly animal testing methods that fail to identify the dangerous and lethal effects of drugs and devices on humans, and yet needlessly inflict pain and suffering on millions of animals each year.”  Although FDA has stated in letters related to the petition (here and here) that “FDA suggests and encourages the development, validations, and utilization of alternatives to animal testing,” the Agency has not formally responded to the citizen petition.  The animal right advocates who have sued FDA allege that the Agency has failed to comply with the Administrative Procedure Act (5 U.S.C. § 555(b) and the Agency’s citizen petition regulations (21 C.F.R. § 10.30(e)) by failing to substantively respond to the November 2007 petition within “a reasonable time,” and request the court to compel FDA to provide a timely substantive response.  Historically, courts have been hesitant to grant such relief (see e.g., here).

Second, earlier this week, a group of ear candle advocates sued FDA after the Agency issued about 15 Warning Letters to companies marketing the products.  According to FDA, ear candles are “hollow cones that are about 10 inches long and made from a fabric tube soaked in beeswax, paraffin, or a mixture of the two” that are being marketed as treatments for a variety of conditions, including “ear wax buildup, sinus infections, hearing loss, headaches, colds, flu, and sore throats.”  Ear candling, also known as “ear coning” or “thermal-auricular therapy,” is an alternative medicine practice that advocates claim improves general health and well-being.  

FDA’s Warning Letters (see e.g., here) state that the products are unapproved medical devices and requests that the companies cease marketing and distributing their products:

Specifically, the ear candle is adulterated under section 501(f)(1)(B) of the Act, 21 U.S.C. 351(f)(1)(B), because you do have an approved application for premarket approval (PMA) in effect pursuant to section 515(a) of the Act, 21 U.S.C. 360e(a), or an approved application for an investigational device exemption (IDE) under section 520(g)of the Act, 21 U.S.C. 360j(g).  Your device is also misbranded under section 502(o) of the Act, 21 U.S.C. 352(o), because you did not notify the agency of your intent to introduce the device into commercial distribution for the intended uses discussed above, as required by section 510(k) of the Act, 21 U.S.C. 360(k).

This is not the first time FDA has taken enforcement action against companies marketing ear candles.  FDA issued similar Warning Letters in 1998 – here and here.

The ear candle advocates (they refer to the products as “Holistic Candles”) allege in their complaint that “Holistic Candle is a generic product that is exempt from defendant FDA’s regulation requirements.”  According to the Plaintiffs:

Holistic Candles are not medical devices.  Properly made Holistic Candles are a natural holistic modality are used for and intended to be used for relaxation, comfort, reduction of stress and for the natural furtherance of the well-being of the user.  The relaxation process, from the viewpoint of any alternative health modality, is for the fostering of and the support for the human body’s own propensity to spontaneously seek natural homeostasis, via relaxed and stress-reducing circumstances, catalysts, or environments.

Such traditional and intended use, usually in a family or private association context does not “treat or cure” any condition of illness, and does not specifically affect any body function.  Alternative modalities simply allow the body to do what the human body does naturally, and that is to find a proper and necessary balance between the integrated components of the mind-body-spirit. This, in essence, is what homeostasis is.

The ear candle advocates seek “that proper Disclosure and Disclaimers be given with regard to Holistic Candles, to save them from being considered Medical Devices,” and contend that Holistic Candles are not medical devices, or if they are, that “they are exempt from registration as Class I Devices,” and if “Holistic Candles are not exempt Class I Devices,” then they are grandfathered “as having been in use prior to 1974.”  (The reference to 1974 should be 1976.  Under the FDC Act, certain devices that were legally marketed prior to the May 28, 1976 enactment of the Medical Device Amendments, and which have not been significantly changed or modified since that time – so-called “preamendment” or “grandfathered” devices – do not require submission of a premarket approval application (“PMA”) (or a 510(k) premarket notification) until after FDA issues a final rule requiring a PMA for that device.)  

By Susan J. Matthees –

By letter of March 26, 2010, FDA denied a 2003 Citizen Petition from CTFA (now PCPC) and The Soap and Detergent Association which had requested FDA to include antiviral indications, labeling, and test methods in the Tentative Final Monograph ("TFM") for OTC Healthcare Antiseptic Drug Products (59 Fed. Reg. 31,402).  The industry had long chafed under FDA’s restriction of OTC topical antimicrobials only to antibacterial use. 

In denying the Citizen Petition, more than 7 years later, FDA concluded that: (1) the data submitted did not “clearly demonstrate” antiviral effectiveness; (2) the proposal to use surrogate viruses to test antiviral effectiveness was unacceptable because of the variability of viruses in their susceptibility to antiseptics; (3) the proposed effectiveness criterion of a 2-log10 reduction was unsupported; (4) the proposed ASTM test methods were inadequate; (5) the proposed antiviral labeling is unsupported by evidence of effectiveness, and may be misleading; and (6) some of the active ingredients are not eligible for inclusion in the OTC healthcare antiseptics review because they did not include antiviral claims in their pre-1972 labeling.

Despite the agency’s across-the-board rejection of the Citizen Petition, the letter asserts:  “we believe that the availability of products with demonstrated antiviral activity would be of benefit to healthcare professionals, consumers, and foodhandlers, and we encourage you to submit additional data on this issue.”  At present, however, the agency does not intend to add antiviral claims to the OTC healthcare antiseptic TFM. 

But in an apparently contradictory statement, FDA was “able to document the pre-1972 marketing of healthcare personnel hand-washes containing benzalkonium chloride, providone-iodine, and triclosan for an antiviral indication.”  Therefore, these products may be eligible for consideration of antiviral claims in the OTC healthcare antiseptic review.  Moreover, these products could be marketed now with antiviral claims while the review is pending, pursuant to FDA’s enforcement policies.  See Compliance Policy Guide (CPG) 7132b.15, CPG Manual 450.200; see also 21 C.F.R. § 330.13.  The agency may have created at least a short-lived marketing opportunity for some products.  

By Jennifer B. Davis –

(1) Regenerative Sciences, Inc. v. FDA.  On March 26, 2010, Chief Judge Wiley Y. Daniel of the United States District Court for the District of Colorado dismissed on “ripeness” grounds a February 22, 2009 action brought by Colorado-based Regenerative Sciences, Inc. (“RSI”).  The lawsuit  – filed after RSI’s receipt and response to an FDA Untitled Letter, and in the midst of a subsequent FDA inspection of its laboratory – sought declaratory and injective relief from FDA jurisdiction and regulation under the Federal Food, Drug, and Cosmetic Act (“FDC Act”), Public Health Service Act (“PHS Act”), and the 21 C.F.R. Part 1271 Human Cells, Tissues, and Cellular and Tissue-Based Products regulations (“HCT/P regulations”) of RSI’s autologous, mesenchymal stem cell (“MSC”) Regenexx™ Procedure for treatment of musculoskeletal and spinal injuries.  To our knowledge, the case represents the first attempt to challenge in federal court the FDA’s claimed legal authority for portions of the HCT/P regulations.  The decision is also notable for its precedent-confirming pronouncement that FDA Warning Letters are not “final agency action.”

In the Regenexx™ Procedure, MSCs isolated from a patient’s bone marrow undergo a 1-2 week expansion in the laboratory using natural growth factors from the same patient’s blood.  The expanded MSCs are then returned to the patient at a site of injury with the goal of regenerating bone and cartilage to repair the degenerated area. 

FDA’s July 25, 2008 letter to RSI advised that based on the review of RSI’s website, the agency determined RSI was promoting “use of [MSCs] under conditions that cause these cells to be ‘drugs’ under section 201(g) of the [FDC Act] (21 U.S.C. §321(g)), and biological products, as defined in section 351(i) of the [PHS Act] (42 U.S.C. §262).”  FDA further asserted that the Regenexx MSCs were HCT/Ps as defined by section 1271.3(d) of the HCT/P regulations, but, that they did not satisfy all of the section 1271.10 criteria establishing when a cellular HCT/P is not subject to the requirements for an approved biologics license application (“BLA”) or investigational new drug application (“IND”).  FDA’s letter advised the company that “implantation of the mesenchymal stem cells for which a valid license or IND is not in effect appears to violate the [FDC] Act and the PHS Act and may result in FDA seeking relief as provided by law.”

RSI argued in response that its MSCs were not “drugs” or “biological products,” and that they should not be regulated by the agency.  Six months later, FDA initiated an inspection of RSI’s facilities under its authority in the FDC and PHS Acts.  RSI then filed its lawsuit claiming that: (1) the Regenexx Procedure constitutes the practice of medicine and is beyond the scope of FDA’s regulatory authority and jurisdiction under the FDC And PHS Acts; (2) FDA’s decision that the manipulation of MSCs renders the cells a “drug” and a “biological product” requiring an IND or BLA was arbitrary and capricious; and (3) FDA’s regulatory definition of “HCT/P,” which fails to distinguish between allogenic or autologous transfers to a “human recipient,” was ultra vires FDA’s authority because Congress did not intend to give FDA authority over the autologous, “practice of medicine” use of HCT/Ps.

Judge Daniel found that RSI’s claim challenging the validity of FDA’s HCT/P regulatory definition was a “purely legal” question “fit” for judicial review, but nevertheless concluded that the claim was not ripe because RSI “ha[d] not shown any specific concrete action taken by the FDA that has harmed it or any specific losses it has suffered as a result of FDA action.”  Adhering to prior precedent, Judge Daniel explained that “the July 25, 2008, FDA warning letter is not a ‘final agency action’ as defined under the APA,” but “a ‘tentative or interlocutory action.’”

Addressing RSI’s other claims – that the Regenexx Procedure constitutes the Practice of Medicine, over which FDA has no authority under the FDC Act or PHS Act, and that FDA’s decision that the MSCs were “drugs” or “biological products” requiring an investigational new drug application (“IND”) or biologics license application (“BLA”) was arbitrary and capricious – Judge Daniel concluded that they, too, were not ripe because such claims would “require a factual inquiry into whether FDA can regulate autologous use of [HCT/Ps] and their functions” and  “do not involve a final FDA action interpreting and applying Part 1271 ‘to a specific set of circumstances as required for the action to be ripe and fit for review.’”   Further explaining his decision, Judge Daniel wrote:

[RSI] asks this Court to find, as a matter of law, that Congress intended to foreclose the possibility that FDA would regulate any autologous use of HCT/Ps – regardless of the type of HCT/Ps, the intended use of the HCT/Ps, the degree to and circumstances under which the HCT/Ps are manipulated prior to implantation, and regardless of how these factors may contribute to the transmission of diseases. . . .  [S]uch a task would be unduly complex and speculative.  The Court would have to assess the likelihood of the transmission of a wide range of diseases, under diverse methods for processing numerous types of HCT/Ps with various autologous uses, to determine at this stage whether FDA’s regulation defining HCT/Ps . . . is “ultra vires” in all possible circumstances.  Only a final FDA action interpreting and applying Part 1271 (including its exceptions) to a specific set of circumstances would reduce this amorphous inquiry to a controversy of ‘more manageable proportions.’

In promulgating the Part 1271 HCT/P regulations, FDA has consistently claimed that its authority comes from section 361 of the PHS Act (42 U.S.C. §264), which allows the agency to make and enforce regulations necessary to prevent the introduction, transmission, or spread of communicable diseases.  As RSI contended in its lawsuit, however, and as other stakeholders have argued in comments on various HCT/P rulemakings and guidance documents, it is not clear that all of FDA’s promulgated HCT/P requirements are actually (or reasonably) related to the prevention, introduction, transmission or spread of communicable disease, or whether – especially in cases of autologous use –  FDA’s HCT/P requirements impermissibly infringe on the congressionally recognized “practice of medicine.”

(2) Independent Turtle Farmers of Louisiana, Inc. v. FDA.  In a coincidental twist of timing, three days after Judge Daniel dismissed the RSI lawsuit, on March 29, 2010, Judge Dee D. Drell of the United States District Court for the Western District of Louisiana, Alexandria Division, ruled in favor of the agency in another case challenging FDA’s authority under section 361 of the PHS Act – to continue its enforcement of a thirty-five-year-old ban on pet turtles.

In 1975, FDA issued a regulation banning the sale of turtles and turtle eggs (21 C.F.R. §1240.62) based on studies showing that fourteen percent of all Salmonella-induced illnesses were “turtle-related.”  (FDA’s determination of its jurisdiction to issue the ban was challenged and upheld in State of La. v. Mathews, 427 F. Supp. 174, 176 (E.D. La. 1977).)  In promulgating the regulation, FDA said it would consider lifting or changing the restrictions based on “future evidence . . . demonstrat[ing] that Salmonella-  . . . free turtles can be produced and that sufficient safeguards exist to prevent a public health hazard through recontamination of turtles after shipment.”  40 Fed. Reg. at 2544.  In 2006, citing improvements in turtle rearing technology, and other scientific Salmonella-reducing advancements such as liquid antibacterial soap, the Independent Turtle Farmers of Louisiana, Inc. (“ITFL”) petitioned FDA to lift the ban. 

FDA denied the ITFL’s request, concluding that its petition “[did] not demonstrate that Salmonella-free turtles can be consistently produced and that, if Salmonella-free turtles are produced, they will not be recontaminated with Salmonella after shipment.”  The agency also rejected the ITFL’s argument that the ban was unfair in light of FDA’s less stringent guidelines for control of Salmonella in food sources.  The ITFL sued the agency in May 2007 claiming, in part, that the turtle ban exceeded FDA’s authority under section 361 of the PHS Act.

Upholding FDA’s decision to retain the turtle ban, Judge Drell concluded that “FDA’s interpretation of [§361] is entitled to wide deference” and that section 361’s enumeration of the actions that could be taken by the agency (i.e., “inspection, fumigation, disinfection, sanitation, pest extermination, destruction of animals or articles found to be so infected or contaminated”) “does not act as a limitation upon the types of regulations that may be enacted under Section 361.”  Moreover, observed Judge Drell, “the Court is obligated to defer to an agency’s interpretation of its own regulations” and “[j]udging from the evidence presently before the Court, and under the FDA’s interpretation of the Turtle ban, the FDA’s decision to deny the ITFL’s petition was not arbitrary or capricious.” 

Despite their coincidental timing, and although both decisions involved challenges to the scope of FDA’s authority under section 361 of the PHS Act, the merits of these two cases have little to do with one another.  We would not expect the outcome of the ITFL case, which implicates the core concern of § 361 to prevent disease transmission, to have any relevant impact on the merits of the RSI case, which questions the extent of FDA's § 361 authority when a regulation’s relationship to preventing disease transmission is more tenuous, and whether the regulation of autologous stem cells infringes the practice of medicine.

By Kurt R. Karst –   

Since 2008, FDA’s annual guidance document agendas (here, here, and here) have noted FDA’s plans to issue guidance on the Agency’s so-called Pre-Launch Activities Importation Request (“PLAIR”) program.  Although FDA officials have discussed PLAIRs in presentations, the Agency has not yet provided any formal guidance, and the PLAIR program remains largely shrouded in mystery.  Despite the lack of guidance to industry, FDA has been implementing its PLAIR program and simultaneously refining its policies.  As such, we think it’s high time to pull back the shroud and demystify FDA’s PLAIR program.

FDC Act § 505(a) prohibits the introduction or delivery for introduction into interstate commerce of a new drug “unless an approval of an application filed pursuant to subsection (b) or (j) is effective with respect to such drug.”  While there are several regulations that permit the transport of unfinished bulk product for further manufacture in anticipation of marketing (see e.g., 21 C.F.R. § 314.410(a)(2) and § 201.122(c)), there is no regulation excepting the domestic transport of finished product in anticipation of marketing approval.  Instead, FDA has historically exercised enforcement discretion to permit these shipments, and has traditionally cited to its authority under FDC Act § 309 as the legal basis for its use of enforcement discretion when the belief is that the public health is best served. 

FDA developed the PLAIR program with an eye towards the increasing globalization of the drug industry, and presumably as a means to both formalize the Agency’s historical use of enforcement discretion and to extend to finished products manufactured overseas the same courtesy FDA extends to unfinished bulk product.  FDA’s PLAIR program allows, on a case-by-case basis, the importation and warehousing of finished drugs where an application for drug approval (i.e., an NDA or ANDA) is pending and where the import and warehousing will expedite the commercial launch of the drug once FDA approves an application.  Specifically, FDA’s Center for Drug Evaluation and Research (“CDER”) and the Division of Import Operations and Policy (“DIOP”) exercise enforcement discretion to permit certain interstate shipments of unapproved products in finished dosage form by the domestic drug industry to prepare these products for market launch in anticipation of approval.  Such shipments are allowed under certain controls and restrictions.  For example, the drug products may only be shipped to facilities identified in a pending NDA or ANDA or to facilities owned and controlled by the applicant.

When pressed, FDA has provided informal guidance on PLAIRs.  In the interest of transparency, that guidance is provided below:

Please provide us with the following information on an electronic compatible file by email. If you have more than one application, please submit these separately.

a. Drug product name (trade and established) and complete product description (color, shape, etc);

b. Name of CDER Project Manager assigned to pending application;

c. Finished bulk drug NDC #, if assigned;

d. Name & address of foreign manufacturer (includes building # and street name) of finished drug product;

e. Name & address of U.S. consignee;

f. Pending application number (and supplement number, if appropriate) and date applicant expects its approval;

g. The name and address of the warehouse or distribution warehouse controlled by or under contract by the applicant where finished dosage form product in final packaged form will be stored pending approval;

h. When finished dosage form drug product in bulk is imported for further processing, the name and address of the facility where further processing activities will occur;

Include description of further processing activities;

If processed product will be transferred, provide information on the location where the product will be stored until the application is approved and effective; and,

i. Letter signed by senior management stating that neither they nor their consignee or distributor in the U.S. will sell, offer for sale, or distribute in domestic commerce this drug product until FDA approval is effective.

After receipt of this information, we will decide on a case-by-case basis, whether to exercise enforcement discretion to permit entry of the unapproved, finished dosage form drugs and notify you if the importation request is acceptable (normally within two weeks or less).  Please that the firm must register and the drugs must be listed once the application is approved.  Although drug listing is not required until the drug product is ready for commercial distribution, it is recommended to list your drug product electronically as this will expedite the listing process once the application is approved.  If changes need to be made, the information can later be updated.  We will also provide an email confirmation to the Division of Import Operations and Policy (DIOP) in the Office of Regulatory Affairs (ORA) that the importation request is acceptable.  You should then provide to DIOP (contacts: Steven Branch and Stella Notzon) the Customs Entry number in advance (at least one month before the expected arrival) your company is importing under the PLAIR enforcement discretion letter.  Also, please note that one shipment meaning one entry regardless of the quantity, batches or lot numbers offered for imports will be acceptable for the initial market launching.  Keep in mind that the amount of product imported into the US must match with what you stated in the PLAIR.  Otherwise, an amended PLAIR must be submitted to CDER-OC-PLAIR@fda.hhs.gov for approval.  You can make the changes on the existing PLAIR request, however, identify your request as an “amendment.”

FDA is reportedly still working through some of the kinks in the implementation of its PLAIR program, and policy changes are expected as the Agency gains greater experience with PLAIRs.  Our experience with FDA’s current PLAIR program, however, has revealed one problem in particular that should be fixed.

The informal PLAIR guidance provided by FDA notes that “one shipment meaning one entry regardless of the quantity, batches or lot numbers offered for imports will be acceptable for the initial market launching.”  Thus, regardless of the amount of drug product FDA authorizes under a PLAIR, if a company’s carrier is unable to ship that full amount because of space limitations and the shipment must be broken up into multiple shipments, we understand that the Agency’s current policy is not to allow a second shipment, absent a public health issue or a shortage.  A similar problem could arise if, for example, there are changed circumstances, such as a decision from FDA concerning 180-day exclusivity eligibility.  If a company has already used up its PLAIR and circumstances change such that additional product will be needed in anticipation of approval, we understand that FDA does not currently allow a company to amend its PLAIR or to obtain a second PLAIR to account for the changed circumstance. 

These limitations to FDA’s current PLAIR program are likely related the Agency’s funding and personnel limitations and concern about losing control of product imported into the U.S.  Hopefully, with time and experience, FDA will be better able to address them, if not universally, then on a case-by-case basis.  (For example, perhaps FDA can integrate an initial PLAIR approval into the Agency’s new PREDICT system for imports, thereby allowing for automated approvals of subsequent shipments.)

By Ricardo Carvajal –

The Office of Inspector General ("OIG") of the U.S. Department of Health and Human Services released a report that finds fault with FDA’s inspection activities for food facilities and recommends several changes, including an expansion of FDA’s statutory authority.  OIG reviewed FDA's food facility inspection activities between FY 2004 and FY 2008.  Among OIG’s findings:

• “On average, FDA inspected less than 25% of food facilities each year, and the total number of inspected facilities declined over time.”
• “56% of food facilities went 5 or more years without an FDA inspection.”
• In FY 2007, “FDA took regulatory action against 46 percent of the facilities with initial OAI classifications [an OAI or 'Official Action Indicated' classification means that objectionable conditions were found that might warrant regulatory action]; for the remainder, FDA either lowered the classification or took no regulatory action.”
• “For 36 % of the facilities with OAI classifications in FY 2007, FDA took no additional steps to ensure that the violations were corrected. For the remaining facilities, FDA took additional steps to ensure that the violations had been corrected. Specifically, FDA reinspected 35 percent of the facilities within a year of the initial inspection. For an additional 30 percent of facilities, FDA reported that it reviewed some type of evidence from the facility that demonstrated that the facility had corrected violations.”

For FY 2008, OIG also found that most of the facilities that received OAI classification had “a history of violations.”  Further, 2% of the facilities that received OAI classification refused FDA requests for access to records. 

Based on these findings, OIG recommended that FDA:

• “Increase the frequency of food facility inspections, with particular emphasis on high-risk facilities.”
• “Provide additional guidance about when it is appropriate to lower OAI classifications.”
• “Take appropriate actions against facilities with OAI classifications, particularly those that have histories of violations.”
• “Ensure that violations are corrected for all facilities that receive OAI classifications.”
• “Consider seeking statutory authority to impose civil penalties through administrative proceedings against facilities that do not voluntarily comply with statutory and regulatory requirements.”
• “Seek statutory authority to allow FDA access to facilities’ records during the inspection process.”

In its response, FDA noted that food safety legislation pending in Congress and supported by FDA would expand civil penalties for food-related violations and would expand FDA’s authority to access records, among other things.  As for its inspection activities, FDA has added nearly 700 field staff to its Foods Program since 2007, and the agency expects a corresponding increase in the number of food inspections; however, FDA noted that calls for increased inspections need to be backed by “a reliable, consistent funding source.”  FDA is also taking additional measures to enhance its inspections, most notably by conducting “intensive environmental sampling” intended to detect “unsuitable manufacturing conditions.” 

With respect to following up on findings of violation, FDA restated its commitment to the enforcement strategies outlined by Commissioner Hamburg in August 2009, including (1) establishing a timeframe for firms to submit responses to FDA findings, (2) streamlining Office of Chief Counsel review of warning and untitled letters, (3) prioritizing follow-up activities on warning letters and recalls with significant health implications, and (4) taking “swift, aggressive and immediate enforcement action in cases where significant health concerns or egregious violations are identified.”

By Susan J. Matthees –

FDA's Center for Veterinary Medicine ("CVM") recently announced an advanced notice of proposed rulemaking (“ANPRM”) to solicit comments on possible changes to the current regulation for veterinary feed directive (“VFD”) drugs.
 
The VFD drug category was established in 1996 as part of the Animal Drug Availability Act (“ADAA”).  A VFD drug is defined as “new animal drug approved under” FDC Act § 512(b) or “listed in the index under section 572 of the act for use in or on animal feed.”  21 C.F.R. § 558.3(b)(6).   In 2000, CVM issued final regulations implementing the VFD drug provisions of the ADAA.  VFD drugs must be used under the professional supervision of a licensed veterinarian. 

Congress intended the VFD drug category to help make more drugs available for animals, but over the past 9 years CVM “has received a number of informal general comments that characterize the current VFD process as being overly burdensome.”  CVM also expressed concern that the program would “become particularly problematic to administer in the future as the number of approved VFD animal drugs increases.”  With these concerns in mind, CVM seeks comments on whether, and if so, how, to improve current regulations and promote efficiency.  CVM asks submitters to organize their comments into 7 distinct categories:

• Conditions that must be met by veterinarians issuing a VFD;
• What veterinarians must do with a VFD (e.g., disposition of original VFD and copies);
• Records that must be kept related to the VFDs;
• Notification requirements for distributors of animal feeds containing a VFD drug;
• Additional recordkeeping requirements that apply too distributors;
• Cautionary statements required for VFD drugs and animal feeds containing VFD drugs; and
• Other.

Comments are due by June 28, 2010.

By Jeffrey K. Shapiro –

We are beginning to suspect that the new transparency of this Administration is a lot like the old transparency.  Or, as The Who sang in We Won’t Get Fooled Again, “meet the new boss / same as the old boss.”

The most recent example:  On April 12-13, the Regulatory Affairs Professionals Society ("RAPS") is holding an FDA-industry meeting in Rockville, Maryland.  The well respected RAPS organization had scheduled this program in close cooperation with FDA more than six months ago.

FDA had agreed to have Heather Rosecrans and Marjorie Shulman, who run the Premarket Notification (510(k)) Section in the Office of Device Evaluation ("ODE"), speak at the program.  They were scheduled to appear on two panels, Device Classification, Strategy and Pre-Submission Research and Premarket Notification Background, Substantial Equivalence and Techniques for Identifying Predicates for 510(k)s. 

These panels are intended to help regulatory affairs professionals learn more about how to interact with FDA on 510(k)s and how to craft and submit successful 510(k) filings.  Ms. Rosecrans, in particular, has spoken frequently to industry groups over many years and has always been a popular and highly regarded speaker.

At the last minute, management at the Center for Devices and Radiological Health ("CDRH") pulled the plug.  They refused to clear either Ms. Rosecrans or Ms. Schulman to speak.  Instead, CDRH management offered up replacement speakers from the Division of Small Manufacturer, International and Consumer Assistance ("DSMICA").  These speakers do not run the 510(k) program and are by necessity not as well versed in it as those actually run the program.

Hyman, Phelps & McNamara, P.C. is not sure what to make of this precipitous last minute withdrawal of scheduled FDA speakers.  Perhaps it has something to do with the 510(k) review now underway.  Yet, the RAPS program was supposed to address the existing 510(k) program, not potential changes.  Removing these speakers deprives industry of a chance to better understand FDA’s current 510(k) program.  This loss of information will deprive industry of the benefit of knowing what FDA is really looking for in 510(k) submissions, and conversely, will burden FDA with 510(k) submissions that are not as well put together as they otherwise might have been.

This mysterious action seems out of sync with FDA's renewed commitment to transparency.

By Riëtte van Laack –

Late last month, the U.S. Court of Appeals for the Ninth Circuit vacated a district court’s injunction against California’s prohibition of the use of non-ambulatory pigs for use in human consumption, Cal. Pen. Code § 599f.  Last year, the district court granted plaintiff National Meat Association (“NMA”) a preliminary injunction against implementation of Section 599f.  According to NMA, the ban would effectively prevent the slaughter of approximately 2.5% of pigs brought to slaughter.  The district court concluded that section 599f was preempted by the Federal Meat Inspection Act (“FMIA”) because downer pigs were not “a type of meat.”  Once California allowed the slaughter of pigs, it could not further restrict what kinds of pigs are eligible for slaughter.  Consequently, the district court granted a preliminary injunction.

The Ninth Circuit disagreed, labeling the district court’s holding as “hogwash.”  According to the Court, “regulating what kinds of animals may be slaughtered [concerns] practical, moral and public health judgments” typically reserved for states.  While FMIA does preempts state laws regulating premises, facilities and operations, those concerning the types of animals that may be slaughtered are not expressly limited by the FMIA.   Moreover, section 599f does not duplicate, interfere with or conflict with procedures under the FMIA.  Thus, section 599f is not expressly or implicitly preempted by the FMIA.  The Court vacated the preliminary injunction and the entire matter was remanded to the district court for further proceedings.

By Kurt R. Karst –   

[We interrupt this blog posting to bring you some breaking news . . . . For those of you following the battle over generic COZAAR/HYZAAR 180-day exclusivity, we updated our April 5th post with information on a D.C. Circuit decision. . . .   Now back to our regularly scheduled post . . . .]

As applied to drugs, the Patent Term Extension (“PTE”) statute at 35 U.S.C. § 156(a) provides that the term of a patent claiming the drug (or a use of the drug or a method of manufacturing a drug) shall be extended from the original expiration date of the patent if: (1) the term of the patent has not expired; (2) the patent has not been previously extended; (3) the PTE application is submitted to the Patent and Trademark Office (“PTO”) by the owner of record within 60 days of NDA approval; (4) the product, use, or method of manufacturing claimed has been subject to a “regulatory review period” before it is commercially marketed; and (5) the NDA is the first permitted commercial marketing or use of the drug product.  The fifth criterion, however, is subject to an exception (35 U.S.C. § 156(a)(5)(B)):

in the case of a patent which claims a method of manufacturing the product which primarily uses recombinant DNA technology in the manufacture of the product, the permission for the commercial marketing or use of the product after such regulatory period is the first permitted commercial marketing or use of a product manufactured under the process claimed in the patent . . . .

This provision underwent significant change during the Hatch-Waxman legislative process (more than 25 years ago).  It was introduced by Representative Henry Waxman (D-CA) as an amendment to H.R. 3605 (the precursor legislation to the Hatch-Waxman Amendments) and included the “first permitted commercial marketing or use” exception for patents concerning recombinant DNA products; however, the amendment also distinguished between method of manufacturing patents that do and do not claim products primarily manufactured using recombinant DNA technology and added several provisos to obtain a PTE for a process patent. 

Specifically, the legislation provided that with respect to the conditions for a PTE applicable to product, method of use, and process patents:

[W]ith one exception, the approved product must have been approved for commercial marketing for the first time.  The exception involves an approved product made under a patented process which primarily uses recombinant DNA technology.  Such an approved product could have received its second approval for commercial marketing, but it must be the first time a product made by the claimed process has been approved. 

H.Rep. No. 98-857, Part I, 98th Cong., 2nd Session, at 38 (1984).  This exception was added “because this innovative, new technique [(i.e., recombinant DNA technology)] is being employed to improve already approved drugs.” 

With respect to the conditions for a PTE applicable to process patents (as opposed to product and method of use patents), however, the legislation differentiated between certain types of process patents.  As explained in the House Report:

[A] process patent, which does not primarily utilize recombinant DNA in the manufacture of the approved product, [may be] extended if two conditions are met:  First, there can not be any issued product patent which claims the approved product or any issued use patent which claims a method of using the approved product for any known therapeutic use.  And, second, there can not be an earlier issued process patent, which does not primarily utilize recombinant DNA and which claims a method of manufacturing the approved product . . . .

[A] process patent, which primarily utilizes recombinant DNA in the manufacture of the approved product, [may be] extended if several conditions are met.  First, the holder of the process patent can not hold a product patent claiming the approved product or a use patent claiming a method of using the approved product.  Second, there can not be an ownership or control interest, either directly or indirectly, between the holder of the process patent and the holder of any product patent claiming the approved product or the holder of any use patent claiming a method of using the approved product.  Third, there can not be any earlier issued process patent which claims a method of manufacturing the approved product by primarily utilizing recombinant technology.

The language in H.R. 3605 differentiating between certain types of process patents was subsequently removed at the PTO’s request by an amendment introduced by Rep. Waxman after the bill was voted out of the U.S. House of Representatives Energy and Commerce Committee.  H.R. 3605 was passed by the U.S. House of Representative with PTE provisions in the form enacted under the Hatch-Waxman Amendments.  See 130 Cong. Rec. H9131-32 (daily ed. Sept. 6, 1984) (statement of Rep. Waxman) (“The one change involves the rules about which patents can be extended.  Under this amendment, the patent holder would be allowed to select the patent to be extended.  Under the bill, the first issued patent would have automatically been extended.”).  The U.S. Senate incorporated H.R. 3605 as an amendment to S. 1538, which became Pub. L. No. 98-417 (the Hatch-Waxman Amendments).  The PTE provisions in H.R. 3605 mirrored previous legislation introduced in the U.S. Senate (e.g., S. 2926). 

Although 35 U.S.C. § 156(a)(5)(B) has been in effect for more than 25 years and remains a viable path to extend a process patent for an approved product that primarily uses recombinant DNA in its manufacture, it has been used very rarely.  In fact, to our knowledge, it has been used only once!  In June 2004, the PTO extended U.S. Patent No. 5,156,957 (“the ‘957 patent”) covering GONAL-F (follitropin alfa) on the basis of 35 U.S.C. § 156(a)(5)(B). 

FDA approved GONAL-F, a recombinant product, under NDA No. 20-378 on September 29, 1997.  Correspondence from the PTO notes that although follitropin was previously approved for commercial use or sale in HUMEGON, PREGONAL, and REPRONEX, which “all contain the active ingredient menotropins (which is naturally occuring and a combination of follicle simulating [sic] hormone (FSH) and luteinizing hormone (LH)),” and in FERTINEX (urofollitropin), the ‘957 patent is eligible for a PTE:

U.S. Patent No. 5,156,957 claims a method of manufacturing a product, GONAL-F, which primarily uses recombinant DNA technology.  As a result, the '957 patent is eligible for extension if the approval of GONAL-F was the first permitted commercial marketing or use of a product manufactured using the recombinant DNA techniques claimed in the patent.  Follitropin alpha/beta, as made by the process claimed in the patent, has not been shown to have been previously approved. 

Moreover, the PTO found that the ‘957 patent was eligible for a PTE notwithstanding the September 29, 1997 approval of another recombinant follitropin product, FOLLISTIM (recombinant follitropin beta), which is the subject of a pending PTE aplication:

The product FOLLISTIM (recombinant follitropin beta)(Organon) was also approved on September 29, 1997, but this date is the same date, not before, the date of approval of GONAL-F.  Thus, the contemporaneous approval of FOLLISTIM, albeit a recombinant DNA product, does not preclude patent term extension based upon the regulatory review period of GONAL-F and the '957 patent is considered to be eligible for extension.

Thus, the PTE for the GONAL-F ‘957 patent not only represents the first (and presumably only) use of 35 U.S.C. § 156(a)(5)(B), but is also a precursor to the PTO’s interpretation of the PTE statute that multiple PTEs are available when two products are approved on the same first day, which we previously discussed (here and here).

By Kurt R. Karst –   

When we last blogged on the issue of 180-day exclusivity for generic versions of Merck & Co., Inc.’s blockbuster drugs COZAAR (losartan potassium) Tablets and HYZAAR (hydrochlorothiazide; losartan potassium) Tablets, FDA had issued an 8-page decision concluding that Teva did not forfeit 180-day exclusivity eligibility under FDC Act § 505(j)(5)(D)(i)(VI).  That provision states that 180-day exclusivity eligibility is forfeited if “[a]ll of the patents as to which the applicant submitted a certification qualifying it for the 180-day exclusivity period have expired.”  FDA issued its response after soliciting public comment on whether Teva forfeited 180-day exclusivity eligibility because the only exclusivity-qualifying patent – U.S. Patent No. 5,608,075 (“the ‘075 patent”), which was previously identified in the Orange Book as expiring in March 2014 – “expired” in March 2009 after Merck ceased paying certain patent “maintenance fees.” 

FDA’s letter decision was curious.  Based on the D.C. Circuit’s recent decision in Teva Pharms USA, Inc. v. Sebelius, 595 F.3d 1303 (D.C. Cir. 2010), in which the court ruled that Teva did no forfeit 180-day exclusivity eligibility under the failure-to-market forfeiture provisions at FDC Act § 505(j)(5)(D)(i)(I), FDA concluded that Teva did not forfeit 180-day under FDC Act § 505(j)(5)(D)(i)(VI).  In that decision, the Court ruled that there is “no reason to conclude that the [2003 Medicare Modernization Act] meant to give the brand manufacturer a right to unilaterally vitiate a generic’s exclusivity.”  The Agency spilled a lot of ink in its March 26th letter decision repudiating its own decision.  This strategic move appeared to us to be an invitation for other generic applicants to sue FDA.  And, as we noted in a March 30th update to our March 29th post, both Apotex, Inc. and Roxane Laboratories, Inc. promptly sued FDA seeking a preliminary injunction (here and here).  The companies argued that FDA’s March 26, 2010 letter decision violates the FDC Act and the Administrative Procedure Act.

The case moved forward last week at breakneck speed.  After the motions for preliminary injunction were filed last Tuesday, Teva intervened in the case and both Teva and FDA filed their responses (here and here) last Wednesday.  FDA’s mere 10-page response contrasted sharply with Teva’s 42-page opposition memorandum.  With allusions to Alice in Wonderland, Teva argued that:

Incredibly, [Apotex and Roxane] now take the position that FDA acted “arbitrarily and capriciously” when it followed the D.C. Circuit’s decision in post-remand administrative proceedings.  There is no basis in law or logic for that remarkable assertion.  Federal agencies, no less than private parties, are bound by the law, and that is so regardless of whether the law is set forth in statutes or court cases interpreting those statutes (at Chevron step one).  If it is arbitrary and capricious for FDA to account for the D.C. Circuit’s teachings, then every agency stands condemned—and “‘judicial review of agency action [would be transformed] into a ping-pong game,’” . . .  in which agencies are free simply to ignore every judicial decision with which they disagree.  That is madness, and this Court should reject plaintiffs’ invitation to Wonderland.  Plaintiffs have no likelihood of success on the merits.

Apotex and Roxane filed their replies (here and here) last Thursday.  On Friday, Judge Rosemary M. Collyer issued an order and a 7-page memorandum opinion ruling denying the Apotex and Roxane preliminary injunction motions.  Judge Collyer, agreed that FDA properly followed the logic of the D.C. Circuit’s decision in Teva:

The Court cannot find that the FDA was arbitrary or capricious when it politely expressed its disagreement with a D.C. Circuit decision that had ruled against the agency, but nonetheless applied the reasoning of the Circuit to a different but, on these facts, closely related question. Given the facts and law in this record, the Court finds that Plaintiffs have a very slim chance of success on the merits. This factor does not support issuance of a preliminary injunction.

Apotex and/or Roxane might very well appeal the decision before FDA approves Teva’s ANDAs with 180-day exclusivity, which is expected on April 6th.  The Solicitor General is considering seeking rehearing of the Teva decision.  We will update this post throughout the day with any additional information.

UPDATES (April 5, 2010):

• On April 5th, Apotex filed with the D.C. Circuit a motion for a summary reversal of the D.C. District Court’s April 2nd decision denying Apotex’s preliminary injunction request and a motion to stay the district court’s judgment pending appeal (here and here).  Apotex argues, among other things, that FDA was not bound to apply Teva because the decision did not address patent expiration.  As such, according to Apotex, “FDA’s determination that it was precluded by Teva from following Chevron deference is a clear error of law.” 
   
• Later on April 5th, Teva submitted its brief opposing Apotex’s stay request, arguing that Apotex’s motion should be summarily denied. “[T]his Court already considered and rejected the assertion that Merck’s unilateral failure to pay maintenance fees on the ‘075 patent provides a basis for stripping Teva of its exclusivity, when FDA raised the same claims Apotex now asserts in post-judgment proceedings concerning issuance of the panel’s mandate,” according to Teva. 

And to further complicate things . . .

• Late in the day on April 5th, FDA filed a petition for panel rehearing and rehearing en banc of the D.C. Circuit's March 2nd decision in Teva.  "The panel's decision conflicts with well established ripeness jurisprudence.  Moreover, its interpretation of the statute is not only contrary to the unambiguous text and Congress's deliberate rebalancing of competing goals, it squarely conflicts with this Circuit's message in other FDA decisions concerning the importance of fidelity to Congress's enactments.  As a result, FDA finds itself whipsawed, with a 'damned-if-you-do, damned-if-you-don't' dilemma in administering this very complex statute," according to FDA. 

UPDATE (April 6, 2010):

• Early on April 6th, FDA filed its opposition brief and stated in the brief that the Agency intends to make approval decisions regarding generic losartan products later in the day.  Later that same day, the D.C. Circuit DENIED Apotex's motion for a summary reversal of the D.C. District Court’s April 2nd decision and DENIED Apotex's motion to stay the district court’s judgment pending appeal.  According to a Teva press release, FDA approved Teva's ANDAs with 180-day exclusivity.

By Kurt R. Karst –   

FDA’s recently posted approval letter for Orchid Healthcare’s (“Orchid’s”) ANDA No. 78-357 for a generic version of Schering-Plough Corp.’s (“Schering’s”) blockbuster drug CLARINEX (desloratadine) Tablets, 5 mg, reads like any run-of-the-mill ANDA approval letter; however, it’s what is not said in the letter that is important and that represents a new 180-day exclusivity forfeiture precedent.

Orchid, and a large cohort of other applicants (based on a review of documents in In Re Desloratadine Patent Litigation (MDL No. 1851 Civil Action No. 07-3930) and other related litigation), submitted ANDAs to FDA on June 21, 2006 for Desloratadine Tablets, 5 mg.  According to FDA’s Paragraph IV Certification List, June 21 , 2006 is the first date on which an ANDA was submitted to FDA containing a Paragraph IV certification – in this case to U.S. Patent No. 6,100,274 (“the ‘274 patent”), the only patent listed in the Orange Book at that time.  Thus, Orchid and other applicants that submitted ANDAs to FDA on June 21, 2006 containing a Paragraph IV certification to the ‘274 patent were first applicants eligible for 180-day exclusivity.  Yet, FDA’s approval letter for ANDA No. 78-357 does not even mention 180-day exclusivity.  That’s because there was a mass forfeiture event.

FDA tentatively approved Orchid’s ANDA on August 25, 2009.  That is more than 30 months after the ANDA was submitted to FDA (i.e., June 21, 2006).  FDC Act § 505(j)(5)(D)(i)(IV) – “Failure to obtain tentative approval” – is one of the six 180-day exclusivity provisions added to the FDC Act by Title XI of the 2003 Medicare Modernization Act (“MMA”), and provides that 180-day exclusivity eligibility is forfeited if:

The first applicant fails to obtain tentative approval of the application within 30 months after the date on which the application is filed, unless the failure is caused by a change in or a review of the requirements for approval of the application imposed after the date on which the application is filed.

The 2007 FDA Amendments Act clarrified FDC Act § 505(j)(5)(D)(i)(IV), such that if “approval of the [ANDA] was delayed because of a [citizen] petition, the 30-month period under such subsection is deemed to be extended by a period of time equal to the period beginning on the date on which the Secretary received the petition and ending on the date of final agency action on the petition (inclusive of such beginning and ending dates) . . . .” (FDC Act § 505(q)(1)(G)).)  In the case of Desloratadine Tablets, 5 mg (and other desloratadine product as well), there was no citizen petition submitted to FDA.  Thus, unless FDA determined that there was “a change in or a review of the requirements for approval,” 180-day exclusivity was forfeited (not only for Desloratadine Tablets, but other desloratadine drug products as well noted in FDA’s Paragraph IV Certification List).

The absence of any mention in FDA’s approval letter for Orchid’s ANDA No. 78-357 of 180-day exclusivity is the Agency’s way of communicating that there was a mass forfeiture of 180-day exclusivity.  That is, that every first applicant forfeited 180-day exclusivity eligibility.  Had FDA determined that there was “a change in or a review of the requirements for approval,” then the Agency would have stated as much, as it did in a recent case concerning a generic version of ALDARA (imiquimod) Cream, 5% (see our previous post here). 

Although most first applicants presumably forfeited 180-day exclusivity eligibility based on FDC Act § 505(j)(5)(D)(i)(IV) (failure to obtain tentative approval), at least one ANDA sponsor likely forfeited based on FDC Act § 505(j)(5)(D)(i)(III).  That provision states that 180-day exclusivity eligibility is forfeited if  “[t]he first applicant amends or withdraws the certification for all of the patents with respect to which that applicant submitted a certification qualifying the applicant for the 180-day exclusivity period.”  FDA tentatively approved Glenmark Pharmaceuticals, Inc.’s (“Glenmark’s”) ANDA No. 78-362 (an ANDA number very close to Orchid’s) on August 24, 2009.  Although that date is more than 30 months after ANDA submission, in March 2008 (less than 30 months after ANDA submission), Glenmark reportedly (see page 57) reached a consent agreement with Schering whereby Glenmark converted its Paragraph IV certification on the ‘274 to a Paragraph III certification.  Thus, Glenmark likely forfeited 180-day exclusivity eligibility under FDC Act § 505(j)(5)(D)(i)(III).   

By Carrie S. Martin & Dara Katcher Levy –

On March 29, 2010, FDA published a proposed rule to amend its direct-to-consumer (“DTC”) regulations to require that prescription drug advertisements present information about side effects and contraindications in a “clear, conspicuous, and neutral manner.”  Current regulations, found in 21 C.F.R. 202.1, require the disclosure of major side effects and contraindications (commonly known as the “major statement”) in either the audio or audio and visual parts of an advertisement and that they be presented in a comparable manner to any statements regarding the drug’s efficacy. 

With the passage of the FDA Amendments Act of 2007 (“FDAAA”), Section 502(n) of the Food and Drug Cosmetic Act (“FDC Act”) now requires that the major statement in television and radio advertisements to consumers be presented in a “clear, conspicuous, and neutral manner.”  The Agency looked to standards set by other agencies for guidance, including the Federal Trade Commission (“FTC”), the Department of Treasury (“DOT”), and the Securities and Exchange Commission (“SEC”).  FDA now proposes to amend Section 202.1(e)(1) to include four criteria as to when a major statement would be considered “clear, conspicuous, and neutral”:

(1)  The information is presented in language that is readily understandable by consumers;

(2)  The audio information is understandable in terms of the volume, articulation, and pacing used;

(3)  The textual information is placed appropriately and is presented on a contrasting background for sufficient duration and in a manner that can be read easily (e.g., in terms of size and style of font); and

(4)  There are no distracting representations, such as statements, text, images, sound, or any combination thereof, that detract from the communication of the major statement.

FDA admits that these guidelines provide “flexibility” for drug sponsors to be creative in how they meet these four criteria.  In addition, the Agency believes that these proposed guidelines are consistent with the draft guidance it issued in May 2009 about the presentation of risk information entitled “Presenting Risk Information in Prescription Drug and Medical Device Promotion” ("Draft Guidance"). 

Unfortunately, both the draft guidance and the proposed regulations fail to clearly articulate what type of language will be clear, conspicuous, and neutral to consumers.  The draft guidance was the first time the "Reasonable Consumer" standard had been proposed as a basis for judging the presentation of risk information in DTC promotion.  The proposed regulations state that information presented must be "readily understandable by consumers."  However, both the draft guidance and the proposed regulations fail to further articulate "who" these consumers are and what education level they might have.  Nor is there any acknowledgment that certain risk information simply cannot be clearly described in supposed "consumer-friendly" language.  Further, the Agency admits that it was not aware of any previous standard of what constitutes "neutral" in the "context of required disclosures" and asks the public for comments specifically addressing this issue.

Written or electronic comments should be submitted by June 28, 2010.  FDA is particularly interested in comments about whether the final rule should require major statements to be presented in both the audio and visual parts of advertisements, as well as comments about the "neutral" standard.  Written comments can be faxed to the Agency (301-827-6870) or sent to the Division of Dockets Management (HFA-305), FDA, 5630 Fishers Lane, rm. 1061, Rockville, MD 20852.  Electronic submissions must go through the following website: www.regulations.gov.