Patent Docs

Guest Post: Will Purple Become The New Orange? FDA Publishes Long-Awaited Lists Governing Biologics

By Anthony Sabatelli* --

Some fashion trends may come and go, but in the not too distant future the majority of prescription drug sales will be purple.¹ For those of you not yet familiar with this latest trend, allow me to explain.

Most drug products are small, synthetically produced substances.  The common pain reliever ibuprofen, for example, contains only 33 atoms and has a molecular weight of 206.  In contrast, there is a whole new class of complex drug products that are isolated or produced from biological sources such as living cells.  These biologically produced drugs, more commonly called "biologics," are orders of magnitude larger than their small molecule cousins and present special challenges in their preparation, isolation, and administration. Insulin is a common example of a biologic.  It is a protein having a molecular weight of approximately 5800.  Another example is the hormone erythropoietin (or "EPO"), which is used to treat anemia.  EPO is a far larger biological drug with a molecular weight of nearly 35,000.

So what does this have to do with the color purple?

First, Enter The Orange Book

Small-molecule prescription drugs are approved by the US Food and Drug Administration (FDA).  In 1984, Congress passed the Drug Price Competition and Patent Restoration Act (commonly known as "Hatch-Waxman") to bring low-cost prescription drug products to consumers, while balancing the competing interests of the branded pharmaceutical industry and generic drug manufacturers.  Hatch-Waxman provided a unique statutory link between the patent and regulatory systems and established a framework under which generic drugs could be marketed.  Hatch-Waxman requires the FDA to publish information on approved drug products with their therapeutic equivalence information.  Also published are patent and other exclusivity information for the approved drugs, setting the grounds for the complex litigation that results when the interests of the branded and generic drug manufacturers clash.  The FDA publication in which this drug and patent information appears is known, not by its lengthy title², but rather by its distinctive orange cover -- hence, the "Orange Book."

Now Enter the Purple Book

Fast forward to 2014, or rather first to 2010.  In March of that year, President Obama signed into law the Patient Protection and Affordable Care Act (more commonly known as "Obamacare").  One of the Act's provisions was the Biologics Price Competition and Innovation Act ("BPCIA"), which created an abbreviated licensure pathway for biologics that are demonstrated to be either "biosimilar" to or "interchangeable" with the originally approved product.³  In other words, the legislation created a regulatory pathway for the approval and marketing of the generic equivalent of a biological drug.  This regulatory pathway is just getting off the ground.  Even though biologics have been around for a long time (synthetic insulin was marketed in 1982), no biosimilar product has as yet been approved in the United States.  In fact, it is believed that only two biosimilar applications are currently pending before the FDA.  However, this will all soon change and the first biosimilars are expected to receive approval in 2015.

Since the passing of the BPCIA, the FDA has issued various announcements on biologics and biosimilars, including a long-awaited Draft Guidance that was published in August.  The big news, however, is that the FDA just published its first edition of the Purple Book, with the lengthy title -- "Lists of Licensed Biological Products with Reference Product Exclusivity and Biosimilarity or Interchangeability Evaluations."  This publication, like its Orange Book Counterpart, lists approved biological drug products and will eventually list biosimilar and interchangeable products as they are approved. The published information, however, is still not complete.  For example the date of first licensure and the expiry of product exclusivity are only listed for three products.  Clearly, the FDA has much work ahead to compile complete information.

Will There Be A Color Clash?

It will be interesting to see how the Purple Book will function.  Will it clash with the Orange Book?  After all, orange and purple are not exactly complementary colors.  Only time will tell as biologics overtake the pharmaceutical market and the first biosimilar and interchangeable products begin receiving approval.

__________________________

[1] As explained in this article, biologically produced drugs ("biologics") will be governed by the US Food and Drug Administration's (FDA's) newly established "Purple Book."  Depending on the source and how the data is analyzed, biologics accounted for just 10 percent of annual prescription drug sales in 2010.  By 2017, that number could well surpass 50 percent.  Notwithstanding the data, the trend is clear that biologics will account for a majority of prescription drug sales.

[2] Approved Drug Products with Therapeutic Equivalence Evaluations

[3] "Biosimilars" and "Interchangeables" are two different types of biological generic products.

* Dr. Sabatelli is a Partner with Dilworth IP.

For additional information regarding this topci, please see:

• "FDA Announces 'Purple Book'," September 16, 2014

FDA Announces "Purple Book"

By Paul Tully --

The new phone book is here?  No, but close.  The Food and Drug Administration ("FDA") announced on Friday that it has published its first listing of approved biologic drugs.  The list will be supplemented with approved biosimilar alternatives to the biologic drugs, termed the "List of Licensed Biological Products with Reference Product Exclusivity and Biosimilarity or Interchangeability Evaluations."  Inevitably given a "color" designation (following the tradition of the "Orange Book" of approved small molecule drugs), the new listing of biologics is colloquially called the "Purple Book."  Both the Center for Drug Evaluation and Research ("CDER") and the Center for Biologic Evaluation and Research (CBER) have published their own versions of the Purple Book (CDER List of Licensed Biological Products; CBER List of Licensed Biological Products; FDA Purple Book webpage).

The new lists disclose all approved biologic drugs and the date a product was licensed, as well as "whether the FDA evaluated the biological product for reference product exclusivity under section 351(k)(7) of the PHS Act."  The Purple Book is intended to permit users to determine whether the FDA has licensed a biosimilar and whether such a biosimilar is interchangeable with an already-licensed reference biological product (i.e., an already-licensed FDA biological product).  Both biosimilar and interchangeable biological products will be listed with regard to the reference product to which biosimilarity or interchangeability was demonstrated.  The agency further announced that these lists will be updated "periodically."

This new resource is certain to become a valuable tool for life-sciences professionals, but it remains to be seen whether relevant patent information will ultimately make its way into the Purple Book, as is prevalent (and required) in its Orange Book cousin.  Stay tuned.

FDA Releases Another Prospective Guidance

By Kevin E. Noonan --

On August 5th, the U.S. Food and Drug Administration issued a "Guidance for Industry" entitled "Reference Product Exclusivity for Biological Products file under Section 351(a) of the PHS Act."  Before setting forth the first word of the Guidance, the Administration set forth the following caveat:

This draft guidance, when finalized, will represent the Food and Drug Administration's (FDA's or the Agency's) current thinking on this topic.  It does not create or confer any rights for or on any person and does not operate to bind FDA or the public.  You can use an alternative approach if the approach satisfies the requirements of the applicable statutes and regulations.  If you want to discuss an alternative approach, contact the FDA staff responsible for implementing this guidance.

The term of market exclusivity under the BPCIA (12 years; Sec. 351(k)(7), codified at 42 U.S.C. 55 262(k)) requires that the agency identify the date from which to calculate the term.  This Guidance, prefaced by the quote set forth above, provides some grounds for making that determination.  However, as with many of the FDA's Guidances on provisions of the law, the tentativeness of the principles set forth are more akin to hints than rules and provide little other than further evidence that the Administration will act with utmost caution (a stance understandable when taken with regard to substantive grounds for biosimilar approval but somewhat less so in the context of this Guidance).

The critical date with which the Guidance is concerned is the "date of first licensure" of the reference product under PHSA Sec. 351(k)(7)(C).  This date determines not only the length of the market exclusivity of the reference product but also the time (4 years) that a biosimilar applicant must wait before filing an application for biosimilar approval.  The Guidance notes that "[n]ot every licensure of a biological product under 351(a) is considered a 'first licensure' that gives rise to its own exclusivity period," where some changes in "previously licensed" reference products, from either the same or "related" reference product sponsors are expressly excluded from being considered as a date of first licensure.  Because the agency recognizes that it is the reference drug sponsor who will have "superior information" about such changes or such relationships between companies, the Guidance sets forth "the types of information that reference product sponsors should provide to facilitate FDA's determination of the date of first licensure for their products."

The Guidance then sets forth these types of "superior information."  Typically, the date of first licensure is "the initial date the particular product at issue was licensed in the United States."  But there are exceptions codified into the statute; these include

• a supplement for the biological product that is the reference product; or

• a subsequent application filed by the same sponsor or manufacturer of the biological product (or a licensor, predecessor in interest, or other related entity) for:

-- a change (not including a modification to the structure of the biological product) that results in a new indication, route of administration, dosing schedule, dosage form, delivery system, delivery device, or strength; or

-- a modification to the structure of the biological product that does not result in a change in safety, purity, or potency.

(These can be seen as "anti-evergreening" provisions.)  The Guidance notes that the Agency has "experience in construing other provisions that require examination of the relationships between business entities to determine eligibility of a new drug application for exclusivity" (citing "Abbreviated New Drug Application Regulations; Patent and Exclusivity Provisions" (patent and exclusivity final rule), published in the Federal Register of October 3, 1994 (59 FR 50338 at 50359 and 50362)).  In view of this experience, the Guidance asserts that the Agency will construe certain terms of the statute consistently to its previous determinations.  Thus:

• the term "predecessor in interest" will be "any entity that the sponsor has taken over, merged with, or purchased, or that has granted the sponsor exclusive rights to market the biological product under the 351(a) application, or had exclusive rights to the data underlying that application";

• a "licensor" will be "any entity that has granted the sponsor a license to market the biological product, regardless of whether such license is exclusive" and shall "include, for instance, entities that continue to retain rights to develop, manufacture, or market the biological product, and/or rights to intellectual property that covers the biological product"; and

• one corporate entity will be considered an "other related entity" "if (1) either entity owns, controls, or has the power to own or control the other entity (either directly or through one or more other entities) or (2) the entities are under common ownership or control" or "if the entities are or were engaged in certain commercial collaborations relating to the development of the biological product(s) at issue."  In this regard, the FDA "expects to consider not only ownership and control of the investigational new drug application (IND) and the BLA, but also the level of collaboration between the entities during the development program as a whole."

Regarding the statutory proscriptions against considering for the date of first licensure situations wherein there is "a new indication, route of administration, dosing schedule, dosage form, delivery system, delivery device, or strength" unless there are "modifications in the structure of the biological product" that results in a change in "safety, purity or potency," the Agency will need to determine what qualifies as "modifications in the structure of the biological product" that satisfy the statute.  To do so, "a sponsor seeking to assist FDA in determining the date of first licensure for a reference product licensed under 351(a), should describe the structural similarities and differences between its proposed product and any previously licensed biological product that was the subject of a 351(a) application filed by the same sponsor or manufacturer (or its licensor, predecessor in interest, or other related entity)."  Specifically, for a protein product the reference drug sponsor should describe "any differences in amino acid sequence, glycosylation patterns, tertiary structures, post-translational events (including any chemical modifications of the molecular structure such as pegylation), and infidelity of translation or transcription, among others."  In addition, the Agency will perform a structural comparison of the reference drug product and the modified product, including "whether the modified product affects the same molecular target as the previously licensed product."  For changes in cell lines to make the reference product, the Agency asserts that "modification of the structure will not simply be presumed" but rather require the product sponsor to submit relevant evidence that establishes the change.

In addition, according to the statute, the reference product sponsor will be required by the Agency to show the structural modification "results in a change in safety, purity or potency" (or alternatively and interchangeably, "safety and effectiveness").  The Agency will do this on a "case-by-case basis" based on scientific data (as provided by the sponsor).  The Agency is willing to presume such a change if the sponsor establishes that the modified "product demonstrates that it affects a different molecular target than the original product" (where the Guidance defines "a difference molecular target" to mean any molecule in the body whose activity is modified by the product, resulting in a desirable therapeutic effect," including "receptors, enzymes, ion channels, structural or membrane transport proteins, nucleic acids, and pathogens, among others").

The final section of the Guidance sets forth expressly the information the Agency "suggests" the reference product sponsor should submit to support its date of first licensure.  This information includes:

1. A list of all licensed biological products that are structurally related to the biological product that is the subject of the 351(a) application being considered. This list should include products that share some of the same principal molecular structural features of the product being considered, but generally can be limited to products that affect the target should be included. Where specific molecular targets have not been defined, this list should include products that share the narrowest target that can be characterized. This may be a pathway, cell type, tissue, or organ system. If this assessment results in the conclusion that no product that has the same molecular target or shares some of the same principal molecular structural features has been licensed, a sponsor should provide an adequate justification to support the assertion that there are no previously licensed products that are relevant for purposes of determining the date of first licensure.

2. Of those licensed biological products identified in item 1 above, a list of those for which the sponsor or one of its affiliates, including any licensors, predecessors in interest, or related entities, are the current or previous license holder.

3. Description of the structural differences between the proposed product and any products identified in item 2 above. For protein products, this should include, but is not limited to, changes in amino acid sequence, differences due to post-translational events, infidelity of translation or transcription, differences in glycosylation patterns or tertiary structure, and differences in biological activities.

4. Evidence of the change in safety, purity, and/or potency between the proposed product and any products identified in item 2 above. This should include, but is not limited to, a description of how the structural differences identified in item 3 above relate to changes in safety, purity, and/or potency.

And, of course, "any other information and data that would assist the FDA in making its determination."

Finally, the Guidance notes that it "is reviewing options for making information publicly available regarding reference product exclusivity and dates of first licensure" and will provide the information to the public on its website when the Agency decision has been made.

FDA Releases Draft Guidance on Biosimilars

Sets Forth Clinical, Pharmacology Data Sufficient to Support Biosimilarity

By Kevin E. Noonan --

The Food and Drug Administration has released the first new Guidance relating to its evolving standards for satisfying the biosimilarity requirements of the Biologics Price Competition and Innovation Act (BPCIA) since its release in February 2012 of three basic Guidances that left many if not most of the relevant details unclear.  This most recent Guidance is more specific, being directed particularly to the type and amount of clinical pharmacology data the Agency will require to demonstrate biosimilarity to a reference product but is expressly "being distributed for comment purposes only" and thus how the FDA will administer the BPCIA remains a work in progress.

The provisionality of the Guidance is acknowledged from the Introduction (Section I), where it is described as being antecedent to a Guidance "in its final form" that will be "one of a series" comprising how the Agency will implement the BPCIA.  This Guidance "discusses some of the overarching concepts related to clinical pharmacology testing for biosimilar products, approaches for developing the appropriate clinical pharmacology database, and the utility of modeling and simulation for designing clinical trials."

The Guidance establishes (in Section II) the relevance of clinical pharmacological data to the question of biosimilarity, stating that "[c]linical pharmacology studies are normally a critical part of demonstrating biosimilarity by supporting a demonstration that there are no clinically meaningful differences between the proposed biosimilar and the reference product."  These data are related to the "degree of similarity in drug exposure" between the reference drug product and the putative biosimilar.  The Guidance also notes that such data typically include pharmacodynamics endpoints and pharmacometric analyses that can reveal "clinically meaningful differences," and thus "can add to the totality of the evidence, reduce residual uncertainty, and thus guide the need for and design of subsequent clinical testing to successfully support a demonstration of no clinically meaningful differences in the overall demonstration of biosimilarity."  Which types of such studies are meaningful in any particular reference biologic product/biosimilar comparison will depend, inter alia, on the "residual uncertainties" remaining when all other types of comparison evidence are considered (e.g., structural, mechanistic and other physicochemical comparisons).

The Guidance sets forth "three key concepts" as being "especially relevant" to their assessment of the similarity of biosimilar products:

• Exposure and response assessment (Section III.A)
• Evaluation of residual uncertainty (Section III.B)
• Assumptions about analytical quality and similarity (Section III.C)

With regard to exposure and response assessment, the Guidance asserts that these data are "important for the determination of safety, purity, and potency of any biological product, as well as for the determination of any potential clinically meaningful difference between two products."  But this assessment is "particularly challenging" in the biosimilar context, because what is being assessed is not a comparison between an active product that is a single molecule and its breakdown products but "a mixture of closely related, complex biological substances."  The Guidance defines "exposure" to related to pharmacokinetic parameter, including dose, drug concentrations in blood, plasma and other biological fluids, and related variable including C_max, C_min , C_trough,ss, and area under the curve (AUC).  Response, on the other hand, is defined in the Guidance as pharmacodynamics, "a direct measure of the pharmacological or toxicological effect of a drug," the assessment of which includes single or multiple biomarkers (where using "broader" biomarker panels are preferred if they "capture multiple pharmacological effects of the [biosimilar] product."  In this regard, the Guidance cites "time of onset" of the marker relative to the combination of the time of onset, the "dynamic range" of the marker, how sensitive the marker is to differences between the reference drug and the biosimilar, relationships between changes in the marker and clinical outcomes, and the relevance of the marker on the mechanisms of action of the molecule.

The Guidance on evaluating residual uncertainty is less expansive, merely setting forth the FDA standard of assessing the "totality of the circumstances" on the evidence and suggesting that this evidence be collected and submitted "in a stepwise manner," including the PK and PD data "obtained in conjunction with clinical pharmacology studies."

Assumptions regarding analytical quality and similarity are defined in the context of such a "stepwise assessment of biosimilarity," wherein "extensive and robust comparative structural and functional studies (e.g. bioassays, binding assays, and studies of enzyme kinetics) should be performed to evaluate whether the proposed biosimilar product and the reference product are highly similar."  This in turn depends on the state of the art regarding analytical assays, including those related to measuring molecular weight, post-translational modifications, heterogeneity, impurity and degradation profiles and functional properties of the biosimilar.

The differences between the reference drug product and biosimilar and the "type, nature, and extent" of those differences need to be supported by relevant information and experimental data, and if necessary additional data, and the Guidance explicitly notes that "certain differences in the results of the analytical characterization may preclude a determination by FDA that the proposed biosimilar product is highly similar to the reference product" and that, as a result the Agency will not approve the biosimilar application.

The Guidance also sets forth four different assessments decisions along a "developmental phase continuum":

• Not similar: Certain differences in the results of the analytical characterization may lead to an assessment of "not similar" and further development through the 351(k) regulatory pathway is not recommended unless, for example, modifications are made to the manufacturing process for the proposed biosimilar product that is likely to lead to a highly similar biological product.

• Similar: Further information is needed to determine if the product is highly similar to the reference product.  Additional analytical data or other studies are necessary to determine if observed differences are within an acceptable range to consider the proposed biosimilar product to be highly similar to the reference product.  As an example, glycosylation plays an important role in the PK of certain protein products.  Manufacturing process conditions may impact glycosylation.  Comparative PK and PD studies of the proposed biosimilar product and the reference product help resolve that some differences in glycosylation identified in the analytical studies would be within an acceptable range to consider the proposed biosimilar product to be highly similar to the reference product.

• Highly similar: The proposed biosimilar product meets the statutory standard for analytical similarity.  The results of the comparative analytical characterization permit high confidence in the analytical similarity of the proposed biosimilar and the reference product, and it would be appropriate for the sponsor to conduct targeted and selective animal and/or clinical studies to resolve residual uncertainty and support a demonstration of biosimilarity.

• Highly similar with fingerprint-like similarity: The proposed biosimilar product meets the statutory standard for analytical similarity based on integrated, multi-parameter approaches that are extremely sensitive in identifying analytical differences.  The results of these fingerprint-like analyses permit a very high level of confidence in the analytical similarity of the proposed biosimilar and the reference product, and it would be appropriate for the sponsor to use a more targeted and selective approach to conducting animal and/or clinical studies to resolve residual uncertainty and support a demonstration of biosimilarity.

The Guidance then sets forth a section (Section III.D) describing the "integrity" of the methods used in PK and PD studies (not surprisingly noting that these "should be accurate, precise, specific, sensitive, and reproducible").  These include (for PK studies) that the analytical method(s) used should be able to detect the active product and not just the total product in the formulation, and (for both PK and PD studies) that the assays chosen should be capable of providing the Agency with data that "are meaningful and reflective of drug exposure, the biological activity, and/or the PD effect of the proposed biosimilar product and the reference product."  A rationale for the choice of assay and its relevance should also be provided.  The Guidance then sets forth considerations regarding a number of specific assays, including:

• Ligand binding assays (differentiating between receptor/ligand and antibody/antigen binding assays);
• Concentration and activity assays (particularly with regard to enzyme replacement); and
• PD assays (noting that the measured activity "should be relevant to the clinical outcome").

With regard to safety and immunogenicity (Section III.E), the Guidance reiterates the caution from the earlier Guidances with regard to immune-mediated toxicity and the extent to which clinical pharmacologic data may be important to indicate differences requiring additional studies and appropriate study types, and that in certain circumstances the results of these studies may indicate that additional studies should not be pursued (because the differences are sufficient for the Agency to deny the biosimilar application).  And the Guidance further cautions that, should the publicly available information on the reference drug product indicate a propensity for immune-mediated toxicity the biosimilar applicant should include assays "capable of detecting binding antibodies (and their neutralizing potential) [] in advance to analyze samples obtained from PK and PD studies, so that immunogenicity may be evaluated in real time" (the Guidance further references its prior FDA guidance for industry Bioanalytical Method Validation).

As it has in earlier Guidances, the Agency urges stakeholders to consult, especially with "critical study design issues," including crossover and parallel designs, which are of "particular relevance" (Section IV.A).  The "preferred design" for PK similarity assessments, according to the Guidance, is a single-dose, randomized, crossover study, particularly with products having a "short" half-life (less than 5 days), "rapid" PD response ("onset, maximal effect, and disappearance in conjunction with drug exposure"), and multiple dosing regimes where "the PD effect is delayed or otherwise not parallel to the single-dose drug PK profile."  Parallel study designs are recommended for biologic drugs having a long half-life and that elicit immunogenic responses.  Regarding the reference drug product used in these studies (set forth in Section IV.B), the Agency states that "a sponsor may use a non-U.S. licensed comparator product in certain studies to support a demonstration that the proposed biological product is biosimilar to the U.S.-licensed reference product" but also should provide "adequate data or information to scientifically justify the relevance of these comparative data to an assessment of biosimilarity and to establish an acceptable bridge to the U.S.-licensed reference product."  The type of "bridging data" the Agency will likely require can include structural and functional analytical data, and PK and PD study data comparing all three products (US reference drug product, non-US reference drug product, and biosimilar).

With regard to appropriate study populations (Section IV.C), the Guidance sets forth the pros and cons for each alternative (healthy volunteers vs. patients affected by the relevant disease or disorder) and the considerations that can be dispositive for the choice of population (generally, those that would provide data that is "the most informative for detecting and evaluating differences in PK and PD profiles between the proposed biosimilar product and the reference product").  Safety (with regard to healthy volunteers) and the possibility for immunogenicity or "known toxicity" (for affected patients) are noted as relevant considerations, and the Guidance also mentions the possible importance of demographics in instances where a particular patient demographic group would be "most likely to provide a sensitive measure of differences between the proposed biosimilar product and the reference product" (while requiring a biosimilar applicant to justify these choices).  In other parts of the Guidance the Agency sets forth relevant considerations for dosing, which include (not surprisingly) a dose that is "most likely to provide clinically meaningful and interpretable data" (wherein the approved dose for the reference product being perhaps the right dose for studies involving affected patients).  Alternative dose choices are also provided  (see Section IV.D).

Other aspects of clinical pharmacologic studies set forth in the Guidance include route of administration (the same as the reference drug product; Section IV.E) and the types of pharmacokinetic (Section IV.F) and pharmacodynamics (Section IV.G) measurements that should be considered, as well as the "appropriate pharmacodynamics time profile" (Section IV.H) and statistics used for comparing PK and PD results from the biosimilar and reference drug product (Section IV.I).

The Guidance also contains a section (Section V) relating to "simulation tools" as part of study design and data analysis. The Guidance asserts that these tools can be useful in making many study choices set forth in earlier portions of the Guidance, and particularly notes the importance of making comparisons on the steep portion of a dose-response curve (which will more readily show differences between the biosimilar and the reference drug product) rather than in the "plateau" potion (which will not).  The Guidance also suggests that a biosimilar applicant who does not have access to exposure-response data on the reference drug product can use such tools to produce a "small study to determine an optimally informative dose" or other alternatives.

The Guidance concludes with a reminder that the Agency has decided that it will assess biosimilarity between a putative biosimilar product and a reference drug product based on the totality of the evidence" (as set forth extensively in earlier Guidances).

One aspect of this Guidance, in addition to its (somewhat) greater specificity, is that what may constitute evidence that the biosimilar should not be approved is more explicitly recited (or at least that non-approval is an outcome dependent on evidence of differences between the reference drug product and the biosimilar).  Generally, however, this Guidance provides an relatively small, specific, incremental advance in setting forth the Agency's course in providing a biosimilar approval pathway under the statute.

As set forth on the first page of the Guidance:

Comments and suggestions regarding this draft document should be submitted within 90 days of publication in the Federal Register of the notice announcing the availability of the draft guidance.  Submit comments to the Division of Dockets Management (HFA-305), Food and Drug Administration, 5630 Fishers Lane, rm. 1061, Rockville, MD 20852.  All comments should be identified with the docket number listed in the notice of availability that publishes in the Federal Register.

For questions regarding this draft document contact (CDER) Sandra Benton at 301-796-2500, or (CBER) Office of Communication, Outreach and Development at 1-800-835-4709 or 301-827-1800.

Copies of the Guidance can be found here.

Interested readers should take the Agency up on this offer; unlike other governmental Guidances, the FDA appears genuinely interested in working with its stakeholders to address their legitimate concerns regardinh how the Agency will administer the law.

FDA Approved 27 New Drugs in 2013

By Donald Zuhn --

Last month, the U.S. Food and Drug Administration (FDA) announced that the agency approved 27 new drugs and biological products in 2013.  According to the FDA release, the 27 new molecular entities (NMEs) that were approved last year include:

The number of new drugs approved in 2013 fell by almost a third from the 39 new drugs approved in 2012 ("New Molecular Entity Approvals for 2012"), and was three less than the 30 new drugs approved in 2011 ("New Molecular Entity Approvals for 2011").

According to a Reuters report, the FDA attributed the drop in approvals to a drop in the number of applications filed, while noting that the 27 approvals were just under the 5-year average of 28.

Top Stories of 2013: #11 to #14

By Donald Zuhn --

Reflecting upon the events of the past twelve months, Patent Docs presents its seventh annual list of top biotech/pharma patent stories.  For 2013, we identified fourteen stories that were covered on Patent Docs last year that we believe had (or are likely to have) the greatest impact on biotech/pharma patent practitioners and applicants.  Today, we count down stories #14 to #11, and then over the next few days, we will work our way towards the top three stories of 2013.  As with our other lists (2012, 2011, 2010, 2009, 2008, and 2007), links to our coverage of these stories (as well as a few links to articles on related topics) have been provided in case you missed the articles the first time around or wish to go back and have another look.  As always, we love to hear from Patent Docs readers, so if you think we left something off the list or disagree with anything we included, please let us know.  In addition, we will be offering a live webinar on the "Top Patent Law Stories of 2013" on January 21, 2014 from 10:00 am to 11:15 am (CT).  Details regarding the webinar can be found here.

14.  23andMe Patent and Diagnostic Test Create Controversy

A patent issued to 23andMe, Inc. in September created some controversy for the Mountain View, California biotech company.  The patent, U.S. Patent No. 8,543,339, is directed to a system for identifying a preferred gamete donor from among the plurality of donors based on a phenotype of interest, the genotype of a recipient, and the genotypes of the donors.  In the wake of the '339 patent's issuance, 23andMe was criticized for its efforts to secure patent protection on a method of creating "designer babies," and in response, the company posted an article on its blog, stating that it "never pursued the concepts discussed in the patent beyond our Family Traits Inheritance Calculator, nor do we have any plans to do so."  In an unrelated matter, the FDA issued a Warning Letter to 23andMe in November, demanding that the company stop selling its Personal Genomic Services (PGS) product without obtaining FDA approval.  The FDA's letter was not well received by some healthcare consumers, who posted a petition on the "We the People" portion of the White House website, calling for the Obama Administration to overrule the FDA and permit 23andMe to continue to market the company's PGS product.  Other consumers, however, initiated a class action lawsuit against 23andMe on behalf of "tens or hundreds of thousands of women" who may have used the PGS testing service.

For information regarding this and other related topics, please see:

• "23andMe Patent Creates Controversy," October 8, 2013
• "Bioethicists 'Urge Maximal Transparency' in Response to 23andMe Patent," October 14, 2013
• "FDA Threatens Agency Action Against 23andMe Over Personal Genetic Testing," November 25, 2013
• "Patients Push Back on FDA Threats to 23andMe Genetic Testing Products," November 26, 2013
• "23andMe Named in Class Action Lawsuit," December 3, 2013

13.  Supreme Court Hears Oral Argument in Medtronic v. Boston Scientific

In November, the Supreme Court heard oral argument in the Medtronic Inc. v. Boston Scientific Corp. case, where the sole issue on appeal concerns whether the patent licensee or patent holder/licensor has the burden of proof on the issue of infringement/non-infringement in a declaratory judgment action brought by the licensee under Medlmmune.  The Court is expected to issue its opinion before the end of June 2014.

For information regarding this and other related topics, please see:

• "Oral Argument in Medtronic Inc. v. Boston Scientific Corp.," November 7, 2013
• "Amicus Curiae Briefs in Medtronic v. Boston Scientific – Legal Scholars Support Medtronic; Tessera Supports Vacatur and Remand," November 4, 2013
• "Amicus Curiae Briefs in Support of Federal Circuit Opinion in Medtronic Inc. v. Boston Scientific Corp.," November 3, 2013
• "United States Weighs-In on the Medtronic Case," August 15, 2013
• "Supreme Court Grants Certiorari in Medtronic v. Boston Scientific," May 22, 2013

12.  Debate Continues on 12-Year Data Exclusivity Period and Biosimilar Substitution

More than three years after President Obama signed the Patient Protection and Affordable Care Act (PPACA) into law, thereby establishing a biosimilar regulatory pathway in the U.S. via the Biologics Price Competition and Innovation Act (BPCIA), the Administration has continued to press for a reduction of the data exclusivity period from 12 years to 7 years.  The debate over the data exclusivity period continued this year, but in the context of negotiations on the Trans-Pacific Partnership Agreement (TPP), a multilateral free trade agreement involving Australia, Brunei, Chile, Malaysia, New Zealand, Peru, Singapore, the United States, and Vietnam.  In March, Senators Max Baucus (D-MT) and Orrin Hatch (R-UT), the Chairman and Ranking Member, respectively, of the Senate Committee on Finance, urged the Acting U.S. Trade Representative in a letter "to seek commitments from our trading partners that reflect the level of protection under U.S. law, for example 12 years of regulatory data protection for biologic pharmaceuticals."  While the Biotechnology Industry Organization (BIO) expressed its support for the 12-year data exclusivity period, the AARP asked the U.S. Trade Representative not to sign onto the TPP if the trade agreement includes the 12-year data exclusivity period.  While the data exclusivity period of the BPCIA was being debated in the context of the TPP, several states were debating legislation on biosimilar substitution under the BPCIA.  In October, California Governor Jerry Brown vetoed a bill in that state that would have authorized a pharmacist to select a biosimilar when filling a prescription order for a prescribed biological product, provided that the prescriber did not personally indicate "Do not substitute."  In a letter to the California Senate, Governor Brown noted that he vetoed the bill because the FDA had not yet determined the standards required for biosimilars to meet the higher threshold for interchangeability, and therefore, requiring physician notification would have been "premature."

For information regarding this and other related topics, please see:

• "AARP Seeks Reduced Data Exclusivity Period in TPP," October 31, 2013
• "Governor Brown Vetoes California Biosimilar Bill," October 16, 2013
• "California Biosimilar Bill Aligns with BIO Principles on Biologic Substitution," October 3, 2013
• "GPhA Opposes California Biosimilar Bill; Points to Report on Savings from Biosimilars," October 2, 2013
• "White Paper Asserts That Existing Trade Agreements Provide No Data Exclusivity for Biologics," August 26, 2013
• "BIO Reiterates Support for 12-Year Data Exclusivity Period for Biologics," August 20, 2013
• "Senators Back 12-Year Data Exclusivity Period for Biosimilars and President Obama (Once Again) Does Not," May 9, 2013
• "WLF Submits Comments on Abbott's Citizen Petition on Biosimilars," March 6, 2013

11.  EU Council Signs Unified Patent Court Agreement, Taking Step Towards Unitary Patent System

In February, the Council of the European Union announced that twenty-four member states had signed the international agreement that would establish a Unified Patent Court (UPC), a specialized court having exclusive jurisdiction over infringement and validity questions related to unitary patents.  The signing initiated the process of ratification by national parliaments, with ratification requiring at least thirteen member states (including France, Germany and the United Kingdom).  Ratification of the UPC agreement will result in implementation of two EU regulations on the unitary patent.  According to some reports, ratification may not take place until at least 2015 or 2016, or perhaps even 2017 or 2018.  Spain, which did not sign the agreement, continued to challenge the regulations underpinning the Unitary Patent System in 2013.

For information regarding this and other related topics, please see:

• "News from Abroad: Spain's Further Challenges to the Unitary Patent Regulations," June 6, 2013
• "Member States Sign Agreement to Establish Unified Patent Court," February 21, 2013

Patients Push Back on FDA Threats to 23andMe Genetic Testing Products

By Kevin E. Noonan --

In a petition published on the "We the People" portion of the White House website, a group of self-titled healthcare consumers call for the Obama Administration to overrule the FDA and permit genetic testing company 23andMe to continue to market the company's Personal Genomic Services (PGS) product.  The petition is a response to the FDA sending a Warning Letter to 23andMe, threatening the company with "seizure, injunction, and civil money penalties" unless the company ceases offering its services until it obtained FDA approval under 21 U.S.C. § 321(h) as a "medical device" (see "FDA Threatens Agency Action Against 23andMe Over Personal Genetic Testing").

The text of the petition reads as follows:

We, the healthcare consumers of America, demand that we maintain access to genomics testing services like 23andMe's, which serve as a 100% privately purchased complement to government-regulated healthcare.

The FDA grossly overstates the risks associated with 23andMe's assessments.  Statements such as those suggesting that dangers like false positives may "lead a patient to undergo prophylactic surgery, chemoprevention, intensive screening, or other morbidity-inducing actions" are outrageous and patently false.

Risks associated with services like 23andMe's are understood by private consumers, while the benefits of these services (such as early diagnoses for chronic diseases) are significant.  The price of over-regulation is lengthy delays in potentially life-saving medical innovations.

The petition has a goal of 100,000 signatures by December 25, 2013 (according to the website) and since it went live yesterday has garnered 1,904 signatures.  The website notes that the purpose of the site is to provide a new way for citizens to petition the government by exercsing their First Amendment rights.  The site asserts that "[i]f a petition gets enough support, White House staff will review it, ensure it's sent to the appropriate policy experts, and issue an official response."  It will be interesting to see what part of the policy apparatus of the Obama Administration responds to the petition (presuming there are enough signatures, where "enough" is undefined):  that part of the Administration having a populist cast that might support the company, or the part responsible for the government's antagonism to diagnostic testing.

FDA Threatens Agency Action Against 23andMe Over Personal Genetic Testing

By Kevin E. Noonan --

As reported in Fierce Medical Devices by Damian Garde, the FDA has issued a Warning Letter to personal genomics company 23andMe, demanding that the company stop selling its Personal Genomic Services (PGS) product without obtaining FDA approval.  The letter characterizes the PGS product of being a "medical device" falling within the scope of Section 201(h) of the Food, Drug and Cosmetic Act (21 U.S.C. § 321(h)) and thus requiring FDA approval prior to marketing (something 23andMe has failed to obtain).

The letter was sent on November 22 by Alberto Gutierrez, Director of the Agency's Office of In vitro Diagnostics and Radiological Health and Center for Devices and Radiological Health to 23andMe's CEO Ann Wojcicki.  In it, the Agency provides its rationale for determining that the company's PGS product is a device within the meaning of the statute, saying that it "is intended for use in the diagnosis of disease or other conditions or in the cure, mitigation, treatment, or prevention of disease, or is intended to affect the structure or function of the body."  The letter cites the company's website for touting the product as providing "health reports on 254 diseases and conditions" (today, the site says 260 diseases and conditions), which include "carrier status" (for the genetic predisposition of particular diseases), "health risks" and drug response[s]"(see "how it works").  Also noted in the letter are 23andMe's claims that its PGS product can be used as "[a] first step in prevention" wherein users can "take steps toward mitigating" disease like diabetes, coronary artery disease, and breast cancer (including Myriad's BRCA genes).  And the letter evinces the Agency's frustration at the company's apparent recalcitrance in obtaining approval, stating that "[m]ost of these uses have not been classified and thus require premarket approval or de novo classification, as FDA has explained to you on numerous occasions."

The Agency's letter sets out as particular concerns inclusion of the BRCA genes in the company's tests, as well as testing related to genetically based, individualized reactions to warfarin, clopidogrel, and 5-fluorouracil "because of the potential health consequences that could result from false positive or false negative assessments for high-risk indications such as these."  At issue is patients undergoing unnecessary prophylaxis or "self-managing" their drug dosing depending on their personal genetic proclivities, in ways that are best done under a doctor's supervision.  The genetic information provided by 23andMe's PGS product could be misinterpreted or provide patients with misunderstood, incorrect, or misleading information, according to the Agency's letter.

The Agency notes that the company submitted an application under Section 510(k) for "several of these indications" but that 23andMe has "failed to address the issues described during previous interactions with the Agency," including specifically requests for additional information sent in September and November, 2012.  As a consequence, 23andMe's applications are considered by the Agency to be withdrawn, meaning there are currently pending no applications for the PGS product as required by law.

The Agency attests to its willingness to "work[] with" 23andMe to assist the company in complying with Agency requirements, and cites its efforts since July 2009 in this regard.  These include:

FDA has spent significant time evaluating the intended uses of the PGS to determine whether certain uses might be appropriately classified into class II, thus requiring only 510(k) clearance or de novo classification and not PMA approval, and we have proposed modifications to the device's labeling that could mitigate risks and render certain intended uses appropriate for de novo classification.  Further, we provided ample detailed feedback to 23andMe regarding the types of data it needs to submit for the intended uses of the PGS.  As part of our interactions with you, including more than 14 face-to-face and teleconference meetings, hundreds of email exchanges, and dozens of written communications, we provided you with specific feedback on study protocols and clinical and analytical validation requirements, discussed potential classifications and regulatory pathways (including reasonable submission timelines), provided statistical advice, and discussed potential risk mitigation strategies.

Nevertheless, the Agency complains that it has not yet received the necessary assurances that the PSG product has been "analytically or clinically validated" for its intended uses, which have "expanded" since the company's original 510(k) submissions (and even in the past week).  Despite a letter from the company in January 2013 attesting that it was "completing the additional analytical and clinical validations for the tests that have been submitted" and is "planning extensive labeling studies that will take several months to complete" that evidence has yet to be submitted.  And these promises were made "months after [23andMe] submitted your 510(k)s and more than 5 years after [23andMe] began marketing" the PGS product.  The litany of failure continues:

You have not worked with us toward de novo classification, did not provide the additional information we requested necessary to complete review of your 510(k)s, and FDA has not received any communication from 23andMe since May.

Instead, the letter alleges, "we have become aware that you have initiated new marketing campaigns, including television commercials that, together with an increasing list of indications, show that you plan to expand the PGS's uses and consumer base without obtaining marketing authorization from FDA."

The FDA then issues the following warning: "23andMe must immediately discontinue marketing the PGS until such time as it receives FDA marketing authorization for the device," which will fall within the scope of the following provisions of FDA law and regulation:

The PGS is in class III under section 513(f) of the FD&C Act, 21 U.S.C. 360c(f).  Because there is no approved application for premarket approval in effect pursuant to section 515(a) of the FD&C Act, 21 U.S.C. 360e(a), or an approved application for an investigational device exemption (IDE) under section 520(g) of the FD&C Act, 21 U.S.C. 360j(g), the PGS is adulterated under section 501(f)(1)(B) of the FD&C Act, 21 U.S.C. 351(f)(1)(B).  Additionally, the PGS is misbranded under section 502(o) of the Act, 21 U.S.C. § 352(o), because notice or other information respecting the device was not provided to FDA as required by section 510(k) of the Act, 21 U.S.C. § 360(k).

The company is given fifteen days to comply, or provide a reason why it cannot comply within this time, and required to provide "the specific actions you have taken to address all issues noted above, [including] documentation of the corrective actions you have taken."  If not, the Agency threatens actions which "include, but are not limited to, seizure, injunction, and civil money penalties."

Despite the copy on 23andMe's website extolling the virtues of its testing for disease prevention and mitigation, it also carries the disclaimer that the results are "intended for research and educational purposes only and [are] not intended for diagnostic use" (which in itself might implicate state consumer protection laws).  The company has acknowledged the FDA's action and issued a statement, as reported on the Fierce Medical Device site that "we have not met the FDA's expectations regarding timeline and communication regarding our submission.  Our relationship with the FDA is extremely important to us, and we are committed to fully engaging with them to address their concerns."

The Agency's actions raise interesting questions on the future of genetic testing, particularly under circumstances where the Supreme Court has raised significant barriers to obtaining patent protection for these types of testing.  In such an environment there may be a much lower impetus for disclosing the "natural law" correlations between disease propensity and genetic variability, because once that disclosure is made it cannot be retracted.  If patent exclusivity is not possible, there could easily arise a "tragedy of the commons," where no company is motivated to undertake the type of efforts demanded by the Agency of 23andMe just to have those efforts coopted by its competitors.  In this situation, the Agency may be required to permit applicants to keep substantial portions of their submissions confidential and be satisfied by a showing that the correlation between a particular genetic variant and a particular disease is sufficiently robust to justify approval.  And even that arrangement is problematical, as most confidentiality provisions in applications for government approval can be overcome on notice to the proprietor that a member of the public has filed a Freedom of Information Act request.  It is hard to discern instances where there would not be intense political pressure to rescind confidentiality for genetic testing regarding a medical disease or condition, with that propensity increasing with increased reliability of the test and incidence of the disease or condition.  Of course, the Agency cannot disclose what it doesn't know, so perhaps (and against the tendencies of governments and particularly science-based government agencies like the FDA) approval could be obtained without disclosing the identities of the genes involved in the testing.  The perpetual nature of this state of nondisclosure is such that even if the Agency were willing to permit nondisclosure for a time it is unlikely that it would agree to less than a reasonable term, for example, 20 years from the date the application was submitted for approval.  Thus it could be that in such a roundabout way Agency action could achieve what the patent system has always provided, but perhaps in a form less amenable to meddling from the Court.

Mutual Pharmaceutical Co. v. Bartlett (2013)

By Kevin E. Noonan --

The old adage "Bad cases make bad law" is invoked when the facts of a case lead a court to rule in favor of the particular entities before it rather than applying the law consistently.  (Although anyone familiar with recent Supreme Court patent jurisprudence would perhaps not be amiss in thinking the adage should be adapted to "Bad analogies make bad law.")  The current Court (or at least a 5-member majority) showed on Monday that it could be immune to these equities in reversing a $21 million judgment to a New Hampshire woman disfigured as a consequence of taking a generic formulation of sulindac, a non-steroidal anti-inflammatory drug (or NSAID).  Once again, the Court waded into the waters of drug regulatory law and the interplay between the provisions of the Federal Food, Drug, and Cosmetic Act (FDCA) and Hatch-Waxman Act and state, common law products liability sounding in tort, with the Court deciding that state law was preempted (to the detriment of the patient's recovery for the "tragic circumstances" of her disfigurement).

The case arose from administration of a generic version of Clinoril (the branded version of the drug sulindac):

made by Mutual Pharmaceutical to Respondent Karen L. Bartlett.  Ms. Bartlett suffered a known -- albeit rare -- side effect of sulindac administration (as well as other NSAIDs), toxic epidermal necrolysis, a skin hypersensitivity reaction.  The consequences for Ms. Bartlett were "horrific" according to the Court:  "[s]ixty to sixty-five percent of the surface of respondent's body deteriorated, was burned off, or turned into an open wound.  She spent months in a medically induced coma, underwent 12 eye surgeries, and was tube-fed for a year.  She is now severely disfigured, has a number of physical disabilities, and is nearly blind."  Significant for the Court's decision, at the time she was administered the drug, the drug label did not contain any specific warning regarding this type of side effect (although the FDA required the package insert to contain a warning regarding the risk of developing this condition); the Agency later required this warning to be on the drug label.

Ms. Bartlett sued in an action eventually transferred to Federal court under state law claims characterized by the Court as "both failure-to-warn and design-defect claims," but the District Court dismissed the former cause of action following her physician's admission that he had not read either the label or package insert.  Ms. Bartlett prevailed on her design defect claim, which under New Hampshire law "requires manufacturers to ensure that the products they design, manufacture, and sell are not 'unreasonably dangerous.'"  According to the Court:

New Hampshire imposes design-defect liability only where "the design of the product created a defective condition unreasonably dangerous to the user," citing Vautour v. Body Masters Sports Industries, Inc., 147 N. H. 150, 153, 784 A. 2d 1178, 1181 (2001); Chellman v. Saab-Scania AB, 138 N. H. 73, 7, 637 A. 2d 148, 150 (1993).  To determine whether a product is "unreasonably dangerous," the New Hampshire Supreme Court employs a "risk-utility approach" under which "a product is defective as designed if the magnitude of the danger outweighs the utility of the product."  Vautour, supra, at 154, 784 A. 2d, at 1182 (internal quotation marks omitted).  That risk-utility approach requires a "multifaceted balancing process involving evaluation of many conflicting factors."  Ibid. (internal quotation marks omitted); see also Thibault, supra, at 809, 395 A. 2d, at 847 (same).

While the set of factors to be considered is ultimately an open one, the New Hampshire Supreme Court has repeatedly identified three factors as germane to the risk-utility inquiry:  "the usefulness and desirability of the product to the public as a whole, whether the risk of danger could have been reduced without significantly affecting either the product's effectiveness or manufacturing cost, and the presence and efficacy of a warning to avoid an unreasonable risk of harm from hidden dangers or from foreseeable uses."  Vautour, supra, at 154, 784 A. 2d, at 1182; see also Price, supra, at 389, 702 A. 2d, at 333 (same); Chellman, supra, at 77-78, 637 A. 2d, at 150 (same).

Moreover, according to the Court this form of liability, while being "strict" product liability is not "absolute" liability; the distinction is that the former imposes a "duty of care" on manufacturers as opposed to the latter form of liability, which is a way states can "spread the risk" of injury due to design or manufacturing defects.  This distinction is relevant, because the Court's determination that Mutual was under a common law-defined duty in New Hampshire implicated the three ways the company could comply with state law, and how two of the three were impossible under Federal law.

The Court's opinion, by Justice Alito joined by Chief Justice Roberts and Justices Scalia, Kennedy, and Thomas, found that Mutual could comply with its state-law imposed duty either by making chemical changes to the drug or changing the drug label (here, by including the more stringent warnings from the package insert on the label, as the FDA was later to do).  The majority found that changing sulindac chemically was impossible both for reasons of "basic chemistry" (i.e., there is little that could be changed in the molecule without changing it into a different molecule) and FDA regulatory law, which required the generic compound to be a copy of the branded drug and to have certain pharmacological properties in common with the branded embodiment.  21 U. S. C. §§ 355(j)(2)(A)(ii), (iii) and (iv), 21 U. S. C. §§ 355(j)(8).  The impossibility of changing the label is a direct consequence of the FDA requirement that a generic drug have the same label as the branded version.  § 355(j)(2)(A)(v).  And a generic drug manufacturer is barred from unilaterally changing either the drug itself, its formulation or its label.  21 CFR § 314.70(b)(2)(i).  Thus, in this case there was a direct conflict between what was required to comply with the state-imposed duties under its tort law and the requirements of Federal drug regulatory law.

Under these circumstances, the Court held that Federal law prevails and preempts state tort liability, citing Maryland v. Louisiana, 451 U. S. 725, 746 (1981), for the principle that "[u]nder Supremacy Clause, state laws that require a private party to violate federal law are pre-empted and, thus, are 'without effect.'"  And the Court rejected the third possibility open to Mutual, which was to stop selling generic sulindac in New Hampshire, saying that if this were the law "impossibility preemption" would be "all but meaningless," citing its recent opinion in PLIVA, Inc. v. Mensing, 564 U. S. ___ (2011), a case involving state law liability on "failure to warn" grounds.  The Court expressly rejected this alternative in the PLIVA case, saying that "[a]dopting the [appellate court's] stop-selling rationale would mean that not only PLIVA, but also the vast majority -- if not all -- of the cases in which the Court has found impossibility pre-emption, were wrongly decided."

That, of course, would never do.  As a consequence, Ms. Bartlett is without a remedy against the generic drug manufacturer, an outcome the majority regrets but does not use to come to a different conclusion:

This case arises out of tragic circumstances.  A combination of factors combined to produce the rare and devastating injuries that respondent suffered:  the FDA's decision to approve the sale of sulindac and the warnings that accompanied the drug at the time it was prescribed, the decision by respondent's physician to prescribe sulindac despite its known risks, and Congress' decision to regulate the manufacture and sale of generic drugs in a way that reduces their cost to patients but leaves generic drug manufacturers incapable of modifying either the drugs' compositions or their warnings.  Respondent's situation is tragic and evokes deep sympathy, but a straightforward application of pre-emption law requires that the judgment below be reversed.

Four Justices dissented.  Justice Breyer, joined by Justice Kagan, writes that there is a fourth alternative, that is for a company to shoulder the burden of "paying a sizable damages" award as a remedy in instances where a rare side effect causes harm to a patient.  This opinion is informed, in part, by an amicus brief submitted by two former FDA Commissioners, who inform the Court that "the FDA has long believed that state tort litigation can 'supplemen[t] the agency's regulatory and enforcement activities.'"  Justice Sotomayor, joined by Justice Ginsburg, is more vociferous, accusing the majority of unnecessarily crafting a rule that "immunize[d] generic drug manufacturers from state-law failure-to-warn claims" in PLIVA v. Mensing and, here, "unnecessarily and unwisely extend[ing] its holding in Mensing to pre-empt New Hampshire's law governing design-defects with respect to generic drugs."  "Of greater consequence," the Justice writes:

[T]he Court appears to justify its revision of respondent Karen Bartlett's state-law claim through an implicit and undefended assumption that federal law gives pharmaceutical companies a right to sell a federally approved drug free from common-law liability.  Remarkably, the Court derives this proposition from a federal law that, in order to protect consumers, prohibits manufacturers from distributing new drugs in commerce without federal regulatory approval, and specifically disavows any intent to displace state law absent a direct and positive conflict.

The majority has gone astray, according to the dissent, for failing to apply the "two cornerstones of our pre-emption jurisprudence":  to discern the "purpose of Congress" in enacting the statute, and to require a "clear and manifest" Congressional intention to supersede the "historic police powers of the States" as embodied in the type of common law tort liability at issue in this case.  The Justice sees this decision as being in contrast to the Court's (correct) decision in Wyeth v. Levine, where state tort law liability was not preempted by Federal drug regulatory law.  State tort law is a complement to Federal drug law in protecting consumers, a situation Congress has not seen fit to alter or correct:

Congress' preservation of a role for state law generally, and common-law remedies specifically, reflects a realistic understanding of the limitations of ex ante federal regulatory review in this context.  On its own, even rigorous preapproval clinical testing of drugs is "generally . . . incapable of detecting adverse effects that occur infrequently, have long latency periods, or affect subpopulations not included or adequately represented in the studies," citing Kessler & Vladeck, A Critical Examination of the FDA's Efforts to Preempt Failure-to-Warn Claims, 96 Geo. L. J. 461, 471 (2008); see National Academies, Institute of Medicine, The Future of Drug Safety: Promoting and Protecting the Health of the Public 37-38 (2007).

Her dissent also notes that "the FDA, which is tasked with monitoring thousands of drugs on the market and considering new drug applications, faces significant resource constraints that limit its ability to protect the public from dangerous drugs," citing Levine, 555 U. S., at 578-579, and n. 11, and that "[t]ort suits can help fill the gaps in federal regulation by 'serv[ing] as a catalyst' to identify previously unknown drug dangers," citing Bates v. Dow Agrosciences LLC, 544 U. S. 431, 451 (2005).

Under these circumstances this dissent finds the facts of this case to be far from the "strict standard for impossibility" that should be required for Mutual to avoid state law tort liability.  And as in Justice Breyer's dissent, Justice Sotomayor did not see Mutual's alteratives to be limited to those "impossible" under Federal law:

A manufacturer of a drug that is unreasonably dangerous under New Hampshire law has multiple options:  It can change the drug's design or label in an effort to alter its risk-benefit profile, remove the drug from the market, or pay compensation as a cost of doing business.  If federal law or the drug's chemical properties take the redesign option off the table, then that does not mean the manufacturer suddenly has a legal obligation under state law to improve the drug's label.  Indeed, such a view of state law makes very little sense here because even if Mutual had strengthened its label to fully account for sulindac's risks, the company might still have faced liability for having a defective design.  . . .  When a manufacturer cannot change the label or when doing so would not make the drug safe, the manufacturer may still choose between exiting the market or continuing to sell while knowing it may have to pay compensation to consumers injured by its product.

While these alternatives may be "unwelcome" from a manufacturer's prospective, "it is a choice that a sovereign State may impose to protect its citizens from dangerous drugs or at least ensure that seriously injured consumers receive compensation."

Ironically, the majority, usually so quick to rely upon Federalism (or "states' rights") principles in other contexts finds state tort law liability to be preempted while the traditionally "liberal" members of the Court would hew to basic Federalism principles in permitting states to protect their citizens under common law tort law.  While the majority "saves for another day the question whether a true absolute-liability state-law system could give rise to impossibility pre-emption," it seems that states adopting an "absolute liability" regime that imposes no affirmative duties contrary to Federal law but merely "spreads the risk" might be one way for the states to regain their traditional right to employ the sovereign police powers to impose tort liability that would escape the wide latitude of preemption embodied in the Court majority's decision.

Mutual Pharmaceutical Co. v. Bartlett (2013)
Opinion by Justice Alito, joined by Chief Justice Roberts and Justices Scalia, Kennedy, and Thomas; dissenting opinion by Justice Breyer, joined by Justice Kagan; dissenting opinion by Justice Sotomayor, joined by Justice Ginsburg

FDA FY2012 Drug Approvals Equal FY2011 Mark

By Donald Zuhn --

Last month, the U.S. Food and Drug Administration released its annual report on innovative drug approvals, noting that the agency approved 35 novel medicines in FY 2012.  The 35 approvals equaled the number of approvals for FY 2011, and marked the highest number of approvals since the FDA approved 36 new drugs in FY 2004.  According to the report on FY 2012 Innovative Drug Approvals, ten of the 35 new drugs were approved for the treatment of cancer, two represent advances in personalized medicine, and nine new drugs were approved for the treatment of orphan diseases.  The report notes that the term "drugs" is intended to include products approved by both the FDA's Center for Drug Evaluation and Research (CDER), which reviews New Drug Applications (NDAs) for pharmaceuticals, and the agency's Center for Biologics Evaluation and Research (CBER), which reviews biological therapeutic agents.

The report indicated that most of the new drugs were approved for U.S. patients before the drugs were available in other countries.  In particular, of the 32 new drugs for which comparisons could made with approvals in other countries, 75% (24) were first approved in the U.S.  The FDA was able to achieve such results by approving 77% of the 35 new drugs on the first cycle of review, without requiring additional information that would have lengthened the approval time.

The 35 new drugs that were approved in FY 2012 include the following:

• AMYVID (florbetapir F18) - Avid Radio-pharmaceuticals, Inc.
• AUBAGIO (teriflunomide) - Sanofi-Aventis, U.S., LLC
• BElVIQ (lorcaserin hydrochloride) - Arena Pharmaceuticals, Inc.
• BOSULIF (bosutinib) - Pfizer Inc.
• CHOLINE C 11 - Mayo Clinic PET Radiochemistry Facility
• ELELYSO (taliglucerase alfa) - Protalix Biotherapeutics Inc.
• ERIVEDGE (vismodegib) - Genentech, Inc.
• ERWINAZE (asparaginase erwinia chrysanthemi) - EUSA Pharma (USA), Inc.
• EYLEA (aflibercept) - Regeneron Pharmaceuticals, Inc.
• FERRIPROX (deferiprone) - Apopharma, Inc.
• GINTUIT (allogeneic cultured keratinocytes and fibroblasts in bovine collagen) - Organogenesis, Inc.
• HEMACORD (hemapoietic progenitor cells, cord (HPC-C) - New York Blood Center, Inc.
• HPC, Cord Blood (hemapoietic progenitor cells, cord (HPC-C) - Clinimmune Labs
• INLYTA (axitinib) - Pfizer, Inc.
• JAKAFI (ruxolitinib) - Incyte Corp.
• KALYDECO (ivacaftor) - Vertex Pharmaceuticals, Inc.
• KYPROLIS (carfilzomib) - Onyx Pharmaceuticals, Inc.
• LINZESS (linaclotide) - Forest Laboratories, Inc.
• MENHIBRIX (Meningococcal Groups C and Y and Haemophilus b Tetanus Toxoid Conjugate Vaccine) - GlaxoSmithKline Biologicals
• MYRBERTIQ (mirabegron) - Astellas Pharma Global Development, Inc.
• NEUTROVAL (tbo-filgrastim) - Sicor Biotech UAB
• OMONTYS (peginesatide) - Affymax, Inc.
• ONFI (clobazam) - Lundbeck, Inc.
• PERJETA (pertuzumab) - Genentech, Inc.
• PICATO (ingenol mebutate) - Leo Pharma AS
• PREPOPIK (sodium picosulfate, magnesium oxide, citric acid) - Ferring Pharmaceuticals
• STIVARGA (regorafenib) - Bayer Healthcare Pharmaceuticals, Inc.
• STENDRA (avanafil) - Vivus Inc.
• STRIBILD (elvitegravir, cobicistat, emtricitabine, tenofovir disoproxil fumarate) - Gilead Sciences, Inc.
• SURFAXIN (lucinactant) - Discovery Laboratories, Inc.
• TUDORZA PRESSAIR (aclidinium bromide) - Forest Laboratories, Inc.
• VORAXAZE (glucarpidase) - BTG international, Inc.
• XTANDI (enzalutamide) - Medivation, Inc.
• ZALTRAP (ziv-aflibercept) - Sanofi-Aventis U.S., LLC
• ZIOPTAN (tafluprost) - Merck Sharp and Dohme Corp.

Top Stories of 2012: #4 to #7

By Donald Zuhn --

Reflecting upon the events of the past twelve months, Patent Docs presents its sixth annual list of top biotech/pharma patent stories.  For 2012, we identified fifteen stories that were covered on Patent Docs last year that we believe had (or are likely to have) the greatest impact on biotech/pharma patent practitioners and applicants.  On Monday and Tuesday, we counted down stories #15 to #8, and today we count down stories #7 to #4 as we work our way towards the top three stories of 2012.  As with our other lists (2011, 2010, 2009, 2008, and 2007), links to our coverage of these stories (as well as a few links to articles on related topics) have been provided in case you missed the articles the first time around or wish to go back and have another look.  As always, we love to hear from Patent Docs readers, so if you think we left something off the list or disagree with anything we included, please let us know.

7.  Federal Circuit Interprets § 271(e)(1) Safe Harbor as Extending to Post-approval Activities

In a case involving whether certain post-approval activities fall within the "safe harbor" of 35 U.S.C. § 271(e)(1), a divided panel of the Federal Circuit in August vacated a preliminary injunction granted by the District Court, holding that acts taken after approval fell with the safe harbor.  According to the majority, it was significant that Congress had not (expressly) limited the scope of the safe harbor to the Food, Drug and Cosmetic Act but had "broadly" included within the scope of the safe harbor "any federal law" that "regulates the manufacture, use, or sale of drugs."  Thus, the majority rejected Momenta's contention that the process and quality control information obtained from Amphastar's infringement was not submitted to the FDA but was retained by defendants, as these "batch records" must be maintained "for at least one year after expiration of the batch" of generic enoxaparin and must be "readily available for authorized inspection" by the FDA."  The majority opinion states that "[w]e therefore hold that post-approval studies that are 'reasonably related to the development and submission of information under a Federal law which regulates the manufacture, use, or sale of drugs' fall within the scope of the § 271(e)(1) safe harbor."  Momenta's request for rehearing en banc was denied by the Federal Circuit in November.

For information regarding this and other related topics, please see:

• "Momenta Pharmaceuticals Inc. v. Amphastar Pharmaceuticals, Inc.: 'The Rest of the Story,'" August 13, 2012
• "Momenta Pharmaceuticals, Inc. v. Amphastar Pharmaceuticals, Inc. (Fed. Cir. 2012)," August 9, 2012
• "Chief Judge Rader (Not Surprisingly) Gets it Right about Chimerical 'Tragedy of the Anti-Commons,'" August 6, 2012

6.  Implementation of Biosimilar Regulatory Pathway Proceeds Despite Opposition

In February, the U.S. Food and Drug Administration published its long-awaited draft guidance on the development of biosimilar products.  The FDA's guidance consisted of three documents:  Scientific Considerations in Demonstrating Biosimilarity to a Reference Product, Quality Considerations in Demonstrating Biosimilarity to a Reference Protein Product, and Biosimilars: Questions and Answers Regarding Implementation of the Biologics Price Competition and Innovation Act of 2009.  The FDA then spent the next few months collecting comments regarding the draft guidance, and in May held a hearing on the draft guidance, where researchers, payors, patient and physician groups, and industry advocates provided their thoughts on the FDA's first attempt to clarify the logistics as to the operation of the BPCIA.  The FDA's efforts to implement the BPCIA, however, did not push implementation of the biosimilar regulatory pathway up to #6 on this year's list.  No, it was the Supreme Court's landmark decision in June upholding the Patient Protection and Affordable Care Act (PPACA) -- of which the BPCIA is a part -- as constitutional under the taxation clause of the Constitution that lifted this topic to #6.  While the Supreme Court's decision in National Federation of Independent Business v. Sebelius did not constitute a direct challenge to the BPCIA, there were a handful of direct challenges to aspects of the BPCIA.  For example, President Obama took yet another shot at the 12-year data exclusivity period specified under the BPCIA in his 2013 budget proposal, calling for a modification of the length of exclusivity to facilitate faster development of generic biologics by "award[ing] brand biologic manufacturers seven years of exclusivity rather than 12 years under current law."  The same modification had been included in the President's 2012 budget proposal.  In addition, Abbott filed a Citizen Petition with the FDA in April, requesting that the agency refrain from accepting biosimilar applications under the BPCIA that cite reference products (biologics) for which a biologics license application (BLA) was submitted to the FDA prior to March 23, 2010 (when the PPACA was signed into law).  Interestingly, in a letter to the FDA, Rep. Anna Eshoo (D-CA), who was one of the principal authors of the BPCIA, stated that "[w]hile Abbott's Citizen Petition argues that pre-BPCIA approved biologic products cannot be subject to the law, l want to state very emphatically that it was Congressional intent for the new pathway to apply to biologics approved before and after the passage of the Affordable Care Act."  In October, the FDA sent a letter to Abbott noting that the agency "has been unable to reach a decision on [Abbott's] petition because it raises complex issues requiring extensive review and analysis by Agency officials."  The agency did not provide a date by which it would respond.

For information regarding this and other related topics, please see:

• "Rep. Eshoo Expresses Views on Abbott's Biosimilars Petition in Letter to FDA," October 25, 2012
• "FDA Continues to Review Abbott Petition on Biosimilars," October 24, 2012
• "Affordable Care Act Survives Supreme Court Review Largely Unscathed, Clearing Way for Biosimilars," June 28, 2012
• "BIO International Convention 2012 Preview - Part II: BIO and Biosimilar Regulations throughout the World," June 12, 2012
• "House Passes User Fee Bill," May 31, 2012
• "Senate Passes User Fee Bill," May 29, 2012
• "FDA Holds Public Hearing on Biosimilar Draft Guidance," May 20, 2012
• "BIO Comments on FDA Biosimilars Guidance: Demand More Testing, Permit Fewer Differences," April 25, 2012
• "Abbott Asks FDA to Refuse Certain Biosimilar Applications," April 23, 2012
• "FDA Discusses Initial Considerations for Biosimilar Guidance Documents," February 27, 2012
• "President's Latest Budget Proposal Seeks Decrease of Data Exclusivity Period and Elimination of Pay-for-Delay Agreements," February 21, 2012
• "More on FDA Draft Guidelines for 'Follow-on' Biologic Drug Approval Pathway," February 14, 2012
• "FDA Publishes Draft Guidelines for Biosimilar Product Development," February 9, 2012

5.  Federal Circuit Confirms Patent Eligibility of Isolated DNA

In August, the Federal Circuit in Association for Molecular Pathology v. U.S. Patent and Trademark Office, decided on remand that, the Supreme Court's decision in Mayo v. Prometheus notwithstanding, claims to isolated human DNA satisfy the requirements of 35 U.S.C. § 101.  Each of Judge Lourie's majority opinion, Judge Moore's concurring opinion, and Judge Bryson's opinion concurring in part and dissenting in part substantially tracked their opinions when the panel first decided AMP v. USPTO.  Had the case ended here, the Federal Circuit's decision would have placed higher on our list (perhaps foreshadowing one of the stories to be discussed in the final installment of our Top Stories series).

For information regarding this and other related topics, please see:

• "Patent Eligibility and Biology," August 23, 2012
• "Association for Molecular Pathology v. United States Patent and Trademark Office (Fed. Cir. 2012)," August 16, 2012
• "AMP v. USPTO -- Federal Circuit Confirms Patent Eligibility of Isolated DNA," August 16, 2012
• "The Proper Scope of DNA (or "Gene") Patent Claims," August 1, 2012
• "Myriad and Prometheus: Do Patents 'Preempt' Follow-On Research?" July 29, 2012
• "Federal Circuit Hears Oral Argument in AMP v. USPTO Remand," July 23, 2012
• "Myriad Genetics Files Supplemental Brief in AMP v. USPTO," July 19, 2012
• "Supplemental Brief for Appellees in AMP v. USPTO," July 19, 2012
• "Biopharmaceutical Companies Weigh-In on Myriad Case," July 17, 2012
• "Health Care Professionals Contend That Isolated DNA and cDNA Are Patent Ineligible," July 16, 2012
• "Coalition of Amici File Brief in Support of Myriad," July 15, 2012
• "Dr. James Watson: Human Genes Should Not Be Patented," July 12, 2012
• "Scientist-Law Professor Files Amicus Brief in Myriad Case," July 11, 2012
• "U.S. Government: Mayo Decision Supports Prior Argument That Isolated Genomic DNA Is Not Patent Eligible," July 10, 2012
• "IPO Amicus Brief Argues for Patent Eligibility of Myriad's Isolated DNA Claims and Method Claim 20," July 9, 2012
• "Eli Lilly & Co. File Amicus Brief in AMP v. Myriad," June 27, 2012
• "Biotech Companies Send Letter on Myriad Case to Attorney General and Solicitor General," June 19, 2012
• "Parties and Amici File Briefs in Myriad Case," June 17, 2012
• "The Aussies Are At It Again," June 14, 2012
• "Federal Circuit Declines Invitation to Reconsider Standing Question," June 13, 2012
• "Plaintiffs Respond to Myriad's 'Suggestion' of Mootness or, Alternatively, Motion for Remand in AMP v. USPTO," June 10, 2012
• "Myriad Files Motion 'Suggesting' Mootness or Seeking Remand in AMP v. USPTO," May 30, 2012
• "Federal Circuit Sets Schedule for AMP v. USPTO," April 30, 2012
• "Supreme Court Remands Myriad Case," March 26, 2012

4.  Supreme Court Grants Certiorari in Monsanto v. Bowman

In October, the Supreme Court granted certiorari in Monsanto v. Bowman, against the advice of the U.S. Solicitor General.  In Bowman, Monsanto's complaint arose from farmer Bowman's "second planting" of herbicide resistant seed that was made using so-called "commodity seed" (seed sold by farmers to local grain elevators for commodity use, for example, as cattle feed).  After planting this seed, which was significantly cheaper than Roundup Ready® seed, farmer Bowman tested the crop for Roundup® resistance and found that substantial amounts of the seed were resistant.  He used Roundup® on these plantings and then replanted the seed.  The District Court granted summary judgment of patent infringement and entered judgment against farmer Bowman, and the Federal Circuit affirmed.  The question presented to the Supreme Court is:

Whether the Federal Circuit erred by (1) refusing to find patent exhaustion in patented seeds even after an authorized sale and by (2) creating an exception to the doctrine of patent exhaustion for self-replicating technologies?

For information regarding this and other related topics, please see:

• "Supreme Court Grants Certiorari in Monsanto v. Bowman," October 22, 2012
• "Bowman Responds to Solicitor General," September 12, 2012
• "Solicitor General Recommends the Supreme Court Deny Cert in Bowman v. Monsanto," August 30, 2012

Image of New Year's Eve ball drop for 2012 in Times Square (above) by Replytojain, from the Wikipedia Commons under the Creative Commons Attribution-ShareAlike 3.0 Unported license.

Rep. Eshoo Expresses Views on Abbott's Biosimilars Petition in Letter to FDA

By Donald Zuhn --

While the U.S. Food and Drug Administration recently noted that the agency "has been unable to reach a decision" on a Citizen Petition regarding the Biologics Price Competition and Innovation Act (BPCIA) filed by Abbott Laboratories last April, the same cannot be said of California Representative Anna Eshoo, who sent a letter to the FDA expressing her views on Abbott's Petition less than three weeks after the Petition was filed.

Abbott filed the Petition on April 2, asking the agency to refrain from accepting biosimilar applications under the BPCIA that cite reference products (biologics) for which a biologics license application (BLA) was submitted to the FDA prior to March 23, 2010 (see "Abbott Asks FDA to Refuse Certain Biosimilar Applications").  The BPCIA, which provides an approval pathway for biosimilar biological products and constitutes a portion of the Patient Protection and Affordable Care Act that was signed into law on March 23, 2010, allows the FDA to accept biosimilar applications four years after a reference product has been licensed and to approve such applications twelve years after the reference product has been licensed.  In a letter sent to Abbott's counsel earlier this month, the FDA noted that it had "not yet resolved the issues raised in [Abbott's] citizen petition," explaining that the Petition "raises complex issues requiring extensive review and analysis by Agency officials" (see "FDA Continues to Review Abbott Petition on Biosimilars).

In a letter sent to FDA Commissioner Dr. Margaret Hamburg on April 20, Rep. Anna Eshoo (D-CA) provided a quick response to Abbott's Citizen Petition.  Rep. Eshoo (at right), who along with Rep. Jan Inslee (D-WA) and Rep. Joe Barton (R-TX) was one of the principal authors of the BPCIA, noted in her letter that the biosimilars regulatory pathway created by the BPCIA "balance[s] the need for patient access with incentives for innovation . . . by establishing 12 years of data exclusivity for innovator products."  The letter points out, however, that "[t]he BPClA clearly states that this period of exclusivity applies to all biologics and the expiration clock is retroactive" (emphasis added).

Rep. Eshoo writes that "[w]hile Abbott's Citizen Petition argues that pre-BPCIA approved biologic products cannot be subject to the law, l want to state very emphatically that it was Congressional intent for the new pathway to apply to biologics approved before and after the passage of the Affordable Care Act [i.e., March 23, 2010]" (emphasis added).  She notes that Congress "specifically designed the legislation this way in order to allow for immediate and/or impending use of biosimilars by patients at a lower cost and to capture the large savings which could be gained from top-selling biologics losing their exclusivity around time of passage."

Rep. Eshoo closes her letter by stating that:

Abbott's actions undermine the very legislation it supported during Congressional debate on this issue.  They were part of a broad coalition that supported the legislation and they never raised the issue throughout the legislative process.  Retroactive application of the 12 years of exclusivity was a guiding principle of the many discussions about the legislation to which Abbott was a party to every step of the way.

She concludes by urging the FDA to reject Abbott's Petition.

For additional information regarding this and other related topics, please see:

• "FDA Continues to Review Abbott Petition on Biosimilars," October 24, 2012
• "Abbott Asks FDA to Refuse Certain Biosimilar Applications," April 23, 2012
• "Representatives Oppose President's Attempt to Reduce Data Exclusivity Period," October 17, 2011
• "Legislators Urge President to Include 12-Year Data Exclusivity Period in Free Trade Agreement," August 15, 2011
• "House Legislators Lobby to Exclude 12-Year Data Exclusivity Period from Free Trade Agreement," Auguts 11, 2011
• "Representatives Send Letter to FDA to Explain Data Exclusivity Provisions of Biosimilars Legislation," January 9, 2011
• "Snatching Defeat from the Jaws of Victory?" January 17, 2010

FDA Continues to Review Abbott Petition on Biosimilars

By Donald Zuhn --

In April, Abbott Laboratories filed a Citizen Petition with the U.S. Food and Drug Administration, asking the agency to refrain from accepting biosimilar applications under the Biologics Price Competition and Innovation Act (BPCIA) that cite reference products (biologics) for which a biologics license application (BLA) was submitted to the FDA prior to March 23, 2010 (see "Abbott Asks FDA to Refuse Certain Biosimilar Applications").  The BPCIA, which provides an approval pathway for biosimilar biological products and constitutes a portion of the Patient Protection and Affordable Care Act that was signed into law on March 23, 2010, allows the FDA to accept biosimilar applications four years after a reference product has been licensed and to approve such applications twelve years after the reference product has been licensed.

In its Petition, Abbott specifically asked the FDA to:

[C]onfirm that it will not accept for filing, file, approve, or discuss with any company, or otherwise take any action indicating that the agency will consider, any application or any investigational new drug application (IND) for a biosimilar that cites, as its reference product, BLA 125057 for Humira® (adalimumab) or any other product for which the biologics license application (BLA) was submitted to FDA prior to March 23, 2010, the date on which the BPCIA was signed into law.

Abbott explained that the FDA should refuse biosimilar applications for all pre-enactment reference products, including its own biologic Humira®, because to approve such applications would constitute a taking under the Fifth Amendment of the U.S. Constitution, which requires just compensation.  Noting that "[a]n innovator's resulting license application typically reflects more than a decade of research and contains analytical, preclinical, and clinical data, as well as detailed manufacturing information, most of which qualifies as trade secrets," Abbott contended that "[t]hese trade secrets are the private property of the reference product sponsor and are therefore protected by the Fifth Amendment to the U.S. Constitution."  According to Abbott's Petition, "[w]hen FDA approves a biosimilar biological product on the grounds that the reference product has been shown safe, pure, and potent, it uses these trade secrets.

In a letter sent to Abbott's counsel on October 1, the FDA noted that it had "not yet resolved the issues raised in [Abbott's] citizen petition."  The letter, which was sent by Jane Axelrad, Associate Director for Policy for the Center for Drug Evaluation and Research (CDER) at the FDA, states that the agency "has been unable to reach a decision on [Abbott's] petition because it raises complex issues requiring extensive review and analysis by Agency officials."  The FDA's letter was provided in accordance with 21 C.F.R. 10.30(e)(2), which requires that the agency respond to a citizen petition within 180 days of receipt by approving the petition, denying the petition, or providing a "tentative response" indicating why the agency has been unable to reach a decision on the petition.  The FDA's letter closes by noting that the agency will respond to the petition as soon as it reaches a decision on Abbott's request.

Additional information regarding the citizen petition can be found here.

House Passes User Fee Bill

By Kevin E. Noonan --

Less than a week after the Senate passed its version of a bill amending the user fee provisions of the Food, Drug and Cosmetic Act (FDCA) for funding FDA review of innovator and generic drugs, medical device and biosimilars (S. 3187; Food and Drug Administration Safety and Innovation Act), the House passed its own version of the bill (H.R. 5651; Food and Drug Administration Reform Act of 2012).  The bill was passed by a vote of 387-5 (with 39 abstentions); the naysayers include Reps. Ron Paul (R-TX-14), Tom McClintock (R-CA-4), Justin Amash (R-MI-3), Raul Labrador (R-ID-1), and Maurice Hinchey (D-NY-22).  Like the Senate bill, the House version reauthorizes prescription drug (PDUFA; Title I) and medical device (MDUFA; Title II) user fees, as well as establishing new user fees for generic drugs (GDUFA; Title III) and biosimilars (BsUFA; Title IV).

The bill is not yet ready for President Obama's signature, however; there are several differences between the Senate and House bills that have been conveniently compared in tabular form by the Congressional Research Service.  There are no significant differences between the bills regarding the biosimilars provisions discussed in an earlier post regarding the Senate bill provisions (see "Senate Passes User Fee Bill").  Notable differences include no counterpart to Senator Coburn's amendment to the Senate bill (Section 723) requiring the Secretary to contract with a "private, independent" consulting firm to assess agency performance of its premarket review of drug applications.  The House bill contains provisions not found in the Senate bill, for example that extend the time for agency approval after an ANDA is filed from 30 months to 45 months.

It is estimated that the bill could be ready for the President's signature by mid-summer.