Patent Docs

GW Pharmaceuticals Wins FDA Approval of First CBD Drug

By Nicole Grimm, George "Trey" Lyons, III, and Brett Scott --

On June 25, 2018, GW Pharmaceuticals plc and its U.S. subsidiary, Greenwich Biosciences, made history in the cannabis industry by winning FDA approval of the drug Epidiolex, a cannabidiol (CBD) oral solution for the treatment of seizures associated with two rare forms of childhood-onset epilepsy (Lennox-Gastaut syndrome and Dravet syndrome).[1]  Both Lennox-Gastaut syndrome and Dravet syndrome are debilitating forms of epilepsy that have been known to be difficult to treat.  Epidiolex is the first FDA-approved drug containing plant-derived CBD, a non-psychoactive cannabinoid naturally produced by cannabis plants.

In approving Epidiolex, the FDA voiced support for further research and studies on medical uses for cannabis through its approval process.  According to FDA Commissioner Scott Gottlieb:

Controlled clinical trials testing the safety and efficacy of a drug, along with careful review through the FDA's drug approval process, is the most appropriate way to bring marijuana-derived treatments to patients . . . .  We'll continue to support rigorous scientific research on the potential medical uses of marijuana-derived products and work with product developers who are interested in bringing patients safe and effective, high quality products.[2]

However, Commissioner Gottlieb cautioned that the FDA is prepared to take action against illegal CBD-products marketed with unproven medical claims.

FDA approval of Epidiolex may also prompt the Drug Enforcement Administration (DEA) to reschedule CBD from a Schedule I drug under the Controlled Substances Act, which would be another historic event for the cannabis industry.  And, in spite of Attorney General Jeff Sessions's continuing war on cannabis, President Trump has indicated support for such a shift.[3]

Rescheduling Epidiolex is necessary for the drug to become available to patients in the U.S.  As part of the approval process, the FDA, through the Department of Health and Human Services, makes recommendations to the DEA regarding scheduling based on scientific and medical studies of scheduled substances such as Epidiolex.  In turn, the DEA is required to make a scheduling determination.  Additionally, in making its determination, the DEA will likely consider the results of clinical and nonclinical studies regarding the abuse potential of CBD that GW Pharmaceuticals conducted as part of its application for Epidiolex.  Although the FDA did not indicate whether it provided a favorable scheduling recommendation for Epidiolex, GW Pharmaceuticals stated in its press release that it expects the DEA to reschedule the drug in the next 90 days.

Rescheduling Epidiolex from a Schedule I drug may have implications for GW Pharmaceuticals' intellectual property surrounding the drug as well.  First, enforcing cannabis patents in federal district courts remains a grey area in the industry since cannabis is currently classified as a Schedule I drug.  By rescheduling Epidiolex, the drug will become legally available by prescription, and GW Pharmaceuticals should be able to enforce the patents covering Epidiolex like any other pharmaceutical patent.  In turn, the company may also experience an increase in inter partes review (IPR) proceedings to challenge patents in its portfolio.  As we have previously discussed, one of GW Pharmaceutical's patents involving treating partial seizure by administering CBD is already involved in an IPR proceeding.

Additionally, while the USPTO has categorically declined to grant trademarks based on the cannabis plant itself (and derivatives thereof), as well as cannabis goods and services that contribute to federally illegal activity (often referred to as those that "touch the plant"), rescheduling cannabis-based pharmaceuticals like Epidiolex may help eliminate any hurdles faced in obtaining federal trademark protection for such pharmaceuticals.  Indeed, unlike Schedule I drugs, scheduled prescription drugs have a legal use in commerce and are therefore routinely granted federal trademark protection.  In fact, the USPTO has already granted a trademark for Epidiolex; but note, in doing so the drug was described broadly, without referring to federally prohibited subject matter (e.g., cannabis), and instead referring to, for example, "medicinal herbs" and "medicinal infusions for the treatment of epilepsy."

Either way, right now the approval and tentative rescheduling of Epidiolex is a step in the right direction and could pave the way for other cannabis-based drugs to gain FDA approval and open up new treatment options for patients suffering from a variety of diseases moving forward.

[1] http://ir.gwpharm.com/news-releases/news-release-details/gw-pharmaceuticals-plc-and-its-us-subsidiary-greenwich

[2] https://www.fda.gov/NewsEvents/Newsroom/PressAnnouncements/ucm611046.htm

[3] See, e.g., https://www.wsj.com/articles/jeff-sessions-struggles-to-get-planned-marijuana-crackdown-going-1528628400

FDA Permits Marketing of First AI-based Medical Device; Signals Fast Track Approach to Artificial Intelligence

By Aaron Gin --

"The first and only autonomous AI system authorized by the FDA"

On April 11, 2018, the U.S. Food and Drug Administration (FDA) permitted marketing of a medical device that utilizes artificial intelligence to diagnose eye disease in diabetic adults.  The device, called IDx-DR from the company IDx, screens patients for diabetic retinopathy using deep learning algorithms.  The screening involves standard retinal imaging, takes less than a minute, and can be performed without a clinician's interpretation of the images or results.  Accordingly, IDx-DR may be used in primary care offices for early detection of retinopathy, which can lead to vision impairment and blindness.

IDx founder Michael Abramoff, a retinal specialist at the University of Iowa, told Science News that the medical device is unique because it operates autonomously and there is no specialist "looking over the shoulder of the algorithm."  "It makes the clinical decision on its own."

The FDA based its decision to permit marketing of IDx-DR, in part, on a clinical trial of the system involving the screening recommendations and corresponding retinal images from over 800 diabetic patients at ten different primary care sites.  The study indicated that IDx-DR correctly identified the presence of more than mild diabetic retinopathy 87.4% of the time and correctly identified patients with less than mild diabetic retinopathy 89.5% of the time.  The former group was referred to a specialist and the latter group was scheduled for a checkup in 12 months.

Tweets from FDA Commissioner Indicate AI Push

On the same day as the IDx-DR announcement, FDA Commissioner Scott Gottlieb M.D. unleashed a string of tweets that strongly endorsed AI-based health care solutions.  Based on Dr. Gottlieb's comments, it appears that the FDA may be currently accelerating review of AI-based systems.  Looking ahead, Gottlieb also signaled that AI-specific fast track regulatory pathways are under development.

Despite such relaxed AI regulations at the FDA, however, Dr. Gottlieb tweeted that the agency's approach would maintain consumer safety by establishing "appropriate guardrails."  Based on Dr. Gottlieb's comments, it will be interesting to track the FDA approval rate and timeline of AI-based healthcare solutions.  Additionally, in the case of new AI-specific regulatory pathways, time will tell what "guardrails" the FDA will put in place to maintain adequate safety as future AI innovations are made available to patients and providers.  Data privacy, algorithmic transparency, and "unbiased" learning datasets are just a few broad areas in which the FDA might regulate artificial intelligence as applied to health care.

For additional information regarding this topic, please see:

• In the future, an AI may diagnose eye problems (Science News, March 4, 2018)
• IDx-DR (IDx LLC Website)
• FDA permits marketing of artificial intelligence-based device to detect certain diabetes-related eye problems (FDA News Release, April 11, 2018)
• Scott Gottlieb, M.D. – Commissioner, U.S. Food and Drug Administration (Twitter: @SGottliebFDA)

FDA Approves First Cancer-Treatment Biosimilar -- Amgen's Mvasi

By Andrew Williams --

Earlier today, the U.S. Food and Drug Administration approved Amgen's application to market Mvasi (bevacizumab-awwb), a biosimilar to Genentech's Avastin therapeutic antibody for the treatment of multiple types of cancer.  This marks the first time that a biosimilar for the treatment of cancer has been approved by the FDA.  According to the FDA's press release, Mvasi was approved for the following indications in adult patients:

• Metastatic colorectal cancer, in combination with intravenous 5-fluorouracil-based chemotherapy for first- or second-line treatment.  Mvasi is not indicated for the adjuvant treatment of surgically resected colorectal cancer.
• Metastatic colorectal cancer, in combination with fluoropyrimidine-irinotecan- or fluoropyrmidine-oxaliplatin-based chemotherapy for the second-line treatment of patients who have progressed on a first-line bevacizumab product-containing regimen.  Mvasi is not indicated for the adjuvant treatment of surgically resected colorectal cancer.
• Non-squamous non-small cell lung cancer, in combination with carboplatin and paclitaxel for first line treatment of unresectable, locally advanced, recurrent or metastatic disease.
• Glioblastoma with progressive disease following prior therapy, based on improvement in objective response rate.  No data is available demonstrating improvement in disease-related symptoms or survival with bevacizumab products.
• Metastatic renal cell carcinoma, in combination with interferon alfa.
• Cervical cancer that is persistent, recurrent, or metastatic, in combination with paclitaxel and cisplatin or paclitaxel and topotecan.

FDA Commissioner Scott Gottlieb, M.D., indicated that the FDA would "continue to work hard to ensure that biosimilar medications are brought to the market quickly, through a process that makes certain that these new medicines meet the FDA's rigorous gold standard for safety and effectiveness."  As apparent evidence of this commitment, Amgen's biosimilar application was filed last November, and accepted by the FDA for review on January 4, 2017 (according to a complaint filed by Genentech in Delaware last February).  This means that the FDA approved this aBLA in less than nine months from the acceptance of the application.

Interestingly, there is currently no litigation pending that could prevent Amgen from launching its new biosimilar drug product.  Even though Amgen had disclosed its aBLA pursuant to the BPCIA, Genentech did file the aforementioned complaint to force Amgen to provide Genentech with manufacturing information allegedly not found in the aBLA.  Genentech had provided Amgen with a written request for information related to, among other things, the host cells used to manufacture the drug, the composition of the cell culture media, the extent and nature of the glycosylation patterns of the drug, the transformation of the culture cells, the sparging of the culture fluid, the Protein A chromatography purification process, any cation or anion exchange chromatography used to purify the drug, any viral inactivation steps, all formulations considered or used, and the filling of vials and/or the use of tangential flow filtration.  Amgen apparently took the position that it had satisfied its obligation under 42 U.S.C. § 262(l)(2)(A) by providing the aBLA.  The Court agreed that Genentech could not obtain relief, granting a 12(b)(1) motion filed by Amgen to dismiss the case for lack of subject matter jurisdiction in light of the Federal Circuit's holding in Amgen v. Sandoz.  No subsequent litigation has yet been filed, so it is unclear whether the Patent Dance has occurred notwithstanding the alleged disclosure deficiency.

Mvasi is the seventh biosimilar application to be approved by the FDA, and the second in less than a month.  In late August, the FDA approved Boehringer Ingelheim's aBLA for Cyltezo (adalimumab-adbm), a biosimilar to Abbvie's Humira^® (see "Boehringer Ingelheim Pharmaceuticals, Inc. receives FDA approval for CyltezoTM (adalimumab-adbm), a biosimilar to Humira®, for the treatment of multiple chronic inflammatory diseases").  This was the second approved biosimilar to this reference product, and the first biosimilar approval obtained by Boehringer Ingelheim.  Nevertheless, just as with Amgen's approved Humira® biosimilar, concurrent litigation will likely keep Cyltezo off the market for the foreseeable future.

We will continue to monitor these situations and report any updates as warranted.

FDA Report: Agency Announces Expedited Review of Certain ANDAs

By Andrew Williams --

On June 27, 2017, the U.S. Food and Drug Administration issued a press release stating how it would begin implementing its plan to increase competition for prescription drugs.  This comes on the heels of FDA Commissioner Scott Gottlieb's blog post last week, in which he indicated that the FDA would begin lifting the barriers to drug competition.  The first of the two new initiatives announced this week was to publish a list of branded drugs that were off patent but nevertheless had no approved generics.  The second initiative was to implement a policy to expedite the review of ANDAs for any drugs until there are three approved generics.  However, even though the press release indicated that these initiatives reflect the Administration's goal of improving access to prescription drugs, it did not address the potential reality that there may be little economic incentive for generic manufactures to seek marketing approval for these drugs.

The FDA press release was accompanied by two documents, each of which was directed to one of the two initiatives.  The first, entitled "List of Off-Patent, Off-Exclusivity Drugs without an Approved Generic," includes two sections: (1) a list of drug products for which the FDA could immediately accept an ANDA; and (2) a list of drug products for which there might be legal, regulatory, or scientific issues.  The FDA suggested that any sponsor wishing to seek approval of a drug product on the second list should first submit an initial inquiry to the Office of Generic Drugs.  Such drug products on this second list can include those that are more appropriate for the 505(b)(2) abbreviated approval pathway, those for which there are "regulatory complexities," and those that are proteins and may be transition products pursuant to the BPCIA.  No NDA drug products that have been approved in the past year have been included, and the FDA suggests that it will update the list every six months.

The second document was an updated "Prioritization of the Review of Original ANDAs, Amendments, and Supplements," as found in the Manual of Policies and Procedures for the Office of Generic Drugs.  The accompanying "Change Control Table" indicates that the revisions found in this version were to "include prioritization of generic products for which there are fewer than three ANDAs approved for the reference listed drug (RLD) and updated certain external references."  Nevertheless, this prioritization appears to be contingent on there being no blocking patents.  For submissions that contain Paragraph IV certifications, additional criteria were provided before expedited review could be received.

These documents related to the expediting of certain ANDAs were released about a week after newly appointed and confirmed Commissioner Gottlieb posted to his blog, the FDA Voice.  In this blog post, Commissioner Gottlieb indicated that the FDA was working on a Drug Competition Action Plan to address "some of the scientific and regulatory obstacles to generic competition across the full range of FDA-approved drugs."  The post, however, explicitly excluded patent and statutory exclusivity periods from these obstacles.  The only example of "gaming" the system provided was the alleged "increasing unavailability of certain branded products for comparative testing," either through restrictions placed on distributors, or the adoption of voluntary Risk Evaluation and Mitigation Strategies (or REMS) by the NDA holder.  The Commissioner also indicated that the FDA would be looking at how best to coordinate with the FTC to identify and publicize anti-competitive practices.  Finally, he announced a July 18 meeting, in which the FDA would seek input from the public about ways in which the current rules were no having their intended effects.  Of course, this post reverses a long-standing principal of the FDA to not get involved in issues of drug pricing.  We will continue to monitor any updates from the FDA or the current administration on any policies related to generic drugs.

Biosimilars Update -- Pfizer's Proposed Epogen®/Procrit® Biosimilar Recommended for Approval

By Andrew Williams --

On May 25, 2017, the FDA's Oncologic Drug Advisory Committee recommended approval of biologics license application ("BLA") 125545 submitted by Hospira Inc., a Pfizer company, for Retacrit, a proposed biosimilar to Amgen Inc.'s Epogen/Procrit (epoetin alfa).  According to a press release from Pfizer, the committee "recommended approval of the Company's proposed epoetin alfa biosimilar across all indications."  Pfizer had sought approval for treatment of anemia due to Chronic Kidney Disease (CKD), for treatment of anemia due to zidovudine in HIV-infective patients, for treatment of anemia in patients with non-myeloid malignancies, and to reduce the need for allogenic RBC transfusions among patients with perioperative hemoglobin.  If ultimately approved, Retacrit would become the sixth biosimilar in the U.S.  And if the experience with the previous five biosimilars is any indication, the FDA should be expected to approve the present application in the next couple of months.  Retacrit would also be the second biosimilar for Pfizer, which began selling Celltrion's biosimilar INFLECTRA^® in late 2016.  As Pfizer's representative Diem Nguyen said in the press release:  "Following the approval and launch of INFLECTRA^® (infliximab-dyyb) in 2016, this positive recommendation -- a first for a proposed ESA [erythropoiesis-stimulating agent] biosimilar -- marks an important milestone for Pfizer's U.S. biosimilars portfolio."

The Retacrit application would also represent the longest delay between submission and approval.  BLA 125545 was originally submitted in December 2014, and according to a Complaint filed by Amgen in September 2015, the application was accepted sometime on or before February 23, 2015.  But on October 27, 2015, Pfizer announced that it had received a complete response letter (CRL) from the FDA that required more evidence to support approval.  According to Pfizer's FDA Advisory Committee Briefing Document, the CRL "requested additional data and sensitivity analysis to align with the most current FDA expectations and to ensure the robustness of the data demonstrating biosimilarity of Epoetin Hospira to the Epogen/Procrit reference product."  This included information in the categories of:  manufacturing process, analytical, clinical pharmacology, clinical efficacy, and clinical immunogenicity.  In response, Pfizer obtained the additional scientific evidence, which it summarized in the following figure that it said "establishes the biosimilarity of Epoetin Hospira to the Epogen/Procrit reference product."

Marketing of the drug will likely be delayed because of the requirement to give the 180-day notice of commercial marketing.  In anticipation, though, Amgen filed a motion for preliminary injunction on May 26, 2017, because (as it alleged in the original underlying Complaint (at paragraph 66)):  "Hospira has indicated that it intends to violate the statute by categorically refusing to provide Amgen with a legally operative notice of commercial marking under 42 U.S.C. § 262(l)(8)(A)."  Of course, according to the Federal Circuit's Amgen v. Sandoz ruling, Hospira cannot give notice until after the FDA has approved the product.  But this requirement may change this month when the Supreme Court issues its decision in the Sandoz v. Amgen case.  The Delaware Court also denied Amgen's request for discovery related to Hospira's manufacturing process that was not supplied during the patent dance.  The appeal from that decision was heard by the Federal Circuit in April 2017, and an opinion is expected within the next few months.

As a reminder, both this author and Kevin Noonan will be attending the American Conference Institute's 8th Annual Summit on Biosimilars next week, June 12-14, 2017 in New York, NY.  Dr. Noonan is co-chair of the conference and will be on a panel reviewing the first 18 months of biosimilars (and looking ahead).  If you are attending, please say hello.  As a reminder, Patent Docs readers are entitled to a 10% discount off of registration using discount code P10-999-PTD17, but hurry because registration is closing soon.

FDA Relents, Grants Premarket Authorization to 23andMe Genetic Diagnostics Test

By Kevin E. Noonan --

On April 6th, the U.S. Food and Drug Administration (FDA) continued to loosen the reins on the genetic diagnostic and DNA analysis company 23andMe with regarding to direct-to-consumer (DTC) genetic testing related to predicting disease risk.  While falling short of permitting the company to provide risk analysis for disease likelihood in individuals per se, the agency granted permission to market its genetic diagnostic kits for a limited number of diseases according to an official announcement.  The agency's actions suggest that it believes there is sufficient evidence that the risks to the public it perceived that motivated its earlier restrictions are not as likely as once thought.

The FDA's actions come on the heels of the agency's approval of DNA diagnostics for Bloom's Syndrome earlier this year (see "23andMe Receives FDA Approval for Genetic Diagnostic Test").  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 its earlier 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.  By complying with the agency by submitting the evidence for approval of a much more limited test, 23andMe was able to get the Bloom's Syndrome test approved.

This most recent approval is for ten genetic diseases as detected by 23andMe's at-home health-and-ancestry DNA testing kit (retailing at $199).  The kit detects single nucleotide polymorphisms (SNPs) related to development of these ten diseases having a genetic component:

• Late-onset Alzheimer's – detecting the ε4 variant in the APO-E gene
• Parkinson's  - the G2019S variant in the LRRK2 gene and the N370S variant in the GBA gene
• Celiac disease - a variant in the HLA-DQ2.5 haplotype
• Hereditary thrombophilia - Factor V Leiden variant in the F5 gene, and the Prothrombin G20210A variant in the F2 gene
• Alpha-1 Antitrypsin Deficiency - PI*Z and PI*S variants in the SERPINA1 gene
• Gaucher's disease type 1 - N370S, 84GG, and V394L variants in the GBA gene
• Early-onset primary dystonia - deltaE302/303 variant in the DYT1 gene,
• Factor XI deficiency - F283L, E117X, and IVS14+1G>A variants in the F11 gene,
• Glucose-6-phosphate dehydrogenase deficiency - Val68Met variant in the G6PD gene,
• Hereditary hemochromatosis - C282Y and H63D variants in the HFE gene

The agency did not grant approval for tests related to developing a disease in an individual, in particular for detecting disease-related variants of the BRCA1 or BRCA2 genes related to breast and ovarian cancer.  Rather, the test results are predictive for the risk of inheritance of these genes by offspring, to be used inter alia to identify prospective parental pairs who both carry a disease-related allele and thus are at heightened risk for having a child with the disease.

FDA approval for genetic health risk reports were evaluated through the de novo classification pathway, a regulatory process for low-to-moderate-risk medical devices, the company said.  In its approval, the FDA indicated it will create a class II exemption for 23andMe's substantially equivalent reports for other diseases and risk-predictive genes, provided that the company complies with agency requirements for establishing efficacy and safety.  These actions open a pathway for the company to release additional genetic health risk reports, 23andMe also said in its announcement.  "These special controls, when met along with general controls, provide reasonable assurance of safety and effectiveness for these and similar [genetic health risk] tests," the FDA added.  And the agency announced that it will outline a pathway for similar exemption for other DTC companies in the Federal Register.

These tests are much more limited in scope than 23andMe's original test, which included more than 250 "diseases and conditions" such as BRCA gene mutations, diabetes, coronary artery disease, an sensitivities to drugs such as warfarin, clopidigrel, and 5-fluorouracil.  But the agency's approval, and avowed intention to permit 23andMe, and other companies, to market DTC genetic diagnostic tests suggest that the dawn of the age of personalized medicine has crept ever closer to breaking.

FDA Issues Guidance Regarding Interchangeability of Biosimilar and Biologic Drugs

By Kevin E. Noonan --

On Tuesday, the U.S. Food and Drug Administration released its latest Guidance for Industry relating to the biosimilar application process set forth in the Biologic Price Competition and Innovation Act of 2009 (BCPCIA).  This Guidance, entitled Considerations in Demonstrating Interchangeability with a Reference Product, Is long-awaited and addresses a important aspect of the biosimilar drug regime.  Interchangeability, which is the standard for conventional, small molecule generic drugs, is challenging for biologic drugs because of their size and complexity, and because the biosimilarity standard encompasses molecules that are not atom-for-atom identical to the reference biologic drug product.  Accordingly, the ease with which conventional generic drugs are substituted for brand name versions is not appropriate for biosimilar drugs, and the statute sets out standards for interchangeability status (Section 351(k)(4) of the PHS Act), wherein FDA must find that:

(A) the biological product—
    (i) is biosimilar to the reference product; and
    (ii) can be expected to produce the same clinical result as the reference product in any given patient; and
(B) for a biological product that is administered more than once to an individual, the risk in terms of safety or diminished efficacy of alternating or switching between use of the biological product and the reference product is not greater than the risk of using the reference product without such alternation or switch.

Interchangeability is important for a variety of reasons, particularly with regard to biosimilar drug acceptance and the ability for the interchangeable biosimilar to be substituted for a reference biologic drug product without intervention or approval of a health care provider.  Accordingly, such drugs are rewarded with additional layers of exclusivity (indeed, the only exclusivity for biosimilar drugs contained in the statute, as set forth in the PHSA under Section 351(k)(6)), wherein FDA shall not grant interchangeability status for any second biosimilar drug until the later of:

(A) 1 year after the first commercial marketing of the first interchangeable biosimilar biological product to be approved as interchangeable for that reference product; [or]
(B) 18 months after –
    (i) a final court decision on all patents in suit in an action instituted under subsection (l)(6) against the applicant that submitted the application for the first approved interchangeable biosimilar biological product; or
    (ii) the dismissal with or without prejudice of an action instituted under subsection (l)(6) against the applicant that submitted the application for the first approved interchangeable biosimilar biological product; or
(C)(i) 42 months after approval of the first inter- changeable biosimilar biological product if the applicant that submitted such application has been sued under sub- section (l)(6) and such litigation is still ongoing within such 42-month period; or
    (ii) 18 months after approval of the first interchange- able biosimilar biological product if the applicant that sub- mitted such application has not been sued under subsection (l)(6).

The Guidance provides FDA's first attempt to operationalize the statutory requirements and give the biopharmaceutical industry guidance on what the agency will require to grant interchangeability status to a biosimilar drug.

The Guidance is expressly focused on therapeutic protein products with regard to the evidence necessary to establish interchangeability with a reference biologic drug product that is a therapeutic protein.  As with almost all other FDA Guidances on biosimilars, this one recites that interchangeability determinations shall be made after consideration of the totality of the evidence that a biosimilar dug satisfies the statutory requirements.  Thus, the first requirement is that a biosimilar applicant show that its drug is biosimilar to the reference biologic drug product, and envisions that first licensure will be on biosimilarity grounds.  With regard to the requirement that a purportedly interchangeable biosimilar drug would be "expected to produce the same clinical result as the reference product in all of the reference product's licensed conditions of use," the Guidance sets forth a nonlimiting set of data and information:

• The identification and analysis of the critical quality attributes
• The identification of analytical differences between the reference product and the proposed interchangeable product, and, in addition, an analysis of the potential clinical impact of the differences
• An analysis of mechanism(s) of action in each condition of use for which the reference product is licensed, which may include the following:
    -  The target receptor(s) for each relevant activity/function of the product
    -  The binding, dose/concentration response, and pattern of molecular signaling upon engagement of target receptor(s)
    -  The relationship between product structure and target/receptor interactions
    - The location and expression of target receptor(s)
• The pharmacokinetics and biodistribution of the product in different patient populations The immunogenicity risk of the product in different patient populations
• Differences in expected toxicities in each condition of use and patient population (including whether the expected toxicities are related to the pharmacological activity of the product or to off-target activities)
• Any other factor that may affect the safety or efficacy of the product in each condition of use and patient population for which the reference product is licensed

If there are differences between the reference biologic drug product and the biosimilar with respect to any of these factors, the Guidance asserts that the biosimilar applicant must supply a scientific justification as to why those differences don't preclude a determination of interchangeability.  However, the Guidance does not envision that satisfying this standard will necessarily require additional clinical studies.  Also, an applicant can (but FDA recommends that she does not) seek approval for less than all the indications approved for the reference biologic drug product (and in this regard the Guidance envisions that an applicant may "extrapolate" the data and information supporting interchangeability for one indication to support interchangeability for additional indications).

As for the other statutory requirement, that "for a biological product that is administered more than once to an individual, the risk in terms of safety or diminished efficacy of alternating or switching between use of the biological product and the reference product is not greater than the risk of using the reference product without such alternation or switch," the Guidance expects a biosimilar applicant will need to do one or more "switching studies" (the general requirements being set forth with some specificity in the Guidance) that will be used to assess the risk to safety or efficacy of alternating between the reference biologic drug product and the biosimilar.

The Guidance provides "an overview of important scientific considerations in demonstrating interchangeability with a reference product," including:

• Data and information needed to support a demonstration of interchangeability
• Considerations for the design and analysis of a switching study or studies to support a demonstration of interchangeability
• Recommendations regarding the use of a U.S.-licensed reference product in a switching study or studies
• Considerations for developing presentations, container closure systems, and delivery device constituent parts for proposed interchangeable products.

And the Guidance then sets forth more detailed explication of these considerations, including product-dependent factors that could influence the data needed to show interchangeability (again urging a "stepwise" approach to establishing interchangeability as FDA has urged for establishing biosimilarity) and showing a high degree of biosimilarity (with reference to biosimilarity Guidances regarding so-called "fingerprint identity" measures of biosimilarity).  The information and data should be aimed at reducing the amount of residual uncertainty, which is expected to depend on the structural and functional complexity of the biosimilar drug.  Particularly called out in this regard is the risk of product-specific immunogenicity, which may be more relevant to some biosimilar drugs than others depending on the nature of the reference biologic drug product.

The Guidance also envisions that interchangeability may require biosimilar product postmarketing data, and that such data would not obviate the need for other, interchangeability-related data (e.g., from switching studies, particularly with regard to comparison of pharmacokinetic or pharmacodynamics parameters).

The Guidance provides detailed discussion of the characteristics of switching studies expected to be required to satisfy interchangeability requirements, for those drugs expected to be administered to a patient more than once (presumably this category encompasses many of not most biologic drugs).  These studies will depend on how the drug will be used in practice, according to the Guidance, and the Guidance sets out considerations regarding study endpoints, design and analysis, sample size and number of switches, sampling for PK, PD and immunogenicity, study population, and study analysis, as well as conditions of use and routes of administration.

There is also a section regarding the conditions under which data can be extrapolated (e.g., from one condition of use to another for which the reference biologic drug product is licensed), supported by scientific justification based on mechanism of action, immunogenicity risk, expected toxicities, or "[a]ny other factor that may affect the safety or efficacy of the product in each condition of use and patient population for which the reference product is licensed."

Unlike the Guidances concerning the grounds for establishing biosimilarity, which permit comparative data with a non-U.S. licensed reference biologic drug products to be submitted, the Guidance states that switching studies must be performed using a U.S. licensed reference biologic drug product.  This is because in these studies the reference biologic drug product is not used just as a control but is also part of the study, administered in both the switching arm and the non-switching arm.  This limitation appears to be based on concerns regarding unpredictable differences in immunogenicity or PK profiles, as well as the existence of several ex-U.S. versions of biosimilar drugs having slight but perhaps clinically relevant differences when used in a switching study that could negatively impact the reliability of study results.

The Guidance ends with a detailed description of presentation designs for the data and information supporting an interchangeability determination (referencing Section VII of FDA's earlier Guidance entitled Scientific Considerations in Demonstrating Biosimilarity to a Reference Product) and a section on postmarketing safety monitoring.  The Guidance also contains an Appendix related to Comparative Use Human Factor Studies.

And like all such Guidances, it contains an express disclaimer:

This guidance represents the current thinking of the Food and Drug Administration (FDA or Agency) on this topic.  It does not establish any rights for any person and is not binding on FDA or the public.  You can use an alternative approach if it satisfies the requirements of the applicable statutes and regulations.  To discuss an alternative approach, contact the FDA office responsible for this guidance as listed on the title page.

FDA Issues Guidance Regarding Biologic Drug Naming

By Kevin E. Noonan --

Late last week, the U.S. Food and Drug Administration released its latest Guidance for Industry relating to the biosimilar application process set forth in the Biologic Price Competition and Innovation Act of 2009 (BCPCIA).  This Guidance, entitled Nonproprietary Naming of Biological Products, extends to both reference biologic drug products and their biosimilar counterparts.  The basis for this naming regime, and its extension to both types of biologic drugs, reflects the agency's rationale for providing a naming convention in the first place and is based on FDA's dual responsibilities to protect the public and at the same time facilitate availability of biosimilar drugs according to Congress's intentions in passing the BPCIA.

In a nutshell, FDA sets forth a regime for a nonproprietary name that is the combination of a core name (equivalent to a generic name for small molecule drugs) combined with a four-letter suffix to designate its source.  The suffix (both the requirement that each biologic drug have one and the "nonsense" ("devoid of any meaning") nature of it) has been the source of much of the criticism of the naming scheme since the agency published a proposed rule in the Federal Register of August 28, 2015 (80 Fed. Reg. 52224) ("Designation of Official Names and Proper Names for Certain Biological Products").  The Guidance provides its rationale for the proposed rule, stating that the naming scheme, which is required "for each originator biological product, related biological product, and biosimilar product," will "facilitate pharmacovigilance" (for all categories of biologic drugs), by permitting a specific biologic dug product to be tracked from its source particularly in instances where other means of doing so are not readily available.  Also, these names would permit accurate source identification by patients, healthcare providers and payors (one of the features that biosimilar advocates fear might lead to discrimination).  For the agency, using source suffixes also provides a means to "minimize inadvertent substitution" (especially when such biosimilar products, like all current biosimilar products have not been determined to be interchangeable; FDA will develop a naming convention based on the same principles for interchangeable biosimilar products but "is continuing to consider the appropriate format of the suffix for these products").  The benefits envisioned by FDA should be to "(1) encourage routine use of designated suffixes in ordering, prescribing, dispensing, recordkeeping, and pharmacovigilance practices and (2) avoid inaccurate perceptions of the safety and effectiveness of biological products based on their licensure pathway" according to the Guidance.

One aspect of the Guidance is that the naming convention will be used for all biologic drug products, both newly licensed as well as previously licensed drugs.  For previously licensed biologic drugs (all of which are innovator-produced "reference biologic drug products") the revised proper (nonproprietary) name would comprise the original name as the core name and have a new distinguishing suffix configured consistent with the Guidance.  While the process for implementing this "renaming" of previously licensed biologic drugs is ongoing, FDA will assign distinguishing suffixes to "a limited group" of these drugs as well as accepting submissions (presumably by the drug sponsor) for supplementing approved drug labels with new nonproprietary names include a proposed suffix.  The names will be required for all "biological products licensed under the PHS Act, such as therapeutic protein products, vaccines, allergenic products, and blood derivatives, and [will] not include certain biological products that also meet the definition of a device in section 201(h) of the FD&C Act (21 U.S.C. 321(h)), such as in vitro reagents (e.g., antibody to hepatitis B surface antigen, blood grouping reagents, hepatitis C virus encoded antigen) and blood donor screening tests (e.g., HIV and hepatitis C)."

Returning to the agency's rationale for the proposed naming convention, the Guidance states that it anticipates "a growing number of biological products" to be entering the marketplace.  The nonproprietary name (in contrast with the proprietary (brand) name, "reflects certain scientific characteristics of the product, such as chemical structure and pharmacological properties" and, inter alia, "helps health care providers identify the product's drug substance and distinguish biological products from one another."  The proposed naming scheme was developed based on comments solicited by the agency from the public (as found in "Federal Register, 'Approval Pathway for Biosimilar and Interchangeable Biological Products; Public Hearing; Request for Comments' (75 FR 61497, October 5, 2010); 'Draft Guidances Relating to the Development of Biosimilar Products; Public Hearing; Request for Comments' (77 FR 12853, March 2, 2012); [and] 'Nonproprietary Naming of Biological Products; Draft Guidance for Industry; Availability' (80 FR 52296, August 28, 2015)").  The Guidance specifically recites that the naming convention is intended to "maximize the success of biosimilar products and interchangeable products and to help ensure the safety of patients receiving biological products licensed under the PHS Act."

The Guidance sets forth the "main considerations" used by the agency in arriving at the naming scheme.  These include "enhancing biological product pharmacovigilance"; "ensuring safe use of biological products"; and "advancing appropriate practices and perceptions regarding biological products."  With regard to pharmacovigilance, the Guidance acknowledges that despite agency efforts to "rigorously assess[]" for biologic (and other) drugs for safety and efficacy, issues can arise post-approval that create a need for the agency to be able to "track adverse events to a specific manufacturer" (or even specific lots or manufacturing sites) in a surveillance system that exists throughout the product's lifecycle.  If the source of a biologic product can be readily identified, remedial action can be taken effectively and not implicate products "for which no problem exists."  Such surveillance systems can be active or passive, and can use identifiers including "proprietary name, proper name, manufacturer, national drug code (NDC) number, lot number, and billing codes."  Unfortunately, many systems have "limited ability" to track products by manufacturer, according to the Guidance, and some identifiers are not recorded routinely (for example, in patient and billing records).  The proposed naming convention is intended to "provide another critical tool for accurately identifying and facilitating pharmacovigilance for originator biological products, related biological products, and biosimilar products."

With regard to safety, the Guidance states that inadvertent substitution is a particular risk for biological products due to their complexity and "unique safety concerns related to immunogenicity."  Inadvertent substitution, particularly wherein patients could receive reference biologic drug product and biosimilar versions thereof serendipitously, raises the specter of unapproved interchangeability, which the agency wishes to avoid until such time as it sets out the scope of what constitutes biosimilar drugs that can be considered interchangeable with the reference biologic drug product.  There is also the risk of different versions of a biologic drug or biosimilar versions thereof to be approved for different indications, and the naming convention is believed to be helpful in ensuring that a drug be administered for just those indications for which it has been approved.  There is the further risk that poorly informed healthcare providers or their patients might assume that a biosimilar drug having the same nonproprietary name as the reference biologic drug product had been approved as being interchangeable.  This risk is mitigated not only by using distinguishable names but by providing in such names a ready distinction in the Purple Book (Purple Book: Lists of Licensed Biological Products With Reference Product Exclusivity and Biosimilarity or Interchangeability Evaluations).

Finally, the Guidance believes that by requiring routine use of a nonproprietary names comprising source-identifying suffix in "ordering, prescribing, dispensing, recordkeeping, and pharmacovigilance practices" it will provide "a consistent, readily available and recognizable mechanism" for patients and healthcare providers to correctly identify the products (and their source) being administered.  FDA also appreciates that by requiring both newly approved biosimilar drugs and previously approved reference biologic drug products to use the naming convention, "inaccurate perceptions" of the safety and efficacy of biosimilar drugs, compared with reference biologic drug products, can be avoided.

In practice, FDA intends to use the core name of a previously approved originator biologic drug for both the reference biologic drug product and all biosimilar versions.  Source will be identified by a four-letter suffix otherwise "devoid of meaning."  This naming scheme will indicate the relationship between the products (the core name) and identify source by the suffix.  The agency also notes that having the distinguishing code as a suffix (instead of a prefix) will facilitate grouping the drugs together in electronic databases and thus help healthcare providers to locate their alternatives.  Applicants for biologic drug products pending approval should propose to FDA up to 10 suffixes from which the agency could choose (and also submit any "supporting analyses" that could influence the agency's decision on the suffix to be used); current BLA holders for approved drugs and biosimilar applicants should do the same.  Guidelines for suffix selection according to the Guidance should have the following characteristics:

The proposed suffix should:

• Be unique
• Be devoid of meaning
• Be four lowercase letters of which at least three are distinct
• Be nonproprietary
• Be attached to the core name with a hyphen
• Be free of legal barriers that would restrict its usage

The proposed suffix should not:

• Be false or misleading, such as by making misrepresentations with respect to safety or efficacy
• Include numerals and other symbols aside from the hyphen attaching the suffix to the core name
• Include abbreviations commonly used in clinical practice in a manner that may lead the suffix to be misinterpreted as another element on the prescription or order
• Contain or suggest any drug substance name or core name
• Look similar to or be capable of being mistaken for the name of a currently marketed product (e.g., should not increase the risk of confusion or medical errors with the product and/or other products in the clinical setting)
• Look similar to or otherwise connote the name of the license holder
• Be too similar to any other FDA-designated nonproprietary name suffix

The Guidance ends with the following statement of FDA policies regarding naming:

The final determination on the acceptability of a proposed suffix is based on FDA's review of all information and analyses described in this guidance, along with any information submitted by the sponsor.

FDA will evaluate proposed suffixes against the factors described in this section and may consider other factors if they impact the utility of the suffix in meeting the goals of the naming convention articulated in this guidance.  Upon completion of the Agency's evaluation, FDA will notify applicants if a proposed suffix is acceptable or if all of the proposed suffixes are determined to be unacceptable.  If all of the proposed suffixes are determined to be unacceptable, applicants may submit additional proposed suffixes for FDA's consideration.  If an applicant does not submit a suffix that FDA finds acceptable or does not propose suffix candidates within an appropriate time frame to allow sufficient time for FDA review, FDA may elect to assign a four-letter suffix for inclusion in the proper name designated in the license at the time FDA approves the application.

And like all such Guidances, it contains an express disclaimer:

This guidance represents the current thinking of the Food and Drug Administration (FDA or Agency) on this topic.  It does not establish any rights for any person and is not binding on FDA or the public.  You can use an alternative approach if it satisfies the requirements of the applicable statutes and regulations.  To discuss an alternative approach, contact the FDA office responsible for this guidance as listed on the title page.

FDA Issues Newest Guidance Regarding Biosimilar Application Process

By Kevin E. Noonan --

On December 29, the U.S. Food and Drug Administration released its latest Guidance for Industry relating to the biosimilar application process set forth in the Biologic Price Competition and Innovation Act of 2009 (BCPCIA).  This Guidance, entitled Clinical Pharmacology Data to Support a Demonstration of Biosimilarity to a Reference Product, is directed to products for which "pharmacokinetic (PK) and pharmacodynamic (PD) data are needed to support a demonstration of biosimilarity" (presumably all biosmilar products).  The rubrics set forth in this Guidance are intended to be relevant for establishing that there are no "clinically meaningful differences" between the biosimilar and the reference biologic drug product.  In particular, the Guidance is to be used to "address residual uncertainties" after comparative analytical data is acquired, and for providing direction and the need for additional clinical studies, as well as adding to the "totality of the evidence" in favor of biosimilarity and "extrapolation of data" regarding additional indications.

While acknowledging that the extent and types of clinical pharmacological data required will depend on each particular biosimilar, the Guidance provides "critical considerations" for using such studies to support a determination of biosimilarity.  These are summarized as "three key concepts": "a PK and PD response assessment, an evaluation of residual uncertainty, and assumptions about analytical quality and similarity," which are especially relevant to biosimilarity determinations.

According to the Guidance, pharmacokinetic and pharmacodynamics studies "should" include exposure and, preferably, exposure-response data (although the Guidance recognizes that informative exposure-response data may be difficult to obtain in view of the complexity and heterogeneneity of biological products).  For pharmacodynamics (PD) studies, a single biomarker is preferred although a composite of more than one biomarker can be used (indeed, the Guidance states that "[u]sing broader panels of PD biomarkers (e.g., by conducting a protein or mRNA microarray analysis) that capture multiple pharmacological effects of the product can be of additional value."  There are five characteristics set forth in the Guidance that should be considered when choosing a PD-relevant biomarker:

• The time of onset of change in the PD biomarker relative to dosing and its return to baseline with discontinuation of dosing;
• The dynamic range of the PD biomarker over the exposure range to the biological product;
• The sensitivity of the PD biomarker to differences between the proposed biosimilar product and the reference product;
• The relevance of the PD biomarker to the mechanism of action of the drug (to the extent that the mechanism of action is known for the reference product); and
• The analytical validity of the PD biomarker assay.

Even when there are no identified biomarkers that meet these criteria, the Guidance encourages applicants to use PD biomarkers "that achieve a large dynamic range over the concentration range in the PK evaluation because these PD biomarkers represent potential orthogonal tests that can support similarity."  And in the absence of sufficiently sensitive PD markers, the Guidance asserts that "derived" PK markers can be used to provide the "primary basis" for evaluating biosimilarity with PD markers being used to augment this data.

The Guidance specifically reasserts the FDA's fundamental policy decision to base approval of biosimilars vel non on the totality of the circumstances, using "a risk-based approach" that includes all relevant data (enumerated as "data from the structural and functional characterizations, nonclinical evaluations, clinical PK and PD studies, clinical immunogenicity testing and an investigation of clinical safety, and, when appropriate, clinical effectiveness").  The protocol FDA has adopted is to require such information in a "stepwise" approach, wherein at each step the agency reviews the amount of residual uncertainty that exists on the question of biosimilarity and fashions what is required to resolve such uncertainty.

While being directed to PD and PK studies the Guidance also reiterates the importance of "extensive and robust comparative structural and functional studies" using "available state-of-the-art" assays for evaluating a variety of physical and biochemical parameters (such as molecular weight, post-translational modifications, heterogeneity, impurity profiles, and others).  FDA requires the biosimilar applicant to identify the "type, nature, and extent" of any differences with the reference biologic drug product.  The Guidance notes the utility of using a "meaningful fingerprint-like analysis algorithm in this regard, specifying that by "fingerprint-like" is meant "[i]ntegrated, multi-parameter approaches that are extremely sensitive in identifying analytical differences."  The Guidance also identifies four categories of analytical results:

• Insufficient analytical similarity (wherein further development is not recommended);
• Analytical similarity with residual uncertainty (requiring additional studies (such as PD or PK studies));
• Tentative analytical similarity (which may require "targeted and selective animal and/or clinical studies); and
• Fingerprint-like analytical similarity (which may still require targeted and selective animal and/or clinical studies).

With regard to specifics of PD and PK study requirements, this Guidance references an earlier one, Bioanalytical Method Validation, and also sets forth both general and specific recommendations.  For PK studies, the Guidance recommends that the selected assay be chosen in view of "a thorough understanding of the mechanism of action" or the structural elements understood to be "critical" for biological activity, and ones that produce concentration data with which the biosmilar and reference product sponsor can be compared.  For PD studies, the Guidance recommends (in addition to choosing the "most suitable" assays) that the sponsor give the agency a rationale for its assay choice and relevance of the assay to biological activity.  The Guidance then sets forth specific considerations for ligand binding assays, concentration and activity assays, and PD assays.

Turning to safety and immunogenicity considerations, the Guidance specifically recites instances where neutralizing antibodies or immune-related toxicity reduces or loses PD efficacy, wherein such data should be disclosed to the agency and perhaps supplemented where appropriate, and should include "relevant patient populations that are not immunocompromised."  The measurements performed on the biosimilar should be chosen using "[p]ublicly available information on the safety and immunogenicity profile of the reference product."  For specifics on immunogenicity assay development the Guidance references a separate Guidance, Immunogenicity Assessment for Therapeutic Protein Products.

This Guidance repeats FDA's prior encouragement for biosimilar applicants to consult with the agency, here for developing its plan for clinical pharmacological evaluation of the biosimilar product.  The Guidance sets forth "[c]ritical topics" what should be discussed with FDA, including specifics on crossover and parallel study designs, which the Guidance characterizes as having "particular relevance."  With regard to crossover study design the Guidance states that "a single-dose, randomized, crossover study is generally preferred" for PK similarity assessments.  The Guidance recommends such studies for products having a half-life shorter than 5 days, or a rapid PD response (i.e., related to "the time of onset, maximal effect, and disappearance in conjunction with drug exposure"), and a low incidence of immunogenicity.  Conversely, a multiple-dose design is recommended for PD similarity assessments.  In either case, the Guidance recommends that "time course of appearance and disappearance of immunogenicity and its relation to the washout period should be considered."  Parallel design studies, according to the Guidance, are more appropriate for the many biologic drug products having a long half-life that are capable of eliciting an immune response.  In any case, the biosimilar applicant should also submit equivalent data on the U.S-licensed reference product.  Non-U.S. licensed reference products can also be used for this comparison, provided that the requirements of PHS Act section 351(k)(2)(A) are met and the biosimilar sponsor provides sufficient evidence to "scientifically justify the scientific relevance of these comparative data to an assessment of biosimilarity and establish an acceptable bridge to the U.S.-licensed reference product."

The Guidance also discusses the patient population, which preferably comprises healthy individuals if the biosimilar can be safely administered to them.  With regard to population demographics, the Guidance recommends selection of such a population what would be "most likely to provide a sensitive measure of differences between the proposed biosimilar product and the reference product" with evidence of which population was selected on this basis.  And of course the total number of patients should be sufficient to provide "adequate statistical power" for PK and PD assessments.  Similarly, dose selection should be chosen the be the most sensitive dose for identifying differences between the biosimilar product and the reference product biologic drug (which may be the approved dose for the reference product), and the route of administration should be the same route as used for the biologic drug reference product (and if there is more than one approved route then the one "most sensitive for detecting clinically meaningful difference" should be chosen").

With regard to PK measures, the Guidance specifically states:

All PK measures should be obtained for both the proposed biosimilar product and the reference product.  The sponsor should obtain measures of peak concentration (C_max) and total area under the curve (AUC) in a relevant biological fluid.  For single-dose studies, AUC should be calculated as the area under the biological product concentration-time curve from time zero to time infinity (AUC_0-∞), where AUC_0-∞ = AUC_0-t + C_t/k_el (or C_t (concentration at the last measurable timepoint) divided by k_el (elimination rate constant)) is calculated based on an appropriate method.  C_max should be determined from the data without interpolation.  For intravenous studies, AUC_0-∞ will be considered the primary endpoint.  For subcutaneous studies, C_max and AUC will be considered coprimary study endpoints.  For multiple dose studies, the measurement of total exposure should be the area under the concentration-time profile from time zero to the end of the dosing interval at steady-state (AUC_0-tau), and is considered the primary endpoint.  Both the concentration prior to the next dose during multiple dosing (C_{trough ss}) and C_max are considered secondary endpoints.  Population PK data will not provide an adequate assessment for PK similarity.

For PK measurements, the Guidance recognizes that sometimes "clinical PK and PD data that demonstrate similar exposure and response between a proposed biosimilar product and the reference product can be sufficient to completely assess whether there are clinically meaningful differences between products" (not taking into consideration the need for separate assessment of immunogenicity).  But in instances where this data is not sufficient to establish biosimilarity, the Guidance states that the human PD data can be used to lead to a more "targeted" approach for developing further clinical comparison studies.  And "sampling strategies" for both PD and PK measurements should be optimized for each, because "the PD-time profile might not mirror the PK-time profile."

For making statistical comparisons of PK and PD results between the biosimilar and reference products, the Guidance recommends a "similarity assessment" that relies on "(1) a criterion to allow the comparison, (2) a confidence interval for the criterion, and (3) an acceptable limit for the biosimilarity assessment."  Applicants should use an "average equivalence" approach (further described in FDA Guidance entitled Statistical Approaches to Establishing Bioequivalence) for comparing AUC and C_max measurements, based on a "two one-sided test procedure that involves calculation of the 90% confidence interval for the ratio of logarithmically transformed averages of the measurements of reference product and biosimilar drugs."

Finally, the Guidance contains a discussion of "simulation tools" for PK/PD study design, wherein these tools are used to select inter alia optimally informative doses for evaluating PD similarity.  However, in such cases the biosimilar applicant should chose informative dosages (on the "steep" part of the dose-response curve) and provide reference to publicly available information for such curves or propose a small-scale study to generate this information, particularly with regard to the 50% maximal response for the biologic drug.

The Guidance ends by stating that:

Clinical pharmacology studies play a critical role in the development of biosimilar products.  These studies are part of a stepwise process for demonstrating biosimilarity between a proposed biosimilar product and the reference product.  These studies may support a demonstration that there are no clinically meaningful differences between the products.  These studies may address residual uncertainties that remain after the analytical evaluation, may add to the totality of the evidence supporting a demonstration of biosimilarity, and may also support a selective and targeted approach to the design of any recommended subsequent clinical studies to support a demonstration of biosimilarity.

And like all such Guidances, it contains an express disclaimer:

This guidance represents the current thinking of the Food and Drug Administration (FDA or Agency) on this topic.  It does not establish any rights for any person and is not binding on FDA or the public.  You can use an alternative approach if it satisfies the requirements of the applicable statutes and regulations.  To discuss an alternative approach, contact the FDA office responsible for this guidance as listed on the title page.

FDA Approves Release of Genetically Engineered Mosquitoes

By Donald Zuhn –-

Lost among reports of the first locally transmitted cases of the Zika virus in the continental United States in late July (as well as concern over Zika transmission at the 2016 Summer Olympics in Rio de Janeiro, Brazil in August), was an announcement last month regarding the U.S. Food and Drug Administration's completion of an environmental review for a proposed field trial of genetically engineered mosquitoes.  The field study will be conducted to determine whether the release of genetically engineered (GE) mosquitoes made by Oxitec Ltd., a British biotechnology company that develops genetically modified insects to assist in insect control, will suppress the local Aedes aegypti mosquito population in the release area at Key Haven, Florida.  The GE mosquitoes carry a self-limiting gene, so when male GE mosquitoes are released into the wild and mate with wild females, their offspring inherit the self-limiting trait.  The resulting offspring will die before reaching adulthood, and the local mosquito population will decline.

The FDA noted that after considering thousands of public comments submitted in response to the agency's draft environmental impact study, the FDA was able to publish a final environmental assessment, entitled "Environmental Assessment for Investigational Use of Aedes aegypti OX513A," and "Finding of No Significant Impact".  The FDA indicated that the latter report agrees with environmental assessment that the proposed field trial will not have significant impacts on the environment.

In making the announcement, the FDA also noted that the release of the environmental assessment and report of no significant impact did not mean that Oxitec's GE mosquitos are approved for commercial use.  Instead, Oxitec will still be responsible for ensuring that all other local, state, and federal requirements are met before conducting the proposed field trial.  Oxitec is partnering with the Florida Keys Mosquito Control District in conducting the proposed field trial.

As of last week, the Centers for Disease Control and Prevention reports that there have been 43 cases of locally acquired mosquito-borne Zika virus in the United States and 17,629 cases of locally acquired mosquito-borne Zika virus in U.S. territories.  All of the U.S. cases to date have been in Florida.

FDA Releases Guidance on Biosimilar Labeling

By Kevin E. Noonan --

The Biologic Price Control and Innovation Act (BPCIA), enacted as part of President Obama's Affordable Care Act (better known as "Obamacare," Public Law 111-148), provided for the first time in the U.S. a path for FDA approval of biosimilar drugs, i.e., "generic" versions of biologic drugs that, unlike generic versions of conventional small molecule drugs are not identical but similar.  Congress did not, however, prescribe the standards for establishing biosimilarity or other aspects of the biosimilar pathway, leaving the details up to the FDA.  As part of fulfilling its mandate under the BPCIA, the FDA has issued a series of Guidances (both in draft and final form) with respect to the procedural and scientific protocols to be followed in filing and pursuing a biosimilar drug application (see "FDA Releases 'Final' Guidances for Industry regarding the Biosimilar Approval Pathway").  On Friday, the FDA issued its latest Guidance, which has to do with labeling of biosimilar drugs.  Far from being merely a technical aspect of the biosimilar program, this Guidance has been subject to pressures from both the innovator biologic drug makers and companies pursuing (or planning to pursue) their own biosimilar drugs.  These pressures have everything to do with the hoped-for acceptance of these drugs (particularly by the U.S. government, the biggest payor for biologic drugs) and fears by innovator biologic drug companies that their drugs might be mistaken for a biosimilar version (especially in the event that a biosimilar is associated with an adverse event).

The Guidance (which is but a draft Guidance for now) on its face is being distributed "for comment only" and in this way reflects the manner in which the FDA has approached its task of implementing the Act, by soliciting public and industry feedback by issuing draft Guidances and holding hearings and other meetings.  In a "black box" at the beginning of the document it states:

This draft guidance, when finalized, will represent the current thinking of the Food and Drug Administration (FDA or Agency) on this topic.  It does not establish any rights for any person and is not binding on FDA or the public.  You can use an alternative approach if it satisfies the requirements of the applicable statutes and regulations.  To discuss an alternative approach, contact the FDA staff responsible for this guidance as listed on the title page.

There are eight sections, providing the Background, General Principles, Specific Recommendations, FDA-approved Patient Labeling, Revised Biosimilar Product Labeling, instructions on how to submit initial and revised labeling, and a short section on Interchangeable Biological Products that does not provide labeling recommendations for interchangeable products (consistent with the agency's refusal to provide Guidance on obtaining approval for interchangeable versions of biologic drugs).  In the short Background the agency explains the context of the biosimilar provisions of the Act and then moves immediately to the General Principles.  There the FDA notes that the biosimilars pathway is provided "to demonstrate biosimilarity between the proposed [biosimilar] product and the reference product, not to independently establish safety and effectiveness of the proposed [biosimilar] product."  Accordingly, the information on the biosimilar label should be the "relevant data and information from the reference product labeling, with appropriate product-specific modifications."  Indeed, "[i]nformation and data from a clinical study of a proposed biosimilar product should be described in its labeling only when necessary to inform safe and effective use by a health care practitioner" and should not include "a description of these data," on the grounds that any clinical study undertaken by the biosimilar applicant should be aimed at establishing biosimilarity (defined as there being no clinically meaningful differenced between the biosimilar product and the reference product) and not at assessing the safety and efficacy of the biosimilar per se.  The Guidance also recites several other labeling rules not limited to the biosimilar context that a biosimilar label is required to follow (see, 21 CFR 201.56(c)(1), 201.56(d) and 201.57, and 21 CFR 201.57(c)(9)(i) through (iii)).

With regard to the Specific Recommendations for biosimilar products, the Guidance accommodates circumstances where the biosimilar product label differs from the reference product label (for example, depending on whether the biosimilar applicant is seeking approval for all or just a subset of indications for which the reference product has been approved).  The Guidance reaches the crux of the matter with regard to product identification; an earlier version of the agency's thinking in this regard was disclosed previously.  The agency recommends using the biosimilar product name "[i]n sections where the information described is specific to the biosimilar product" and "[f]or directive statements and recommendations for preventing, monitoring, managing, or mitigating risks."  The reference product name should be used "[w]hen clinical studies or data derived from studies with the reference product are described in biosimilar product labeling," particularly with regard to clinical studies and adverse reactions.  The "core" name (which is the nonproprietary name without the source-specific suffix) should be used when the property or risk applies to both the reference and biosimilar products (exemplified in the Guidance as "BOXED WARNING, CONTRAINDICATIONS, WARNINGS AND PRECAUTIONS, ADVERSE REACTIONS (Postmarketing Experience)" which would reflect the commonality of these properties for both products.  The FDA also apprehends situations where "[t]here may be text appropriately based on the reference product labeling where more than one of these product identification approaches should be used to accurately convey information."  For instances where a biosimilar has sought (and been approved for) fewer than all the indications approved for the reference product, information relating to these indications should not be included unless it is necessary for safety or efficacy (whilst ensuring that it is clear that the biosimilar is not approved for such uses).

The Guidance then recites the recommendation for specific language regarding a biosimilar:

[BIOSIMILAR PRODUCT'S PROPRIETARY NAME (biosimilar product's proper name)] is biosimilar* to [REFERENCE PRODUCT'S PROPRIETARY NAME  (reference product's proper name)] for the indications listed.

The INDICATIONS AND USAGE section of the label "should be specific to the approved indications for the biosimilar product and should be consistent with language previously approved for the reference product for those indications" including text from the reference product related to Limitations of Use.  The FDA also recommends specific language related to immunogenicity:

As with all therapeutic proteins, there is potential for immunogenicity.  The detection of antibody formation is highly dependent on the sensitivity and specificity of the assay.  Additionally, the observed incidence of antibody (including neutralizing antibody) positivity in an assay may be influenced by several factors, including assay methodology, sample handling, timing of sample collection, concomitant medications, and underlying disease.  For these reasons, comparison of the incidence of antibodies to [reference product's proper name] in the studies described below with the incidence of antibodies in other studies or to other products may be misleading.

Not surprisingly, the agency recommends that Patient Labeling follow the reference product except when differences are necessary to properly describe the biosimilar product.

The agency also recognizes that changes may arise during the life cycle of a biosimilar product and provides mechanisms for updating safety information, particularly when "new information" relating to use of the product under "more widely or [] diverse conditions."  Specifically, "[a]s with any biological product, a biosimilar product application holder must promptly review all adverse drug experience information obtained or otherwise received from any source, foreign or domestic, including information derived from commercial marketing experience, postmarketing clinical investigations, postmarketing epidemiological studies/ postmarketing adverse event surveillance, reports in the scientific literature, and  unpublished scientific papers; and the biosimilar product application holder," citing 21 CFR 600.80.  And if any information is found to be inaccurate, prompt correction is mandated by the statute (see, 21 CFR 601.12).  The Guidance also provides for post-approval licensure for additional indications for which the reference product has been approved.

How such labeling information should be submitted is set out as requiring:

• A clean version of reference product labeling that was used to develop the biosimilar product labeling

• A tracked changes and annotated version of proposed biosimilar product labeling explaining the differences from the reference product labeling

• A clean version of the proposed biosimilar product labeling

Finally, the Guidance indicates that, while "FDA continues to consider the types of data and information that would support a demonstration that a biological product is interchangeable with a reference product" that Guidance will not be found here.

As noted above the FDA is soliciting comments; as the face of the Guidance states, "[c]omments and suggestions regarding this draft document should be submitted within 60 days of publication in the Federal Register of the notice announcing the availability of the draft guidance," with electronic copies to be sent to http://www.regulations.gov and questions to Sandra Benton at 301-796-1042 or (CBER) Office of Communication, Outreach and Development, 800-835-4709 or 240-402-8010.

Sandoz Petitions for Certiorari over 180-day Notice Provision in BPCIA

By Kevin E. Noonan --

As reported earlier today in IP Law360, Sandoz has petitioned the U.S. Supreme Court for certiorari to review the Federal Circuit's decision that reversed the District Court in Amgen v. Sandoz.  In its decision, two members of the Federal Circuit panel (Judges Lourie and Newman) held that the BPCIA required notice of commercial marketing of a biosimilar product be given by the biosimilar applicant to the reference product sponsor only after the FDA had given regulatory approval for the biosimilar.  Judge Chen dissented, on the grounds that this constituted an extra 180 days of regulatory exclusivity beyond the 12 years expressly set forth in the statute.

Sandoz argues that this decision was outside the scope of the plain meaning of the statutory language, was inconsistent with the policy objectives of the BPCIA and in conflict with Supreme Court decisions on statutory interpretation.  Specifically, Sandoz argues that Amgen's remedy to prevent commercial marketing immediately upon approval was to ask a district court for an injunction based on patent infringement, which Amgen has not done (and Sandoz pointed out to the Court).  Indeed, Sandoz inferred that Amgen could not do so, based on SEC filings concerning whether Amgen owned an unexpired patent related to filgrastim.

Sandoz's petition also argues that the decision "disrupts the careful balance struck by Congress by delaying the launch of every biosimilar product by six months" (emphasis added).  Again in this argument Sandoz maintains that the only remedy in the statute providing for an injunction was based on patent litigation, either pursuant to the "patent dance" or, according to its successful arguments below, as provided by the "remedies" in the statute when a biosimilar applicant refuses to provide the reference product sponsor with its application or relevant manufacturing methods.  According to Sandoz, the statute is clear that "once the expressly granted [12 year] exclusivity period has run, the FDA's approval is 'made effective,' and the biosimilar applicant should be able to market immediately, absent the successful assertion by the sponsor of any valid patent claims."

The last portion of Sandoz statutory arguments contends that the Federal Circuit's interpretation "erroneously divorced the notice of commercial marketing provision from the patent resolution scheme and created an extra-textual injunctive remedy to enforce it."  Sandoz characterizes the Federal Circuit's action as an extra-statutory judicial intervention into the process, by granting an injunction against commercial marketing (that was lifted 180 days after FDA approval, on September 4, 2015).  Sandoz's point is that an "already approved biosimilar" was (and will be, for other biosimilars) kept off the market for an additional 180 days "without regard to whether the sponsor could show any valid patent rights or any irreparable harm."  The argument with regard to the statutory scheme is as follows:

With the exception of the confidentiality provision -- which is not applicable here -- Congress did not make the provisions in Section 262(l) specifically enforceable.  In other words, it created no cause of action for either the applicant or the sponsor to obtain an injunction to compel the other party to comply with any of the provisions in that subsection.  In contrast, Congress expressly made the confidentiality provision enforceable by an injunction -- and that provision proves that Congress knew how to provide an injunctive remedy when it wished to do so.

Further:

As particularly relevant here, and consistent with the BPCIA's overall patent-based remedial approach, the remedy Congress provided for the failure to provide the notice of commercial marketing under subsection (l)(8)(A) is the ability to bring an artificial infringement suit.  Specifically, when an applicant engages in the patent exchange process, yet does not provide notice of commercial marketing: "the reference product sponsor, but not the subsection (k) applicant, may bring" an action for a "declaration of infringement, validity, or enforceability" with respect to certain patents identified earlier in the patent exchange process.

Sandoz also noted that the Federal Circuit did not consider the "traditional equitable factors" involved in a decision to grant an injunction, which decision is in conflict with the Court's eBay decision.

The petition also makes the public policy argument that, left intact, the Federal Circuit's decision will impact not only Sandoz but every biosimilar applicant, supporting this argument with citations to the FTC's Report on biosimilars and other references regarding the importance of biosimilar drugs to patient accessibility to biologic drugs.  This outcome will "disrupt[] the careful balance struck by Congress between competition and innovation" Sandoz asserts, in language certain to get the attention of at least some members of the Court.

The Court will take up the petition in due course (and in view of the public policy implications may solicit the Solicitor General's views), and of course Amgen will have the opportunity to oppose.  There were a few amici who filed briefs supporting Sandoz's position on these issues in its petition for rehearing en banc, and briefs from those and any other amici will be due in the coming weeks.

Celltrion's Proposed REMICADE® Biosimilar Recommended for Approval

By Andrew Williams --

Earlier today, the FDA's Arthritis Advisory Committee recommended approval of biologics license application ("BLA") 125544 submitted by Celltrion, Inc. for CT-P13, a proposed biosimilar to Janssen Biotech Inc.'s REMICADE (infliximab) anti-TNF-α antibody.  According to a press release from Celltrion, the committee voted 21-3 to recommend approval for all sought indications, including treatment of a variety of autoimmune diseases such as Crohn's disease, ulcerative colitis, and rheumatoid arthritis.  This would be the second biosimilar ever approved in the United States (U.S.) pursuant to the Biologics Price Competition and Innovation Act (BPCIA), and the first biosimilar therapeutic monoclonal antibody.  If the experience with Sandoz's Zarxio^TM biosimilar is any indication, the FDA should be expected to approve the application in the next couple of months.  Marketing of the drug may be delayed, however, pending the outcome of Janssen's motion for partial summary judgment and a preliminary and permanent injunction.  A key consideration of that case is the Federal Circuit's Amgen v. Sandoz decision and its interpretation, which may delay marketing for an additional six months because the Notice of Commercial Marketing cannot be effective until approval by the FDA.

Last week, in advance of today's meetings, staff at the FDA released a briefing document in which they reported that the data submitted by Celltrion showed "that CT-P13 is highly similar to US-licensed Remicade, notwithstanding minor differences in clinically inactive components, and that there are no clinically meaningful differences between CT-P13 and US-licensed Remicade in terms of the safety, purity, and potency of the product."  Importantly, much like Sandoz's experience with Zarxio, Celltrion benefited from the fact that CT-P13 has already been approved outside the U.S. for similar indications.  For example, in the EU, South Korea, Japan, and India, Celltrion's biosimilar has been approved for all US-approved indications under the trade names Inflectra and Remsima (although no name has yet been assigned to the U.S. version of the drug).  In Canada, however, the same drug has been approved for all indications except ulcerative colitis and Crohn's Disease.  Because the development of CT-P13 occurred entirely outside of the U.S., Celltrion had to provide additional comparative data -- in order to "scientifically justify the relevance of that data by establishing an adequate scientific bridge between EU-approved Remicade, the US-licensed reference product and CT-P13."  The FDA explained that this bridging data should always include results from analytical studies, such as structural and functional data that directly compares all products, and should also include bridging PK and/or PD clinical data.

The FDA's briefing document also said that Celltrion had "provided an extensive data package to address the scientific considerations for extrapolation of data to support biosimilarity to other conditions of use and potential licensure of CT-P13 for each of the seven indications for which US-licensed Remicade is currently licensed and for which CT-P13 is eligible for licensure."  Celltrion is seeking to market CT-P13 for the following indications: (1) Crohn's Disease (CD), (2) Pediatric CD, (3) Ulcerative Colitis (UC), (4) Rheumatoid Arthritis, (5) Ankylosing Spondylitis, (6) Psoriatic Arthritis, and (7) Plaque Psoriasis.  In addition, Celltrion is seeking approval for Pediatric CD, but according to the briefing, this indication is protected by orphan drug exclusivity until September 23, 2018.  Unlike in Canada, the committee recommended approval for all sought-after indications in the U.S.

Once the FDA accepts the committee's recommendation and approves Celltrion's application, it may still be at least six months before the biosimilar drug can be marketed.  Unlike Sandoz in the case of Zarxio, Celltrion provided Janssen with its aBLA after it was accepted by the FDA.  Nevertheless, according to the Complaint filed by Janssen in the U.S. District Court for the District of Massachusetts, Celltrion refused to provide the requisite "other information" required by the BPCIA, which would describe the manufacturing process.  Moreover, Celltrion served a notice of commercial marketing on February 5, 2015, indicating that it would begin selling the product as early as August 4, 2015.  Of course, even though this notice occurred after Celltrion's application was accepted, it was significantly before actual approved (especially considering the biosimilar is not yet approved).  Celltrion has responded to Janssen's injunction motions by alleging that the Notice-of-Commercial-Marketing provision of the BPCIA is not a stand-alone provision and that because it took part in the "Patent Dance," it is not required to give such notice.  While Janssen's motion is pending, the Federal Circuit will be considering the almost identical issue in the Amgen v. Apotex case, which we will preview in an upcoming post.

Nevertheless, the committee's vote today is especially significant considering the intense interest focused on biosimilar therapeutic antibodies.  Going into this meeting, there was a lot of uncertainty about just how much information the FDA would require in order for a biosimilar applicant to establish "no clinically meaningful differences" between its biosimilar drug and the reference product.  Of course, Celltrion benefited from extensive data that it had already generated outside of the U.S.  It therefore remains to be seen just how much data the FDA will require for biosimilar therapeutic antibodies that do not have such a history.

Top Stories of 2015: #11 to #15

By Donald Zuhn --

After reflecting upon the events of the past twelve months, Patent Docs presents its ninth annual list of top patent stories.  For 2015, we identified twenty 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.  Last week, we counted down stories #20 to #16, and today we count down stories #15 to #11 as we work our way towards the top five stories of 2015.  As with our other lists (2014, 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 2015" on January 21, 2016 from 10:00 am to 11:15 am (CT).  Details regarding the webinar, which will focus on a handful of the most important stories, can be found here.

15. Federal Circuit Decides Biosig v. Nautilus on Remand

In April, the Federal Circuit considered the question of indefiniteness on remand from the Supreme Court's reversal in Nautilus v. Biosig and found again that the Biosig's claims were not indefinite.  In the earlier proceedings in the case, the District Court found the term "in spaced relationship" indefinite as a matter of law, and the Federal Circuit reversed, using its "insolubly ambiguous" test to hold that the claim was amenable to construction and thus not indefinite.  The Supreme Court rejected the Federal Circuit's standard, holding that "a patent is invalid for indefiniteness if its claims, read in light of the specification delineating the patent, and the prosecution history, fail to inform, with reasonable certainty those skilled in the art about the scope of the invention," and reversed and remanded for reconsideration by the Federal Circuit under this standard.  On remand, the Federal Circuit again reversed the District Court's indefiniteness determination, noting that that "an ordinarily skilled artisan would be able to determine this language requires the spaced relationship to be neither infinitesimally small nor greater than the width of a user's hands," and concluding that "[t]he term 'spaced relationship' does not run afoul of 'the innovation-discouraging 'zone of uncertainty' against which [the Supreme Court] has warned,' and to the contrary, informs a skilled artisan with reasonable certainty of the scope of the claim."

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

• "Biosig Instruments, Inc. v. Nautilus, Inc. (Fed. Cir. 2015)," April 27, 2015

14.  Supreme Court Decides Kimble v. Marvel

In August, the Supreme Court let stand its fifty-year ban on royalties post patent expiry (Brulotte v. Thys Co., 1964).  The case involved U.S. Patent No. 5,072,856 to Kimble, directed to a toy that simulated the web-shooting devices used by the fictional Spiderman, which Kimble attempted to license to Marvel (which owns the rights to the Spiderman character, comic books, movies, and ancillary merchandise).  Marvel instead chose to copy the invention, bringing their own version of the toy to market, and the parties subsequently settled the resulting patent infringement lawsuit on terms wherein Marvel purchased the patent for a lump sum (~$500,000) plus a 3% royalty; the settlement containing no limit on this royalty obligation with regard to patent expiry.  Marvel brought a declaratory judgment action against paying post-expiry royalties in which it prevailed, and the Supreme Court majority refused to overrule the Brulotte rule.  Although the majority recognized that royalty plans like the one at issue here can have advantages including "draw[ing] out payments over time and t[ying] those payments, in each month or year covered, to a product's commercial success," the majority believed that the principle of limiting the exclusive right to the statutory term is sufficiently important to require patentees and their licensees to "find ways around Brulotte" using other means.

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

• "Kimble v. Marvel Entertainment, LLC (2015)," August 20, 2015

13.  FDA Approves First Biosimilar

In January, the FDA's Oncologic Drugs Advisory Committee ("ODAC") recommended the approval of Sandoz's biosimilar filgrastim application to market a version of Amgen's NEUPOGEN^® biologic drug, making Sandoz's application the first to be accepted under the new biosimilar pathway created by 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."  Two months later, the FDA approved the biosimilar version of Neupogen® for sale in the U.S. -- thus becoming the first biosimilar to be approved under the BPCIA (a mere ten months after Sandoz filed its biosimilar application).  Sandoz (a division of Novartis) began selling its biosimilar product in September under the brand name Zarxio™.  Sandoz also avoided the disclosure provisions of the BPCIA in 2015, successfully arguing that those provisions were optional before the District Court and the Federal Circuit (but that's a "top story" for another day).

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

• "Sandoz' NEUPOGEN® Biosimilar Now on the Market," September 7, 2015
• "The First Biosimilar Application Has Been Approved -- But What About the Patent Issues?" March 12, 2015
• "FDA Approves Sandoz Filgrastim Biosimilar," March 8, 2015
• ""No Clinically Meaningful Differences": The First Accepted Biosimilar Application Has Been Recommend for FDA Approval," January 14, 2015

12.  Patent Reform Stalls in Congress

The year began with Rep. Bob Goodlatte (R-VA), the Chairman of the House Judiciary Committee, introducing his "Innovation Act" bill (H.R. 9), which sets forth several "reforms" of U.S. patent law, in substantially the same form as in the last Congress.  In July, Rep. Goodlatte released a 200-page Report on H.R. 9.  While many considered eventual passage of H.R. 9 to be a near certainty, the bill did not come to the House floor for a vote before the August recess and the year concluded with the bill sitting on the House calendar.  Although the Innovation Act is primarily directed to addressing the "problem" of so-called "patent trolls," over the course of 2015 a different patent reform issue (especially in the biopharm sector) started to gain traction.  In an article published last fall on Medium, Biotechnology Industry Organization (BIO) President and CEO Jim Greenwood highlighted this issue, urging Congress to modify the inter partes review (IPR) system, which he argued had "turn[ed] the serious business of medical innovation and entrepreneurial risk-taking into a casino."  In a letter sent to the Senate and House Committees on the Judiciary, 101 patient organizations also expressed "concern[] that, as currently written, H.R. 9 falls short of preserving important patent protections for the biopharmaceutical innovation our communities rely on to achieve a better quality of life."  The group of patient organizations contended that "IPR[s] opened the door to abuses that threaten the unique and specialized mechanisms under the Drug Price Competition and Patent Term Restoration Act (commonly referred to as the Hatch-Waxman Act) and the Biologics Price Competition and Innovation Act (BPCIA)."  Whether the Innovation Act moves to a House vote, and whether that bill (or an alternative) proposes any reforms to the IPR system, will begin to play out as Congress reconvenes this week.

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

• "BIO CEO: IPR System Threatens Medical Innovation," December 6, 2015
• "Pigs Fly, Hell Has Frozen Over, and the New York Times Supports Small Inventor and University Patenting," October 28, 2015
• "101 Patient Organizations Ask Congress to Curb IPR Abuse," October 11, 2015
• "PTAB Denies Inter Partes Review Petitions Against Two Acorda Patents," August 24, 2015
• "Ferrum Ferro Capital Files Motion to Strike Allergan's Complaint Alleging Misuse of IPR Process," August 12, 2015
• "Representatives Seek Protections for Hatch-Waxman and BPCIA in Innovation Act," August 6, 2015
• "Rep. Goodlatte Releases Report on H.R. 9," August 4, 2015
• "CBO Provides Cost Estimate to Government to Implement Innovation Act," July 27, 2015
• "Allergan Fights Back, Files Complaint Against Venture Fund That Filed IPR Petition," July 13, 2015
• "A Sea Change for IPRs? -- Part II," June 10, 2015
• "A Sea Change for IPRs?" June 9, 2015
• "Senate Judiciary Committee Passes PATENT Act," June 4, 2015
• "Group of National and State Organizations Asks Congress to Enact Legislative Reforms to Maintain Strong Patent System," June 1, 2015
• "A Modest Proposal (or Two)," April 22, 2015
• "Legislation Introduced in House to Eliminate Uncertainty Regarding AIA Grace Period," April 20, 2015
• "STRONG Patents Act of 2015 -- An Alternative Patent Reform Bill," March 4, 2015
• "Rep. Goodlatte Introduces His Patent Reform Bill (Again) -- Part II," February 9, 2015
• "Rep. Goodlatte Introduces His Patent Reform Bill (Again)," February 5, 2015
• "Pro-Patent Coalition Writes Letter to the House and Senate Judiciary Committees," January 29, 2015
• "Big Ten Lobbies Congress to Tread Lightly on "Patent Reform"," January 29, 2015

11.  Australia Follows U.S. Lead on DNA Claims

In June, the High Court of Australia heard the long anticipated appeal from the unanimous decision of a 5-judge bench of the Full Federal Court to allow Myriad's claims to isolated nucleic acids.  In October, the High Court of Australia handed down its decision in D'Arcy v Myriad Genetics Inc [2015] HCA 35, unanimously striking down the validity of the first three claims of Myriad's patent, which related to isolated nucleic acid sequences of the BRAC1 gene.  In reaching that decision, the majority judgment characterized the claimed invention as "information" rather than a chemical product, because it was defined as a code for the BRAC1 gene, which can be stored in various products, such as the isolated DNA of a person or cDNA where the introns in the sequence have been excised.  The product was merely the medium in which that information resides.  The High Court's decision marked a dramatic departure from the Australian Parliament's position on "gene patents" in recent years.  Australia Patent Law only expressly excluded from patentability "human beings and biological processes for their generation", and in 2010 the Patent Amendment (Human Genes and Biological Materials) Bill 2010, which sought to exclude not only DNA and RNA, but all biological entities from patentability, failed to pass after the Senate Legal and Constitutional Affairs Legislation Committee (SLCALC) recommended against the Bill.  As one of Patent Docs correspondents noted, the High Court's decision in D'Arcy v Myriad Genetics Inc brought Australia's position on isolated DNA and RNA in line with that of the United States, while representing a marked deviation from major trading partners such as Europe and the U.S. on the issue of patentability of cDNA.

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

• "Australian High Court Has Ruled in Myriad Gene Patent Case," October 8, 2015
• "High Court Rules Myriad's BRCA Genes Not Patentable Subject Matter in Australia," October 8, 2015
• "Isolated Nucleic Acids Not Patentable in Australia," October 7, 2015
• "Isolated Gene Sequences Suffer A Cruel Fate in the Hands of the High Court of Australia," October 7, 2015
• "High Court of Australia Hears Myriad Appeal," June 16, 2015