Patent Docs

FDA Releases "Final" Guidances for Industry regarding the Biosimilar Approval Pathway

    By Kevin E. Noonan --

About three years ago, and less than two years after Congress passed and President Obama signed the Biologics Price Competition and Innovation Act (BPCIA) into law, the U.S. Food and Drug Administration issued a series of draft Guidances indicating how it was considering implementing the biosimilar approval pathway contained in the Act.  The Guidances (see "FDA Publishes Draft Guidelines for Biosimilar Product Development" and "More on FDA Draft Guidelines for "Follow-on" Biologic Drug Approval Pathway") were expressly "draft" in nature, and were the subject of public hearings with the Agency welcoming industry input.  This input was necessary; even a cursory review of the pathway provisions of the law would strike one with the frequency with which Congress delegated to the FDA the details of setting out the requirements for biosimilar approval.  This did not come as a shock, it being rational that Congress should recognize that Agency expertise was particularly important in developing standards for approving drugs as complex as biosimilars under circumstances where the "follow-on biologic" drugs were frankly not identical to the approved reference biologic product.

In April the Agency released "final" Guidances that look remarkably like the originals; these Guidances are entitled:

• Scientific Considerations in Demonstrating Biosimilarity to a Reference Product [link]

• Quality Considerations in Demonstrating Biosimilarity of a Therapeutic Protein Product to a Reference Product [link]

• Biosimilars: Questions and Answers Regarding Implementation of the Biologics Price Competition and Innovation Act of 2009 [link]

The FDA has released an additional, more explicit Guidance related to the requirements for establishing biosimilarity since promulgating these first three (see "FDA Releases Draft Guidance on Biosimilars: Sets Forth Clinical, Pharmacology Data Sufficient to Support Biosimilarity") as well as a Guidance on market exclusivity (see "FDA Releases Another Prospective Guidance").  More importantly, the Agency recently approved the first biosimilar drug in the U.S. (see "FDA Approves Sandoz Filgrastim Biosimilar").  But as noted in the letter from several Senators discussed yesterday (see "Senators Send Letter on Biosimilars to FDA"), this progress has not come fast enough for some.  In addition, the Agency has made at least one no-decision decision (using an "interim" non-proprietary name for Sandoz XARZIO^TM product (filgastrim–sndz)) and has not yet addressed the standards for interchangeability.  However, such carping seems unfairly critical from the institution that left it to the Agency to actually develop a biosimilars pathway and, of course, be ready to take the blame for any problems arising along the way.

Amgen Receives No Help from the FDA -- A Biosimilar Update

By Andrew Williams --

Near the end of last month, the U.S. Food and Drug Administration ("FDA") denied a citizen petition filed by Amgen in which it requested that action be taken to ensure that biosimilar applicants comply with the disclosure and exchange provisions described in the Biologics Price Competition and Innovation Act ("BPCIA").  Amgen had filed its petition on October 29, 2014, after Sandoz refused to disclose a copy of its biosimilar application related to Amgen's NEUPOGEN^® (filgrastrim) biologic drug product.  More precisely, Sandoz had alleged that the disclosure provision of the BPCIA was not mandatory.  Instead, as noted in the petition, Sandoz had independently offered to provide Amgen with the information, but with conditions and restrictions not found in the statute.  Amgen requested in the petition that the FDA require all new biosimilar applicants to certify that they would comply with the disclosure provisions (in a manner similar to how an ANDA filer must provide a certification in the Hatch-Waxman context).  However, the FDA denied this request because the provisions of the BPCIA do not in fact impose such a certification requirement, which stands in opposition to the explicit certification requirement for ANDA filers as found in the Hatch-Waxman statute.

Of course, this comes on the heels of the Northern District of California's denial of Amgen's motion for a preliminary injunction and partial judgement on the pleadings in the Amgen v. Sandoz case.  As previously reported here, the Court in that case sided with Sandoz in determining that the disclosure provisions were not mandatory.  In large part, the Court based its decision on the fact that, even though the BPCIA states that the biosimilar applicant "shall provide to the reference product sponsor a copy of the application," and other information related to the manufacturing process, the statute also provides the "penalty" for not so disclosing.  Essentially, Sandoz was just opting for the penalty -- being subject to "an action under section 2201 of Title 28, for a declaration of infringement, validity, or enforceability of any patent that claims the biological product or a use of the biological product."  42 U.S.C. § 262(l)(9)(C).  The obvious problem, however, is that a product sponsor will likely not be aware of which patents it can assert in the absence of such a disclosure.

In its citizen petition to the FDA, Amgen again alleged that the disclosure provisions and patent exchanges dictated by the BPCIA -- the so-called biosimilar "patent dance" -- were mandatory, not optional or discretionary.  Amgen pointed to the text and the history of the statute for the support.  In fact, without the initial disclosure by the biosimilar applicant, the "patent dance" cannot even begin.  "All of these provisions quickly become nullities if biosimilar applicants are free to simply ignore the requirements of § 351(l)(2)(A)," Amgen asserted.  This can become an even more serious issue when considering "interchangeable" biosimilar products.  Such products earn a period of exclusivity tied in part to any potential litigation.  As such, it would behoove a biosimilar applicant to delay, or even eliminate, any litigation by not disclosing its application or manufacturing information.  Indeed, if a biosimilar applicant were not required to disclose that it had, in fact, filed an application, it could maintain the fact that it had filed an application secret.  This could not have been what Congress intended, Amgen contended.

Momenta Pharmaceuticals also submitted a paper to the FDA in response to Amgen's citizen petition on November 25, 2014.  This paper echoed Momenta's comments that it submitted to the FDA in May 2012, expressing concern that the "patent dance" provisions of the BPCIA would be converted to an FDA regulated regime.  Instead, Momenta alleged that granting Amgen's petition would be contrary to the intent of Congress.  Specifically, Momenta asserted that Congress intended:

• to separate the FDA from the patent resolution process;
• to allow applicants to choose to engage in the patent exchange process at the time a 351(k) Application is filed when appropriate;
• to provide reference biologic sponsors with procedural patent exchange protections should applicants elect to seek patent resolution early; and
• to allow for specific remedies should applicants elect not to seek patent resolution prior to commercial launch.

In the end, the FDA sided with Momenta and denied Amgen's petition.  "Neither section 351(k) nor section 351(l) requires the FDA to impose certification requirements as part of the biosimilar review process."  This is, again, in contrast to the Hatch-Waxman statute, which requires ANDA filers to certify regarding each patent listed in the FDA's Orange Book.  "Viewed against the explicit requirements under the FD&C Act, the Petition's contention that FDA 'should' require a certification for biosimilar applications implicitly acknowledges that imposing such a requirement is a matter of regulatory discretion and not compelled under the PHS Act."  With regard to that discretion, the FDA noted that the issue about whether the disclosure provisions were mandatory was being resolved in the Federal courts.  Nevertheless, the FDA did provide Amgen with a glimmer of hope, if not for now than for the future:  "In light of the ongoing litigation regarding interpretation of section 351(l) of the PHS Act, at this time, the Agency denies the request to exercise its discretion to require biosimilar applications to include a certification to FDA that the applicant will timely comply with section 351(l)(2)(A) of the PHS Act" (emphasis added).  Of course, this likely provides little solace to Amgen, because if it does receive a favorable ruling on appeal in the Amgen v. Sandoz case, such FDA action will not be necessary.

FDA Approves Sandoz Filgrastim Biosimilar

By Kevin E. Noonan --

On Friday, the Food and Drug Administration approved a biosimilar version of Amgen's Neupogen® (filgrastim) product for sale in the U.S.  This is the first biosimilar to be approved under the provisions of the Biologics Price Competition and Innovation Act (BPCIA), which was part of the healthcare reform package passed in 2010 and commonly referred to as "Obamacare."  Sandoz (a division of Novartis) will sell its biosimilar under the brand name Zarxio™.

The drug is a recombinantly produced version of human granulocyte colony stimulating factor (methionyl-human granulocyte colony stimulating factor or r-metHuG-CSF) and is used to stimulate neutrophil production in patients undergoing chemotherapy.  Amgen has obtained FDA approval for Neupogen® for treating the following five conditions:

• Cancer patients receiving myelosuppressive chemotherapy;
• Cancer patients with acute myeloid leukemia receiving induction or consolidation chemotherapy;
• Cancer patients undergoing bone marrow transplantation;
• Patients undergoing autologous peripheral blood progenitor cell collection and therapy; and
• Patients with severe chronic neutropenia.

Sandoz provided the FDA with a wide variety of evidence of biosimilarity since it filed its application under Section 351(k) of the Public Health Service Act last July; this evidence included "structural and functional characterization, animal study data, human pharmacokinetic and pharmacodynamics data, clinical immunogenicity data and other clinical safety and effectiveness data" and, importantly, an absence of immunogenicity in human subjects, together demonstrating the biosimilarity of Sandoz product Neupogen® according to the FiercePharma website.  In particular, Sandoz performed a head-to-head comparison between its biosimilar drug and Neupogen® showing a level of biosimilarity sufficient for the FDA to approve Zarxio™ for all of Amgen's approved indications.

Neupogen® is a $1.2-1.4 billion dollar per year product for Amgen and part of the significance of FDA approval is economic.  Industry estimates have Sandoz selling Zarxio™ for 15-30% less than Amgen's current price, which estimates are expected to reduce the cost of the drug by an equivalent amount once this biosimilar becomes accepted by physicians.  Unlike conventional "generic," generally small molecule, drugs (which cause upwards of 90% reductions in drug prices from the innovator brand price), biosimilar drugs are both more complex than small molecule drugs and are administered by physicians (typically by injection) and thus continue to actively involve medical personnel during a course of treatment.  Consequently, physician acceptance of biosimilar drugs is much more of an issue than for generic drugs and thus market penetrance is expected to be delayed for 1-5 years, even by Sandoz.  These estimates are in line with industry expectations for biosimilar drugs in general; for example, Express Scripts has estimated that while U.S. healthcare costs may be reduced by about $250 million between 2015 and 2025, biosimilar sales worldwide will only increase from $1.3 billion to $35 billion by 2020, even taking into account the robust approval climate for biosimilar drugs on Europe (where the EMEA has approved 21 biosimilar drugs over the past 10 years; it should be noted that cost savings in Europe from biosimilars amount to about a 10% reduction).

(For those paying attention, another reason that marketing of Sandoz's Zarxio™ product may be delayed is that Amgen and Sandoz are embroiled in litigation over whether Sandoz is required to participate in the litigation provisions of the BPCIA); that case is ongoing (see "'No Clinically Meaningful Differences': The First Accepted Biosimilar Application Has Been Recommend for FDA Approval").

The other basis for considering approval of Zarxio™ to be significant is that, as the first biosimilar approved, it will be a bellwether for how well the FDA has implemented the BPCIA and performed in its role in protecting public health.  The complexity of both biologic drugs themselves (which typically comprise thousands of atoms; the chemical formula of filgrastim for example is C₈₄₅H₁₃₄₃N₂₂₃O₂₄₃S₉) and the methods by which they are made (typically using recombinant cells expressing genetically engineered genes transferred from one organism (here, human) to another such as bacteria) provide much greater challenges for the agency in performing its review of safety, potency and efficacy.  While the EMEA in Europe has successfully approved biosimilar drugs for a decade, in the U.S. doubts are likely to remain until experience (both the agency's and the public's) has shown them to be unfounded.

There is one aspect of the FDA's approval of Zarxio™ that remains controversial, and that is the non-proprietary (or common) name the agency has given to Sandoz's product.  The name, filgrastrim-sndz, has been called a "placeholder" by the agency because it has not yet decided whether to give different names to biosimilar versions of branded biologic drugs (as innovator biotechnology companies have advocated to ensure that any adverse events be properly ascribed to the biosimilar) or to use the same name as the innovator biologic drug (as urged by groups like the Generic Pharmaceutical Association (GPhA) and health organization to minimize the chance of confusion by medical personnel).  These sentiments were voiced on Friday by Ralph G. Neas, President and CEO of GPhA, who stated that his organization "reiterate[s] our stance that the Agency's departure from the currently accepted international nonproprietary name (INN) system could disrupt the ability to track and dispense these medicines, risking provider confusion and patient safety."

One thing the FDA did not do was approve Zarxio™ as an interchangeable product, because inter alia the agency has not yet developed standards for making this determination.  In addition to the absence of "no clinically meaningful differences" required to be shown between the branded (or reference product sponsor's) product and the biosimilar drug for approval as a biosimilar, to be interchangeable there must be no differences in outcomes when a patient is switched to an interchangeable biosimilar drug product than occur when the innovator's product is administered.  Interchangeability when achieved will have the advantage that switching to the interchangeable version will not require physician approval and will be eligible for at least a one-year exclusivity period for the successful interchangeable biosimilar applicant.

This is but the first of many biosimilar approvals waiting FDA action; these include applications by Apotex for its version of Neupogen® (which was accepted by the FDA last month and is sold in Europe under the name Grastofil) as well as a biosimilar version of Amgen's Neulasta® (a PEGylated version of the molecule).  Pundits and politicians have pontificated about the benefits to be had by adopting a biosimilar approval pathway in the U.S., and those predictions have begun the process of being tested with approval of Zarxio™.

23andMe Receives FDA Approval for Genetic Diagnostic Test

By Kevin E. Noonan --

Last Thursday the genetic diagnostic and DNA analysis company 23andMe announced that the FDA had granted the company approval to market a genetic diagnostic test for Bloom's Syndrome, the first such approval for this rare genetic disease.  The news is tempered by the company's further announcement that it will not offer the test to consumers "until it completes the regulatory process for additional test reports and can offer a more comprehensive product offering."

Readers may recall that the FDA effectively stopped 23andMe from selling its genetic analysis kit, which the company marketed as Personal Genomic Services (PGS) in November 2013 by issuing a Warning Letter to the Company (see "FDA Threatens Agency Action Against 23andMe Over Personal Genetic Testing").  According to the FDA, genetic diagnostics assays fall under the agency's purview and authority because they are medical devices (21 U.S.C. § 321(h)).  According to the letter, the testing service offered "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."  At that time, the agency professed a desire to work with the company to assist in developing the type and quantity of evidence required for approval, but warned that it had spent "significant time" evaluating the PGS test and providing feedback to 23andMe.  It appears that the company complied with the agency by submitting the evidence for approval of a much more limited test (i.e., limited to Bloom's Syndrome), compare to the tests offered previously (which included more that 250 "diseases and conditions" such as BRCA gene mutations, diabetes, coronary artery disease, an sensitivities to drugs such as warfarin, clopidigrel and 5-fluorouracil).

The test is described as a "spit test kit and a chip array platform," and approval is limited at this time to detecting genetic markers for Bloom's syndrome.  Bloom's syndrome is a genetic disease inherited in an autosomal recessive manner, that predisposes individuals to certain cancers and is also associated with short stature, sensitivity to sunlight exposure and shortened lifespan.  The locus of the mutation is in the BLM gene on chromosome 15 (at 15q26.1) and encodes a DNA helicase.  Defects in this gene cause a dramatic (~ten-fold) increase in homologous recombination in cells from affected individuals, resulting in genomic instability.  Genetic testing is the only way to predict risk for passing the disease to offspring, as parents having only one copy of the gene show no symptoms.

The FDA's decision to permit 23andMe to offer the test, while important to the company and to those individuals who may be at risk for passing on the Bloom's syndrome trait to their children, is also significant for the type of testing the FDA required and the evidence it mandated for approval.  For example, 23andMe in an announcement stated that it "conducted extensive comprehension studies with consumers from different backgrounds, education levels and incomes," as well as test accuracy and validity.

The company's future in the genetic diagnostics space remains uncertain, however, in view of the following disclaimer on its website:

Updated February 19, 2015b: 23andMe provides ancestry-related genetic reports and uninterpreted raw genetic data only.  We intend to add some health-related genetic reports in the future once we have a comprehensive product offering.  At this time, we do not know which health reports might be available or when they might be available.

A disturbing note was struck by Alberto Guitierrez, Director of the Office of In Vitro Diagnostics and Radiologic Health in the agency's Center for Devices and Radiologic Health, who stated that "[t]he FDA believes that in many circumstances it is not necessary for consumers to go through a licensed practitioner to have direct access to their personal genetic information," and that the FDA intended to "exempt these devices from FDA premarket review."  How disturbing this sentiment may be will depend on how widespread access to genetic testing becomes and the extent to which providers such as 23andMe provide information to consumers receiving this information; indeed, the company's disclaimer suggests that FDA action has encouraged it not to provide any interpretation for the "raw genetic data" it supplies to consumers.  For all the criticism that has been leveled against Myriad (some of which may have been justified) the company acted responsibly by ensuring that its customers had access to genetic counselors who explained the significance of their test results and provided options for accommodating the consequences of any propensities their genetics disclosed.  Among all the negative press Myriad received there were two types of stories that did not appear: one, that the company had provided a misdiagnosis (of either type); and two, that someone had decided to end their life because they misinterpreted the results of their test or its implications on their health.  Minimizing the risk of the latter outcome will depend even more heavily on adequate counseling as more individuals have more tests for more genetic diseases, particularly as those diseases expand to include those that are less determinative than tests like the BRCA test or 23andMe's Bloom's Syndrome test and as there are more opportunities for behavioral modifications that could modulate patient outcomes.  Mr. Gutierrez is also reported to have said that authorization of 23andMe's test "supports innovation and will ultimately benefit consumers."  But that innovation will be costly if it is not accompanied by the appropriate amount of interpretation so individuals can make the best-informed choices for themselves.

Guest Post: 41 New Drugs Approved in '14 -- A Random Spike or a Growing Trend of Drug Innovation?

By Cambria Alpha-Cobb* and Anthony D. Sabatelli** --

If innovation drives progress, then 2014 was the year of progress!  During the past year the U.S. Food and Drug Administration approved 41 new drugs.  That is 14 more than 2013 and the highest number in 18 years!  What spurred this increase?  And what challenges do these new drugs face in the 2015 market?

The FDA publishes the drug approval data based on New Molecular Entities (NMEs) [1].  These drugs can be both the traditional small molecule drugs in addition to newer high-molecular weight biologics.  For information on NMEs and how they are classified, see "The Scorecard- Fewer New Drug Approvals in 2013: What's in store for 2014?" [2] a previous blog post by Dr. Anthony Sabatelli.  Using data published annually from the FDA, we plotted the number of approved NMEs since the 1940s [1][3], below.  After a dramatic peak in 1996, our plot shows a steady decline in approvals, followed by very little turnaround throughout the first decade of the 21st century and then a slow recovery in the past few years.  Not only does this 2014 spike continue a slow upward trend, but also the new generation of drugs it embodies is believed to represent key advances in new drug development, suggesting a more broad-based recovery [4].

One of the main changes to the drug pipeline has been the expansion of treatment options. Many of the breakthrough discoveries from the past year are diverging from the traditional small molecules into whole new technologies and therapies. Nearly 4 out of 10 of the approved NMEs in 2014 were for biologics, a dramatic increase from 1 in 10 biologic NMEs approved in 2005 [5]. The 2014 NMEs spanned 10 therapeutic areas, up from 8 last year, with infectious diseases dominating with 12 approvals [4]. Next in line were approvals for cancer treatments (8) and rare disease drugs (5), emphasizing the industry's focus on specialized products [6].

Chart of New Molecular Entities approved: Annual approved NMEs based on data from [1] and [3].

While this innovation is helping restore our faith in the drug industry, these drugs are arriving into a market where high prices are coming under attack, and more competition will only increase these attacks.  Fierce Pharma identified six therapeutic areas, including some rare diseases and cancer treatment, where increased competition could lead to heavy price competition [7].  This competition raises questions about future commercial prospects and could suggest reduced future development efforts due to these new pricing pressures [8].

As John Carroll, editor of Fierce Biotech, states, "Approvals aren't enough to determine whether a pipeline strategy is successful or not." [8]  However 2014 was the best year since 1996, and the innovative technologies provide encouragement that this spike might be part of a long-lived trend.  Competition in pricing may hinder the sales of some of these new drugs, however the future is promising as firms venture from their comfort zones and embrace these breakthrough discoveries [8].

* Dr. Cambria Alpha-Cobb is a Technology Specialist at Dilworth IP
** Dr. Sabatelli is a Partner with Dilworth IP

---

[1]http://www.fda.gov/Drugs/DevelopmentApprovalProcess/DrugInnovation/ucm20025676.htm
[2]http://www.dilworthip.com/scorecard-fewer-new-drug-approvals-2013-whats-store-2014/
[3]http://www.fda.gov/AboutFDA/WhatWeDo/History/ProductRegulation/SummaryofNDAApprovalsReceipts1938tothepresent/default.htm
[4]http://www.forbes.com/sites/bernardmunos/2015/01/02/the-fda-approvals-of-2014/
[5]http://www.fda.gov/Drugs/DevelopmentApprovalProcess/HowDrugsareDevelopedandApproved/DrugandBiologicApprovalReports/NDAandBLAApprovalReports/ucm373420.htm
[6]http://in.reuters.com/article/2015/01/01/pharmaceuticals-approvals-idINL6N0UE2C120150101
[7]http://www.fiercepharma.com/story/limited-attention-span-focus-these-market-shake-ups-2015/2014-12-24
[8]http://www.fiercebiotech.com/special-reports/biopharma-posts-chart-topping-41-new-drug-approvals-2014/2015-01-02?utm_medium=nl&utm_source=internal

Top Stories of 2014: #10 to #7

By Donald Zuhn --

After reflecting upon the events of the past twelve months, Patent Docs presents its eighth annual list of top patent stories.  For 2014, we identified eighteen stories that were covered on Patent Docs last year that we believe had (or are likely to have) the greatest impact on patent practitioners and applicants.  On New Year's Eve, we counted down stories #18 to #15, and on New Year's Day, we covered stories #14 to #11.  Today, we count down stories #10 to #7 as we work our way towards the top three stories of 2014.  As with our other lists (2013, 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 2014" on January 20, 2015 from 10:00 am to 11:15 am (CT).  Details regarding the webinar can be found here.

10.  While FDA Accepts First Biosimilar Application, Some Biosimilar Applicants Try to Bypass BPCIA

In July, Sandoz announced that the U.S. Food and Drug Administration had accepted its application to market a version of the protein filgrastim.  The reference product is Amgen's NEUPOGEN®.  Sandoz markets a biosimilar filgrastim outside the U.S. under the brand name ZARZIO®.  Interestingly, in October, Amgen announced the results of a Phase III clinical trial of its own biosimilar drug (designated ABP 501) for moderate-to-sever plaque psoriasis conducted in comparison with adalimumab (sold by AbbVie as Humira®).  Amgen and Sandoz were both involved in a BPCIA dispute that was resolved by the Federal Circuit in December.  In what some perceived as an attempt to sidestep the requirements of the BPCIA, Sandoz filed a declaratory judgment action against Amgen and Roche related to its etanercept biosimilar drug product, which it developed to compete with Amgen's Enbrel® TNF inhibitor.  In Sandoz v. Amgen, the Federal Circuit affirmed the District Court's dismissal of Sandoz's suit because "Sandoz did not allege an injury of sufficient immediacy and reality to create subject matter jurisdiction."  In other biosimilar developments, the FDA issued a "Guidance for Industry" in August entitled "Reference Product Exclusivity for Biological Products file under Section 351(a) of the PHS Act."  The Guidance provides some grounds for determining the term of market exclusivity under the BPCIA (12 years; Sec. 351(k)(7), codified at 42 U.S.C. 55 262(k)).

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

• "Celltrion Healthcare Co. v. Kennedy Trust for Rhematology Research (S.D.N.Y. 2014); Hospira Inc. v. Janssen Biotech Inc. (S.D.N.Y. 2014)," December 11, 2014
• "Sandoz Inc. v. Amgen Inc. (Fed. Cir. 2014)," December 9, 2014
• "Amgen Poised to Enter Biosimilars Market," October 8, 2014
• "FDA Releases Another Prospective Guidance," August 13, 2014
• "Finally, A Biosimilar Application Has Been Accepted By The FDA ," July 28, 2014
• "FDA Releases Draft Guidance on Biosimilars," May 14, 2014
• "Indiana Governor Signs Biosimilar Substitution Bill," April 10, 2014

9.  Congress and Tech Sector Wage Battle Against Patent Trolls

Despite having passed patent reform legislation -- the Leahy-Smith America Invents Act -- in September 2011, many in the patent community expected Congress to pass another piece of patent reform legislation in 2014 -- this time addressing patent litigation and the problem of so-called patent trolls.  However, after taking up and tabling legislation in March and April, Senator Patrick Leahy (D-VT), Chairman of the Senate Committee on the Judiciary, announced that he was taking the Patent Transparency and Improvements Act of 2013 (S. 1720) off the Committee's agenda because of a lack of "sufficient support behind any comprehensive deal."  Meanwhile, the tech sector continued to lobby for patent litigation reform.  Congress may take up patent reform again this year.

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

• "More Misinformation Regarding the Patent System and Non-Practicing Entities," December 18, 2014
• "Patent Litigation Reform -- Will the Outcome of the Mid-Term Elections Matter, and Is Reform Still Necessary?" October 30, 2014
• "Teva v. Sandoz -- Is Deferential Review a Boon for Patent Trolls?" October 14, 2014
• "House Tries One More Time: Targeting Rogue and Opaque Letters Act of 2014 ("TROL Act")," July 17, 2014
• "Patent Reform Legislation Off The Table -- For Now," May 21, 2014
• "Senate Judiciary Committee Tables Patent Reform, Again," April 3, 2014
• "Stopping Bad Legislation -- The Innovation Alliance Speaks Out," April 2, 2014
• "Stopping Bad Patents -- Senator Schumer Takes on the "Patent Trolls"," April 1, 2014
• "New York Times Op-Ed Argues Law Takes Misguided Approach to Software Patents," March 30, 2014
• "Senate Judiciary Committee Takes Up, Then Tables, Patent Reform," March 27, 2014
• "A Rebuttal to The Economist's "Stalking Trolls"," March 13, 2014
• "Senate Legislation Update -- The Commerce Committee Gets in the Act," March 5, 2014

8.  Courts and PTAB Deal with Fallout of Alice Corp. v. CLS Bank

In June, the Supreme Court issued its opinion Alice Corp. v. CLS Bank International, affirming the Federal Circuit's per curiam opinion in CLS Bank International v. Alice Corp. (stay tuned for more on that decision as we move closer to the top three stories of 2014).  However, the impact of the Supreme Court's Alice Corp. opinion on Federal Circuit and Patent Trial and Appeal Board decisions made it to #8 on the list.  Patent Docs covered nine such decisions during the second half of 2014, and in only one case (DDR Holdings, LLC) did the Federal Circuit conclude that computer-implemented claims survive a § 101 challenge.  Readers can look for more discussion of this top story, as well as the Supreme Court's Alice Corp. decision, during our live webinar on the "Top Patent Law Stories of 2014" on January 20, 2015.

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

• "DDR Holdings, LLC v. Hotels.com, L.P. (Fed. Cir. 2014)," December 8, 2014
• "Ultramercial Inc. v. Hulu LLC (Fed. Cir. 2014)," November 16, 2014
• "Ultramercial Inc. v. Hulu LLC -- Party Briefs," November 6, 2014
• "Cambridge Assoc., LLC v. Capital Dynamics (PTAB 2014); PNC Bank v. Secure Axcess, LLC (PTAB 2014)," October 16, 2014
• "U.S. Bancorp v. Solutran, Inc. (PTAB 2014)," September 10, 2014
• "Planet Bingo, LLC v. VKGS LLC (Fed. Cir. 2014)," August 27, 2014
• "I/P Engine, Inc. v. AOL Inc. (Fed. Cir. 2014)," August 18, 2014
• "Stewart Title Guaranty Co. v. Segin Software, LLC (PTAB 2014)," July 23, 2014
• "Digitech Image Technologies, LLC v. Electronics For Imaging, Inc. (Fed. Cir. 2014)," July 14, 2014
• "Cyberfone Systems, LLC v. CNN Interactive Group, Inc. (Fed. Cir. 2014)," March 3, 2014
• "SmartGene, Inc. v. Advanced Biological Laboratories, SA (Fed. Cir. 2014)," January 29, 2014

7.  Supreme Court Addresses Fee Shifting Determinations in Exceptional Cases

In April, the Supreme Court issued opinions in Octane Fitness, LLC v. ICON Health & Fitness, Inc. and Highmark Inc. v. Allcare Health Mgmt. Sys., Inc.  The issue in both cases centered on the attorney fee-shifting provision of 35 U.S.C. § 285.  In Octane Fitness, a mostly unanimous court held that "an 'exceptional' case is simply one that stands out from others with respect to the substantive strength of a party's litigating position (considering both the governing law and the facts of the case) or the unreasonable manner in which the case was litigated," the Court leaving the determination of whether a case is "exceptional" to the discretion of the District Court judge.  In Highmark, the Supreme Court determined that "an appellate court should apply an abuse-of-discretion standard in reviewing all aspects of a district court's §285 determination," even though "questions of law may in some cases be relevant to the §285 inquiry."  The Supreme Court's decisions make it easier for a trial court to shift fees to the non-prevailing party if it believes that the litigation was brought or conducted in an abusive manner, and also make it more difficult for an appellate court to overturn such a determination.

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

• ""Standing Out" -- A Closer Look at the "Exceptional Case" Standard Articulated in Octane Fitness," April 29, 2014
• "Patent Trolls Beware -- Supreme Court Issues Decisions in Octane Fitness and Highmark," April 29, 2014
• "Oral Arguments in the Supreme Court Octane Fitness, LLC v. ICON Health & Fitness, Inc. Case," February 27, 2014
• "Supreme Court to Hear Oral Arguments in Attorney Fee Shifting Cases," February 25, 2014
• "Supreme Court Preview -- Highmark Inc. v. Allcare Health Mgmt. Sys., Inc.," February 19, 2014
• "Supreme Court Preview -- Octane Fitness, LLC v. ICON Health & Fitness, Inc.," February 13, 2014

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.