Posts Tagged ‘Innovation Act’

Podcast Review: Quiet Innovation Podcast on Obtaining $ for Your Startup

Reporter: Stephen J. Williams, Ph.D.


I wanted to highlight an interesting interview (What it Really Takes to Get Money for Your Startup) with David S. Rose, serial entrepreneur and Founder and CEO of Gust.com, which is a global collaboration platform for early stage angel investing, connecting hundreds of thousands of entrepreneurs and investors in over 75 countries. The interview with David and CFA John P. Gavin was broadcast on the podcast Quiet Innovation (from PodCast Addict @Podcast_Addict) from. I had tweeted it out on my Twitter account below (see the http link)


… but will include some notes from the podcast here. In addition you can link to the podcast directly using the links below:

QI-013 David Rose Interview_01.mp3

Or download the mp3


This post is a followup from yesterday’s post Protecting Your Biotech IP and Market Strategy: Notes from Life Sciences Collaborative 2015 Meeting.

Some highlights from the podcast


David Rose discusses how there are hundreds of thousands of new ideas, some which are great some which are not… having an idea may be an initial step but for an investor to even consider your idea it is more important to have


This is what David feels is critical to investors, such as himself, to decide whether your idea is investable. A startup needs to show they can accomplish their goal and show at least a rudimentary example of this, whether it is putting up a website or writing up a design blueprint for a new widget. He says starting a business today (either tech or manufacturing) requires a lot less capital than years ago (unless you are starting a biotech). He gives an example of internet startups he had founded in the 90’s versus today… in the 90’s you needed $2 million… today you can do it for $2,000. But the ability to show that you can EXECUTE this plan is CRITICAL.

David sites three aspects which are important to investors:

  1. Integrity – Be humble about yourself. He says there are way too many people who claim ‘our idea is the best’ or ‘we do it better than anyone’ or ‘we are the first to have this idea’. As he says Jeff Bezos of Amazon was not the first to have the idea of selling books over the internet, he just EXECUTED the plan extremely well.
  2. Passion- Investors need to see that you are ‘all in’ and committed. A specific example is angels asking how much money have you put into your idea (skin in the game)
  3. Experience- David says there are TWO important types of experience in developing startups and both valid. The first is how many startups have you done and succeeded and the second is how many startups have failed. He says investors actually like if you have failed because they are learning experiences, just as valuable if not more than having startups always succeed. Investors need to know how you can deal with adversity. All three points goes back to execution.

David Rose gave some reading suggestions as well including

Lucky or Smart? Secrets to an Entrepreneurial Life by Bo Peabody – He highlights this book to help people understand that a startup entrepreneur should always hire someone smarter than themselves.

Derek Sivers post Ideas Are Just a Multiplier of Execution  – where a great idea is worth $20 but a great idea plus execution is worth $20 million.

Eris Reese’s post The Lean Startup in his blog StartUpLessonsLearned – being frugal (gets back to what he said about not needed as much capital as you would think i.e. Don’t Burn Through the Cash) and also get metrics on your startup or idea (as long as you have the IP). He suggests taking out an ad to see what the interest is out there. You can measure the clicks from the ad and use that as a marketing tool to potential investors i.e. Getting Feedback

Some other posts on this site about Investing and Startups include:

Protecting Your Biotech IP and Market Strategy: Notes from Life Sciences Collaborative 2015 Meeting

THE BLOOMBERG INNOVATION INDEX: Country Rankings by Six Measures of the Capacity to Innovate as a Nation

Updated: Investing and Inventing: Is the Tango of Mars and Venus Still on

Sand Hill Angels

The Bioscience Crowdfunding Environment: The Bigger Better VC?

Technion-Cornell Innovation Institute in NYC: Postdocs keep exclusive license to their IP and take a fixed dollar amount of Equity if the researchers create a Spinoff company

Tycho Brahe, where art thou? Today’s Renaissance of the Self-Funded Scientist!



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USPTO Guidance On Patentable Subject Matter

USPTO Guidance On Patentable Subject Matter

Curator and Reporter: Larry H Bernstein, MD, FCAP

LH Bernstein

LH Bernstein







Revised 4 July, 2014



I came across a few recent articles on the subject of US Patent Office guidance on patentability as well as on Supreme Court ruling on claims. I filed several patents on clinical laboratory methods early in my career upon the recommendation of my brother-in-law, now deceased.  Years later, after both brother-in-law and patent attorney are no longer alive, I look back and ask what I have learned over $100,000 later, with many trips to the USPTO, opportunities not taken, and a one year provisional patent behind me.

My conclusion is

(1) that patents are for the protection of the innovator, who might realize legal protection, but the cost and the time investment can well exceed the cost of startup and building a small startup enterprize, that would be the next step.

(2) The other thing to consider is the capability of the lawyer or firm that represents you.  A patent that is well done can be expected to take 5-7 years to go through with due diligence.   I would not expect it to be done well by a university with many other competing demands. I might be wrong in this respect, as the climate has changed, and research universities have sprouted engines for change.  Experienced and productive faculty are encouraged or allowed to form their own such entities.

(3) The emergence of Big Data, computational biology, and very large data warehouses for data use and integration has changed the landscape. The resources required for an individual to pursue research along these lines is quite beyond an individuals sole capacity to successfully pursue without outside funding.  In addition, the changed designated requirement of first to publish has muddied the water.

Of course, one can propose without anything published in the public domain. That makes it possible for corporate entities to file thousands of patents, whether there is actual validation or not at the time of filing.  It would be a quite trying experience for anyone to pursue in the USPTO without some litigation over ownership of patent rights. At this stage of of technology development, I have come to realize that the organization of research, peer review, and archiving of data is still at a stage where some of the best systems avalailable for storing and accessing data still comes considerably short of what is needed for the most complex tasks, even though improvements have come at an exponential pace.

I shall not comment on the contested views held by physicists, chemists, biologists, and economists over the completeness of guiding theories strongly held.  Only history will tell.  Beliefs can hold a strong sway, and have many times held us back.

I am not an expert on legal matters, but it is incomprehensible to me that issues concerning technology innovation can be adjudicated in the Supreme Court, as has occurred in recent years. I have postgraduate degrees in  Medicine, Developmental Anatomy, and post-medical training in pathology and laboratory medicine, as well as experience in analytical and research biochemistry.  It is beyond the competencies expected for these type of cases to come before the Supreme Court, or even to the Federal District Courts, as we see with increasing frequency,  as this has occurred with respect to the development and application of the human genome.

I’m not sure that the developments can be resolved for the public good without a more full development of an open-access system of publishing. Now I present some recent publication about, or published by the USPTO.


Dr. Melvin Castro - Organic Chemistry and New Drug Development

Dr. Melvin Castro – Organic Chemistry and New Drug Development









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USPTO Guidance On Patentable Subject Matter: Impediment to Biotech Innovation

Joanna T. Brougher, David A. Fazzolare J Commercial Biotechnology 2014 20(3):Brougher














Abstract In June 2013, the U.S. Supreme Court issued a unanimous decision upending more than three decades worth of established patent practice when it ruled that isolated gene sequences are no longer patentable subject matter under 35 U.S.C. Section 101.While many practitioners in the field believed that the USPTO would interpret the decision narrowly, the USPTO actually expanded the scope of the decision when it issued its guidelines for determining whether an invention satisfies Section 101.

The guidelines were met with intense backlash with many arguing that they unnecessarily expanded the scope of the Supreme Court cases in a way that could unduly restrict the scope of patentable subject matter, weaken the U.S. patent system, and create a disincentive to innovation. By undermining patentable subject matter in this way, the guidelines may end up harming not only the companies that patent medical innovations, but also the patients who need medical care.  This article examines the guidelines and their impact on various technologies.

Keywords:   patent, patentable subject matter, Myriad, Mayo, USPTO guidelines

Full Text: PDF


35 U.S.C. Section 101 states “Whoever invents or discovers any new and useful process, machine, manufacture, or composition of matter, or any new and useful improvement thereof, may obtain a patent therefor, subject to the conditions and requirements of this title.

” Prometheus Laboratories, Inc. v. Mayo Collaborative Services, 566 U.S. ___ (2012)

Association for Molecular Pathology et al., v. Myriad Genetics, Inc., 569 U.S. ___ (2013).

Parke-Davis & Co. v. H.K. Mulford Co., 189 F. 95, 103 (C.C.S.D.N.Y. 1911)

USPTO. Guidance For Determining Subject Matter Eligibility Of Claims Reciting Or Involving Laws of Nature, Natural Phenomena, & Natural Products.


Funk Brothers Seed Co. v. Kalo Inoculant Co., 333 U.S. 127, 131 (1948)

USPTO. Guidance For Determining Subject Matter Eligibility Of Claims Reciting Or Involving Laws of Nature, Natural Phenomena, & Natural Products.


Courtney C. Brinckerhoff, “The New USPTO Patent Eligibility Rejections Under Section 101.” PharmaPatentsBlog, published May 6, 2014, accessed http://www.pharmapatentsblog.com/2014/05/06/the-new-patent-eligibility-rejections-section-101/

Courtney C. Brinckerhoff, “The New USPTO Patent Eligibility Rejections Under Section 101.” PharmaPatentsBlog, published May 6, 2014, accessed http://www.pharmapatentsblog.com/2014/05/06/the-new-patent-eligibility-rejections-section-101/

DOI: http://dx.doi.org/10.5912/jcb664


Science 4 July 2014; 345 (6192): pp. 14-15  DOI: http://dx.doi.org/10.1126/science.345.6192.14


Biotech feels a chill from changing U.S. patent rules

A 2013 Supreme Court decision that barred human gene patents is scrambling patenting policies.


A year after the U.S. Supreme Court issued a landmark ruling that human genes cannot be patented, the biotech industry is struggling to adapt to a landscape in which inventions derived from nature are increasingly hard to patent. It is also pushing back against follow-on policies proposed by the U.S. Patent and Trademark Office (USPTO) to guide examiners deciding whether an invention is too close to a natural product to deserve patent protection. Those policies reach far beyond what the high court intended, biotech representatives say.

“Everything we took for granted a few years ago is now changing, and it’s generating a bit of a scramble,” says patent attorney Damian Kotsis of Harness Dickey in Troy, Michigan, one of more than 15,000 people who gathered here last week for the Biotechnology Industry Organization’s (BIO’s) International Convention.

At the meeting, attorneys and executives fretted over the fate of patent applications for inventions involving naturally occurring products—including chemical compounds, antibodies, seeds, and vaccines—and traded stories of recent, unexpected rejections by USPTO. Industry leaders warned that the uncertainty could chill efforts to commercialize scientific discoveries made at universities and companies. Some plan to appeal the rejections in federal court.

USPTO officials, meanwhile, implored attendees to send them suggestions on how to clarify and improve its new policies on patenting natural products, and even announced that they were extending the deadline for public comment by a month. “Each and every one of you in this room has a moral duty … to provide written comments to the PTO,” patent lawyer and former USPTO Deputy Director Teresa Stanek Rea told one audience.

At the heart of the shake-up are two Supreme Court decisions: the ruling last year in Association for Molecular Pathology v. Myriad Genetics Inc. that human genes cannot be patented because they occur naturally (Science, 21 June 2013, p. 1387); and the 2012 Mayo v. Prometheus decision, which invalidated a patent on a method of measuring blood metabolites to determine drug doses because it relied on a “law of nature” (Science, 12 July 2013, p. 137).

Myriad and Mayo are already having a noticeable impact on patent decisions, according to a study released here. It examined about 1000 patent applications that included claims linked to natural products or laws of nature that USPTO reviewed between April 2011 and March 2014. Overall, examiners rejected about 40%; Myriad was the basis for rejecting about 23% of the applications, and Mayo about 35%, with some overlap, the authors concluded. That rejection rate would have been in the single digits just 5 years ago, asserted Hans Sauer, BIO’s intellectual property counsel, at a press conference. (There are no historical numbers for comparison.) The study was conducted by the news service Bloomberg BNA and the law firm Robins, Kaplan, Miller & Ciseri in Minneapolis, Minnesota.

USPTO is extending the decisions far beyond diagnostics and DNA?

The numbers suggest USPTO is extending the decisions far beyond diagnostics and DNA, attorneys say. Harness Dickey’s Kotsis, for example, says a client recently tried to patent a plant extract with therapeutic properties; it was different from anything in nature, Kotsis argued, because the inventor had altered the relative concentrations of key compounds to enhance its effect. Nope, decided USPTO, too close to nature.

In March, USPTO released draft guidance designed to help its examiners decide such questions, setting out 12 factors for them to weigh. For example, if an examiner deems a product “markedly different in structure” from anything in nature, that counts in its favor. But if it has a “high level of generality,” it gets dinged.

The draft has drawn extensive criticism. “I don’t think I’ve ever seen anything as complicated as this,” says Kevin Bastian, a patent attorney at Kilpatrick Townsend & Stockton in San Francisco, California. “I just can’t believe that this will be the standard.”

USPTO officials appear eager to fine-tune the draft guidance, but patent experts fear the Supreme Court decisions have made it hard to draw clear lines. “The Myriad decision is hopelessly contradictory and completely incoherent,” says Dan Burk, a law professor at the University of California, Irvine. “We know you can’t patent genetic sequences,” he adds, but “we don’t really know why.”

Get creative in using Draft Guidelines!

For now, Kostis says, applicants will have to get creative to reduce the chance of rejection. Rather than claim protection for a plant extract itself, for instance, an inventor could instead patent the steps for using it to treat patients. Other biotech attorneys may try to narrow their patent claims. But there’s a downside to that strategy, they note: Narrower patents can be harder to protect from infringement, making them less attractive to investors. Others plan to wait out the storm, predicting USPTO will ultimately rethink its guidance and ease the way for new patents.


Public comment period extended

USPTO has extended the deadline for public comment to 31 July, with no schedule for issuing final language. Regardless of the outcome, however, Stanek Rea warned a crowd of riled-up attorneys that, in the world of biopatents, “the easy days are gone.”


United States Patent and Trademark Office

Today we published and made electronically available a new edition of the Manual of Patent Examining Procedure (MPEP). Manual of Patent Examining Procedure uspto.gov http://www.uspto.gov/web/offices/pac/mpep/index.html Summary of Changes

PDF Title Page
PDF Foreword
PDF Introduction
PDF Table of Contents
PDF Chapter 600 –
PDF   Parts, Form, and Content of Application Chapter 700 –
PDF    Examination of Applications Chapter 800 –
PDF   Restriction in Applications Filed Under 35 U.S.C. 111; Double Patenting Chapter 900 –
PDF   Prior Art, Classification, and Search Chapter 1000 –
PDF  Matters Decided by Various U.S. Patent and Trademark Office Officials Chapter 1100 –
PDF   Statutory Invention Registration (SIR); Pre-Grant Publication (PGPub) and Preissuance Submissions Chapter 1200 –
PDF    Appeal Chapter 1300 –
PDF   Allowance and Issue Appendix L –
PDF   Patent Laws Appendix R –
PDF   Patent Rules Appendix P –
PDF   Paris Convention Subject Matter Index 
PDF Zipped version of the MPEP current revision in the PDF format.

Manual of Patent Examining Procedure (MPEP)Ninth Edition, March 2014

The USPTO continues to offer an online discussion tool for commenting on selected chapters of the Manual. To participate in the discussion and to contribute your ideas go to:

Manual of Patent Examining Procedure (MPEP) Ninth Edition, March 2014
The USPTO continues to offer an online discussion tool for commenting on selected chapters of the Manual. To participate in the discussion and to contribute your ideas go to: http://uspto-mpep.ideascale.com.

Note: For current fees, refer to the Current USPTO Fee Schedule.
Consolidated Laws – The patent laws in effect as of May 15, 2014. Consolidated Rules – The patent rules in effect as of May 15, 2014.  MPEP Archives (1948 – 2012)
Current MPEP: Searchable MPEP

The documents updated in the Ninth Edition of the MPEP, dated March 2014, include changes that became effective in November 2013 or earlier.
All of the documents have been updated for the Ninth Edition except Chapters 800, 900, 1000, 1300, 1700, 1800, 1900, 2000, 2300, 2400, 2500, and Appendix P.
More information about the changes and updates is available from the “Blue Page – Introduction” of the Searchable MPEP or from the “Summary of Changes” link to the HTML and PDF versions provided below. Discuss the Manual of Patent Examining Procedure (MPEP) Welcome to the MPEP discussion tool!

We have received many thoughtful ideas on Chapters 100-600 and 1800 of the MPEP as well as on how to improve the discussion site. Each and every idea submitted by you, the participants in this conversation, has been carefully reviewed by the Office, and many of these ideas have been implemented in the August 2012 revision of the MPEP and many will be implemented in future revisions of the MPEP. The August 2012 revision is the first version provided to the public in a web based searchable format. The new search tool is available at http://mpep.uspto.gov. We would like to thank everyone for participating in the discussion of the MPEP.

We have some great news! Chapters 1300, 1500, 1600 and 2400 of the MPEP are now available for discussion. Please submit any ideas and comments you may have on these chapters. Also, don’t forget to vote on ideas and comments submitted by other users. As before, our editorial staff will periodically be posting proposed new material for you to respond to, and in some cases will post responses to some of the submitted ideas and comments.Recently, we have received several comments concerning the Leahy-Smith America Invents Act (AIA). Please note that comments regarding the implementation of the AIA should be submitted to the USPTO via email t aia_implementation@uspto.gov or via postal mail, as indicated at the America Invents Act Web site. Additional information regarding the AIA is available at www.uspto.gov/americainventsact  We have also received several comments suggesting policy changes which have been routed to the appropriate offices for consideration. We really appreciate your thinking and recommendations!

FDA Guidance for Industry:Electronic Source Data in Clinical Investigations

Electronic Source Data

Electronic Source Data








The FDA published its new Guidance for Industry (GfI) – “Electronic Source Data in Clinical Investigations” in September 2013.
The Guidance defines the expectations of the FDA concerning electronic source data generated in the context of clinical trials. Find out more about this Guidance.

After more than 5 years and two draft versions, the final version of the Guidance for
Industry (GfI) – “Electronic Source Data in Clinical Investigations” was published in
September 2013. This new FDA Guidance defines the FDA’s expectations for sponsors,
CROs, investigators and other persons involved in the capture, review and retention of
electronic source data generated in the context of FDA-regulated clinical trials.In an
effort to encourage the modernization and increased efficiency of processes in clinical
trials, the FDA clearly supports the capture of electronic source data and emphasizes
the agency’s intention to support activities aimed at ensuring the reliability, quality,
integrity and traceability of this source data, from its electronic source to the electronic
submission of the data in the context of an authorization procedure. The Guidance
addresses aspects as data capture, data review and record retention. When the
computerized systems used in clinical trials are described, the FDA recommends
that the description not only focus on the intended use of the system, but also on
data protection measures and the flow of data across system components and
interfaces. In practice, the pharmaceutical industry needs to meet significant
requirements regarding organisation, planning, specification and verification of
computerized systems in the field of clinical trials. The FDA also mentions in the
Guidance that it does not intend to apply 21 CFR Part 11 to electronic health records
(EHR). Author: Oliver Herrmann Q-Infiity Source: http://www.fda.gov/downloads/Drugs/GuidanceComplianceRegulatoryInformation/
Webinar: https://collaboration.fda.gov/p89r92dh8wc


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Curator: Aviva Lev-Ari, PhD, RN


For Financial Aspects of Biosimilars, go to:

Biosimilars: Financials 2012 vs. 2008



For CMC and Regulatory Affairs of Biosimilars, go to:

Biosimilars: CMC Issues and Regulatory Requirements



In this post we focus on the Legal Scene of Intellectual Property Creation & Protection by Pioneer & by Biosimilar Manufacturers.

The regulatory pathway for biosimilars has an impact on biopharma R&D, M&A and valuation of companies and products. Industry and investors were uncertain if biosimilar will be approved, the impact a new biosimilar will have on rate of return and sales of pioneer innovators which are big pharma with dedicated divisions to biosimilars as well as on new entrants as biosimilar manufacturers.

Biosimilars, aka biogeneric, biocomparable or follow-on biologic are different than traditional pharmaceuticals, aka small molecules produced by chemical reactions, subjected to generic competition. Biosimilars include proteins produced by genetically engineered organisms, have not been challenged by generic competion.The generic  competition provisions of the Drug Price Competition and Patent Term Restoration Act of 1984 (Hatch-Waxman Act) apply to products approved under the Food, Drug, and Cosmetic Act, which include small molecule pharmaceuticals, but not to products approved under the Public Health Service Act, which include biologics.

It is estimated that, within a few years, biologics will be half of the biopharmaceutical market. As a result there have been mounting calls for a biosimilar pathway for companies obtaining Food and Drug Administration (FDA) approval of generic versions of existing biologics based upon lesser showings of safety and efficacy than is required for a pioneer biologic.

Like Hatch-Waxman Act for generic drugs, The Biologics Price Competition and Innovation Act (BPCIA) aka Biosimilar Act of 2009  (1) establishes standards for application and approval; (2) provides a term of data exclusivity; and (3) establishes a scheme for handling patent disputes. The similarities, however, end with these broad constructs, as the details involved with each are quite different.

Patent Disclosure Requirements

The Biosimilar Act imposes completely new disclosure requirements for patents that are demanding and time-sensitive, and it imposes these requirements on both pioneer and biosimilar manufacturers. These requirements will be required after submission of a biosimilar application and will demand sophisticated legal counseling and planning. These requirements are as follows:

• The biosimilar applicant must provide a copy of the application to the pioneer manufacturer (reference product sponsor) within 20 days of being notified that its application has been accepted by the FDA.

• The pioneer manufacturer must provide the applicant with a list of patents that it believes “could reasonably be asserted” with respect to the pioneer product within 60 days of receiving a copy of the application. The list must identify which patents the pioneer manufacturer would be prepared to license to the biosimilar applicant.

• The biosimilar applicant must provide the pioneer manufacturer with a detailed statement describing its opinion that any patent listed is invalid, unenforceable, or will not be infringed by the commercial marketing of the biosimilar, or a statement that it does not intend to begin commercial marketing of the biosimilar before the expiration of the listed patent(s), within 60 days of receiving the list of patents.

• The pioneer manufacturer must provide the biosimilar applicant with a detailed statement describing its opinion that its patent(s) will be infringed by the biosimilar, as well as a response concerning the validity and enforceability of its patent(s) within 60 days of receiving the biosimilar applicant’s detailed statement.

• The biosimilar applicant must notify the pioneer manufacturer 180 days before the first commercial marketing of the biosimilar. The pioneer manufacturer may then seek a preliminary injunction.

After these required exchanges, the act requires good faith negotiations by the parties to agree on which patents will be the subject of any infringement action. Within 30 days of either agreeing on this list of patents, or exchanging each party’s final list of patents, the pioneer manufacturer must bring an infringement action. The pioneer manufacturer also has 30 days to amend this list after the issuance, or exclusive licensing, of a new patent that it believes is infringed by the biosimilar. If the pioneer manufacturer prevails in this action before approval of the biosimilar, the court must enter a permanent injunction prohibiting further infringement.

Failure to bring an infringement action within the 30-day mandate (or bringing an infringement action that was dismissed without prejudice or was not prosecuted to judgment in good faith) will result in the available remedy being limited to a reasonable royalty only. Finally, failure by the pioneer manufacturer to timely include a relevant patent in the exchanged list will preclude the pioneer manufacturer from later bringing an infringement action against the biosimilar applicant with respect to that undisclosed patent.

Intellectual Property Considerations

As a result, it is feasible that a biosimilar may be similar enough to qualify as a biosimilar under the Biosimilar Act but not similar enough to be covered by a patent claim. Accordingly, pioneer manufacturers should take care in obtaining valid claims that afford broad patent protection of their biologics. To do so, pioneer manufacturers should consider, for example, protecting not only the biologic itself but also, if possible, the target molecule(s) of the biologic, methods of use and methods of production. In addition, pioneer manufacturers should also contemplate how their biologics may be modified and consider obtaining patent protection for those modifications. While this is generally a common practice in patent law, it has been less important in pharamceuticals, where the focus has been on the patents that protect the drug itself rather than methods of its manufacture, and on obtaining protection from a generic (a bioequivalent drug, rather than a less equivalent drug that could treat the same condition).

Biosimilar manufacturers, on the other hand, should analyse how the pioneer’s biologic is protected by one or more patents and consider how they may be able to escape patent protection. Biosimilar manufacturers should also be careful of what admissions they make in regard to what is and is not equivalent in an application under the Biosimilar Act. Such admissions may be considered by manufacturers of the pioneer biologic for possible infringement positions. Under the Biosimilar Act, there is a certain amount of protection afforded through data exclusivity for a pioneer biologic. Pioneer biologic manufacturers, however, should not solely rely on this period of exclusivity for protection. Not only may patent protection go beyond the protection afforded by the data exclusivity period for a pioneer biologic, but an additional data exclusivity period may not be available under the Biosimilar Act. As a result, it is important for pioneer manufacturers to consider obtaining patent protection for improvements to their pioneer biologic.

Likewise, biosimilar manufacturers should also seek patent protection for their biosimilars and improvements to them, and consider the pioneer biologic and associated patents in doing so. Patent protection may be available for biosimilar biologics even when data exclusivity under the new act is not. In regard to the patent disclosure requirements, the scheme of the new act appears to avoid many of the problems that have arisen under the Hatch-Waxman Act for generic pharmaceuticals, such as the numerous issues regarding the requirement to list relevant patents in the Orange Book.

However, the completely new patent disclosure scheme for biosimilars will take years for the FDA and the courts to sort out. In the end, it may very well be more burdensome on the  parties than the Hatch-Waxman Act, which has spawned a tremendous amount of litigation. At the very least, the patent provisions of the Biosimilar Act establish demanding and time-sensitive disclosure requirements for both the pioneer and biosimilar applicant. Given the detail required and the complexity of the issues, both parties should conduct the necessary investigation and analysis well before a biosimilar application could be filed. Some steps that may be taken include: identifying all relevant patents, determining expiration dates and potential patent term extensions, and identifying patent owners and licenses. Based on the investigation and analysis, both parties should develop detailed infringement, validity, and enforceability positions before receiving the other party’s patent list or positions. Failing to take early action will likely result in a party rushing to prepare the very detailed statements required by the law for both parties, running the serious risk of making a potentially determinative mistake. Both parties also face penalties for failing to comply with the disclosure requirements.

In all, it will be important for pioneer and biosimilar manufacturers to fully understand their patent portfolios as well as those of their competitors and to review these portfolios regularly. The requirements of the Biosimilar Act will necessitate sophisticated and extensive legal counseling, active portfolio diligence, and time-sensitivity



Greater clarity in the biopharma and pharma market place was achieved on June 28, 2012 when the US Supreme Court has upheld ObamaCare, ensuing that the pathway for biosimilars included with the law will remain intact.

The US paved the way for biosimilar approval in 2012 as part of the Patient Protection and Affordable Care Act (PPACA). A major element of the healthcare reform law is The Biologics Price Competition and Innovation Act (BPCIA) aka Biosimilar Act of 2009 provision of that bill said that biological products that are demonstrated to be highly similar (biosimilar) to or interchangeable with an FDA-licensed biological product may be approved under an abbreviated pathway similar to the process for small molecule generics.

With the upheld ObamaCare, critical parts of the PPACA constitutional, and with it the BPCIA giving the FDA authority to approve biosimilars.

Had the PPACA been stricken in part or in its entirety, it would have presented obstacles to the BPCIA surviving in its present form. The US government has been critical of the 12-year data exclusivity period for Pioneer Innovators, calling for it to be shortened to 7 years (12 years is favorable to Pioneer Innovators and less favorable for Biosimilar manufacturers). The upheld ObamaCare, PPACA and BPCIA, constitutional, has prevented a multiyear delay in biosimilar approval. Thus, it was the best scenario for the biologics industry.

BPCIA provides the approval of biological products as biosimilar or interchangeable (BPCIA 351(k)). As part of the FDA’s approval process, biosimilar products would need to produce the same clinical effect and if a multi-dose product, not present any greater safety or efficacy risk to patients in switching from the reference product. There would have to be “clinically meaningful differences” between the pioneer biologic reference product and the biosimilar product in order to gain FDA approval.

Congress granted the FDA flexibility for approval standards for biosimilars, i.e., what type of clinical studies required, what differences in approval process from biologics license applications (BLA) are appropriate.

1. Pioneer inventors are granted 12 years of data exclusivity, barring FDA approval of a 351 (k) application from “the date on which the reference product was first licensed”

2. An application can’t be submitted to the FDA until 4 years after the date on which the BLA for the reference product was first granted.

3. FDA sets approval requirements unless FDA waives them: analytical studies demonstrating the biosimilar is highly similar to the reference product, animal studies, a clinical study sufficient to demonstrate safety, purity, potency, same mechanism of action, route of administration, dosage form and strength.

Hatch-Waxman Act for generic drugs patent challenge provisions are different from BPCIA‘s patent challenge provisions.

  • BPCIA require “negotiation” of patent disputes and exchanges of patent information between parties prior to instituting patent litigation.
  • BPCIA mandates risk evaluation and mitigation strategy (“REMS”) requirements, shall apply to biosimilars as they do to reference pioneer biologic.
  • Reimbursemwnt for biosimilars is set at Average  Sales Price (ASP) plus 6% of the amount determined for the amount determined for the reference pioneer biologic.
  • BPCIA allows for imposition of user fees to review biosimilars
  • Naming biosimilars: generic vs. proprietary naming requirements for drug safety and/or recalls, tracking adverse events,  as well as reimbursement
  • Unanswered, if a biosimilar applicant needs to provide data on al approved indications of the reference product, and can a biosimilar be better than a reference product (i.e., “biobetters”), if so in what way (e.g., safety or efficacy).

On 2/9/2012 – FDA issued 3 draft guidance documents intended to facilitate the submission of marketing applications for biosimilars

1.  Biosimilars Q&A: provide guidance on the content of 351(k) applications. Recommendations that sponsors meet early with FDA to discuss plans. Guidance sets out the FDA’s current view that comparative animal or clinical data developed using non-US-licensed product can provide evidence that proposed product is biosimilar to a US-licensed reference product.

2. Biosimilars Scientific Guidance – three approaches to establish demonstrated biosimilarity.

a.  “stepwise” approach comparison of proposed product with reference product with respect to structure, function, animal toxicity, human pharmacokinetics (PK) and pharmacodynamics (PD), cinical immunogenicity, and clinical safety and effectiveness.

b.  “totality-of-the-evidence” approach

c.  “general scientific principles” in conducting comparative structural and functional analysis, animal testing, human PK and PD studies, clinical immunogenicity assessment and clinicall safety and effectiveness studies (study design issues)

3.  Biosimilar Quality Guidance provides directions on analytical studies assessing if the proposed biosimilar protein product and the reference product are “highly similar” Guidance suggests that there may be an opportunity for pioneer innovators to argue that current technology does not permit for demonstration of  “biosimilarity” of a potentially competitive product in a manner adequate to gain approval under 351(k), thus necessitating the filing of full BLA.

Outstanding issues under BPCIA’s provisions related to marketing and development could affect biopharma investment:

1.  effects on coverage and reimbursement of the pioneer biologic based on approval of a biosimilar, reimbursement of biosimilars themselves

2. biosimilars and not expressly treated in the new act under Medicare Part B, Medicare Drug Pricing Program, Medicaid, 340B program.

3. non clear is biosimilars will constitute “multi-source drugs.”

Unlike the generic drugs market, the biosimilars market is likely to have a smaller number of entrants, greater costs of applications and testing, less reduction in price from that of a pioneer biologic and necessity of marketing staff.

It is unclear when the cost of the drug will become a switching factor in purchasing a biosimilar. purchaser resistance  note withstanding price advantage did occur in the past. There eexist potential purchaser/payor concerns regarding interchangeability, safety, efficacy (i.e., potency). There is concern over evergreening strategy by pioneer inventors to use drug modifications to extend the exclusivity period thus, deterring the entrance of biosimilars.

In June 2011, the European Medicines Agency (EMA) and FDA issued a joint report noting the interactions between the two agencies, when a biosimilar version of a mococlonal antibody, Remicade was filed in the EU.

Defining Protein Therapeutics

FDA promises a risk-based “totality-of-the-evidence” approach to reviewing biosimilars. Novo Nordisk and Pfizer urged FDA to rethink its definition of proteins as excluding alpha amino acid polymers with fewer than 41 amino acids. Jim Shehan, Novo Nordisk’s corporate vp, legal, government, and quality affairs, noted that the definition clashed with statutes defining biological products as including any polypeptide except for those that are chemically synthesized.

“We believe they have selected an arbitrary cutoff,” Shehan told GEN. “It can conflict with the statutory language and it really isn’t grounded in science either,” an exception, he said, to the guidance’s overall focus on respect for science and patient safety. “In broad strokes, they met the mark in seeming to have a healthy respect for the need to have data in order for biosimilars to come to market.”

F. Owen Fields, Ph.D., Pfizer vp, worldwide regulatory strategy, worldwide R&D, suggested a case-by-case review of proteins with 40 or fewer amino acids. He cited Nisin, a 37-amino-acid polypeptide derivative approved by FDA as a food preservative, as an example among natural peptides best treated as proteins because of their potential for use as substrates for new drug development. “There are structures less than 41 amino acids that present regulatory science issues that are more similar to biologically synthesized proteins than to chemically synthesized peptides,” Dr. Fields pointed out at the hearing.

Keeping Trade Secrets Secret

Abbott called for additional FDA efforts to protect trade secrets of reference drugs during agency review of biosimilar applications. “Safeguards are needed to ensure that the agency doesn’t unintentionally, inadvertently, but nevertheless impermissibly use or disclose to a biosimilar applicant an innovator’s trade secrets,” Neal Parker, an Abbott attorney, said at the hearing.

Among safeguards suggested by Parker were FDA developing IT systems tracking employee involvement with BLAs and biosimilar applications, creating policies and procedures and training employees in them, and preventing FDA reviewers “significantly” involved in reviewing specific U.S.-licensed innovator BLA products from any biosimilar application review activities or any communications with biosimilar applicants seeking to rely on those same reference products.

Abbott recently submitted a citizen’s petition requesting that the agency not consider any applications for biosimilars based on biologic reference products for which a BLA was submitted before March 23, 2010, the date that President Barack Obama signed the Biologics Price Competition and Innovation Act. The request would effectively shield Abbott’s mAb therapeutic and biggest-selling treatment Humira from biosimilar competition. The company is about to spin off its brand-name drug development operations, remaining as a maker of medical equipment and generic drugs.

Fine-Tuning Data Requirements

Kalyan R. Anumala, Ph.D., senior director of Therapeutic Proteins, suggests that the agency should only require Phase II and III trials where it establishes a need after reviewing a submission. He also said the agency should encourage new characterization methods rather than clinical trials.

Also calling for additional characterization methods is the only U.S. company marketing biosimilar drugs, Hospira. Its products include anemia treatment Retacrit in the EU and biosimilar filgrastim product Nivestim, sold in the EU and Australia for stimulating production of white blood cells in patients receiving cytotoxic chemotherapy.

Samant Ramachandra, M.D., Ph.D., Hospira’s senior vp, R&D and regulatory and medical affairs and CSO, also urged FDA to account for reference product variability and clarify the required approach to show clinical immunogenicity assessment.

Dr. Ramachandra and James M. Roach, M.D., svp and CMO of Momenta Pharmaceuticals, urged FDA to permit the use of bridging data in return for allowing non-U.S. reference products. “This is critical if the goal is to implement a global development program that is feasible to conduct,” Dr. Roach added. Eli Lilly’s Gregory C. Davis, Ph.D., pressed FDA for more guidance on the type and extent of bridging data that would be permissible.

Abbott, by contrast, said data from studies involving a foreign comparator product cannot be considered pivotal if the foreign comparator is different from the U.S. reference product. FDA has stated that clinical comparisons with a non-U.S. licensed product do not provide an adequate basis to support interchangeability.

Jay P. Siegel, M.D., chief biotechnology officer and head of global regulatory affairs for Janssen Pharmaceutical, echoed many brand-name drug developers by urging FDA to maintain the draft guidance’s standard for interchangeability. Applicants would have to demonstrate biosimilarity and the ability of the biological product to produce the same clinical result as the reference product in any given patient.

If biosimilarity is established, it should also be extrapolated to pediatric populations, said Karl Heinz Emmert, Ph.D., managing director for Merckle Biotec, a Teva Group member. Dr. Emmert contended that FDA need not require clinical studies of pediatric populations with a biosimilar product. That differs from the thinking of Pfizer, which while supportive of extrapolations between populations within an indication, suggested an exception: diseases where pediatric pathophysiology differs from that of adults.

With regard to manufacturing concerns, Paul Eisenberg, an Amgen svp, argued in part: “Requiring the maintenance of biosimilarity over time would inhibit manufacturing and quality improvements and unduly burden industry without benefiting patients.” Mark McCamish, M.D., Ph.D., head of global biopharmaceutical development for Sandoz Biopharmaceuticals, disagreed.

Determining Label Details

Amgen did not address manufacturing issues in testimony but focused instead, along with several other companies, on how biosimilars should be identified and labeled to ensure accurate tracking and tracing. Suggestions included biosimilar names sharing a common root but having a unique suffix and/or prefix to denote biosimilarity and interchangeability.

“Having unique names will avoid unintended substitution, minimize risk of medication errors, allow for essential elements of pharmacovigilance such as traceability and follow-up of adverse drug reactions, as well as facilitate prescriber-patient decision making,” commented Michelle Rohrer, Ph.D., vp, U.S. regulatory affairs at Genentech.

Teva’s Dr. Emmert and Ahaviah Diane Glaser, vp for policy and strategic alliances with the Generic Pharmaceutical Association (GPhA), noted, however, that while all biologics should be uniquely tracked, biosimilars should not require unique International Nonproprietary Names (INNs) from their reference products. Glaser said different INNs would impede market competition because it would likely require a different marketing campaign, thus raising costs, and would also complicate collection of global safety data and could increase medical errors.

Embracing Biosimilars

Further guidance on naming biosimilars and interchangeables was one point agreed upon by industry and patient groups, so it’s likely FDA will oblige. That’s the easy issue for the agency. Tougher will be how to balance shepherding biosimilars and interchangeable products to market without sacrificing patient safety.

“If FDA issues product-specific guidances with very clear mandates that to get a biosimilar approved, you need to run a Phase III-like trial of X size, evaluating X, Y, and Z, it takes away from the incentive to put that much more time and scientific thought into proving from a structural and functional basis that you have the same compound,” Dr. Roach of Momenta told GEN.

Years ago EMA developed solid scientific guidelines, then product-specific rules that succeeded in bringing biosimilars to Europe. Sandoz’ Dr. McCamish credited EMA’s consistent standards with health authorities embracing biosimilars. It’s a lesson the U.S. will have to learn as FDA builds the pathway for biosimilars to finally reach the American market. 


On February 9, FDA issued long-awaited guidelines designed, according to FDA drug division director Janet Woodcock, M.D., “to help industry develop biosimilar versions of currently approved biological products.” Paul Calvo, Ph.D., a director at Sterne, Kessler, Goldstein & Fox, told GEN, “There were no major surprises” in the guidelines.

“It is clear that FDA wants to move forward with biosimilar approvals and they will be looking to a totality of the evidence as the standard for a determination of biosimilarity.” He also commented that FDA wants a constant dialog with biosimilar sponsors and all the structural and functional data up front. “Their goal for the up-front data is to be involved in design of the clinical trials in order to maximize the data provided.”

FDA’s new documents describe a step-wise approval pathway, starting with extensive analytical, physico-chemical, and biological characterization data that will have to demonstrate a high degree of similarity to the reference product. FDA will evaluate that data and then provide advice to the sponsor on the extent and scope of animal and human testing needed to show biosimilarity. The agency will consider multiple factors in making study determinations, including product complexity, formulation, stability, structure-function relationships, manufacturing process, and clinical experience with the reference product.

While the pathway to the agency’s decision making will be abbreviated, “it will depend on existing data,” Rachel Sherman, M.D., director of the Office of Medical Policy in FDA’s Center for Drug Evaluation and Research, said during a conference call. “We do not want companies repeating studies that do not need to be done.” As to whether most biosimilar applicants will be expected to carry out clinical trials, decisions will be made on a product by product basis.

Another topic of note is that the FDA has said that there could be extrapolation of clinical data to other diseases to give companies developing biosimilars approval for use in multiple indications for a given product. “But for therapeutics like Rituxan with two disparate indications, one for lymphoma and another for rheumatoid arthiritis, two sets of clinical trials will likely be required,” Dr. Calvo explained.

Interchangeability and Exclusivity

Importantly for the industry, the guidance documents indicate that the agency hasn’t settled some important biosimilars policy questions, including requirements for demonstrating interchangeability of a biosimilar with a reference product and terms for establishing the exclusivity period for pioneer biologics.

The Patient Protection and Affordable Care Act, signed into law by President Barack Obama on March 23, 2010, mandated the creation of an abbreviated approval pathway for biosimilars and proposed a 12-year data exclusivity period. The president’s budget proposal for fiscal 2013 released February 13, however, suggests that exclusivity should be lowered to seven years.

With regard to interchangeability, FDA states that it “is continuing to consider the type of information sufficient to enable FDA to determine that a biological product is interchangeable with the reference product.” Dr. Calvo explained that “interchangeability is important because it provides for a period of market exclusivity as well for automatic substitution of the interchangeable for the approved biologic without intervention from the prescribing physician.”

“However,” Dr. Calvo added, “given how new the whole process for biosimilar approval is, it would have been surprising if the FDA would have said there would not be any issues in determining interchangeability.” But, he noted, the agency has said that right now it doesn’t have the scientific ability to approve biosimilars as interchangeable.

An Amgen spokesperson commented that “FDA’s acknowledgement that determining interchangeability is scientifically difficult at this time is important. Patient safety does not stop at approval, and Amgen believes that post-approval activities including ongoing monitoring are essential to patient safety.”

Dr. Sherman believes that the hurdles for interchangeability would be high. Biologic drugs carry the added risk of prompting an immune response, she noted, and the FDA would “almost certainly” require clinical trials in which a patient is switched from the branded drug to the biosimilar and back to rule out the risk of triggering the immune system.

Potential Cost Savings

Dr. Calvo pointed out that “the ability to have a high level of FDA input will likely increase the chance that biosimilars will soon enter the U.S. market.” However, he added, the price erosion that occurs with small molecules “will not happen for biosimilars to even close to the extent that it occurs with small molecules, mainly because there will not be a mechanism for automatic substitution and because clinical studies will be required at least to some degree.”

For more complex products such as antibody conjugates or highly purified protein mixtures, “it is highly likely that more sophisticated manufacturing and analytical methods and possibly clinical trials will be required, therefore increasing costs for biosimilar entrants,” Jefferies analyst Biren Amin said in a note to clients. “This could apply to products like Seattle Genetics’ Adcetris or ImmunoGen and Roche’s T-DM1.”

The Congressional Budget Office still estimates that biosimilars would save the government $25 billion in healthcare spending during the coming decade. While generic chemical compounds like Norvasc and Metoprolol usually sell for less than 20% the cost of the brand product, biosimilars are expected to sell for 60% to 80% of the cost of branded biologics. The difficulty of producing and gaining approval for biosimilars will provide manufacturers increased pricing power and larger margins compared to traditional generic medications.

Biosimilars represent a tremendous opportunity for pharma and biotech companies that can successfully manufacture and market them. The global market for biosimilars will range between $11 billion and $25 billion by 2020, accounting for 4 to 10 percent of the total market for biotech drugs, according to IMS Health. Despite the potential hurdles to both interchangeability and exclusivity, patent expiries in the next two years put around $11 billion in biologic drug sales into play. That kind of potential along with the establishment of a designated approval pathway clears away some lingering doubts about the viability of generic competition.

As for the industry, potential biosimilar manufacturers continue to make deals. While there are no currently marketed biosimilars in the U.S., so-called innovator companies including Amgen, Pfizer, Novartis, and Eli Lilly have joined the ranks of generic firms such as Teva in developing biosimilars. Amgen told GEN that as a leading provider of high-quality biologic medicines, it understands the challenges of developing and manufacturing innovative and biosimilar medicines and appreciates the agency’s efforts on the guidelines, and encourages adoption of a thorough review and approval process.

While it remains to be seen whether approved biosimilars provide the savings in healthcare costs that the Congressional Budget Office optimistically predicted, both the FDA and the industry are moving toward making them a reality in the U.S. As per the three dozen or so requests for meetings, FDA staffers are holding pre-IND meetings with sponsors and encouraging all prospective biosimilar makers to seek early advice. Nine INDs for biosimilar have been filed so far, and the agency is anticipating a full 351(k) application soon.


More than a year after launching a dialogue with industry regarding biosimilars, FDA is holding a morning-long public meeting today. The proposed approval pathway and fees drug developers must pay for the five fiscal years starting October 1, 2012, will be discussed. The agency is soliciting public comment through January 6, 2012

Those comments are expected to shape a final FDA recommendation on biosimilar user fees, which the agency plans to send to Congress by January 15, 2012. On December 7, the agency published “Biosimilar Biological Product Authorization Performance Goals and Procedures, Fiscal Years 2013 through 2017.”

The user fee program is expected to aid FDA in developing the final abbreviated approval pathway for biosimilars, which was required under the Biologics Price Competition and Innovation Act (BPCIA) of 2009. BPCIA was tucked into page 686 of the Patient Protection and Affordable Care Act enacted last year by President Obama. Janet Woodcock, M.D., director of FDA’s Center for Drug Evaluation and Research co-authored a paper published this August in The New England Journal of Medicine that provided some clues on the overall approval pathway.


The initial fee would be 10% of the fee established for a drug application under PDUFA each year from FY 2013 through 2017. The agency would collect only one initial BPD fee per product, regardless of the number of proposed indications.

Sponsors that submit marketing applications would pay fees equal to those established for drug applications under PDUFA minus the cumulative amount of BPD fees. Under PDUFA, 2012 fees for drug products go up as high as $1.84 million.

“By providing FDA with these resources, they would be able to meet with sponsors, provide clear and established guidelines for regulatory action, and as a result that should reduce the barriers to market entry even more than what would be represented through a modest fee like this,” Emmett said. Since established biopharma companies are more likely to produce biosimilars than early-stage companies, “I wouldn’t anticipate that $180,000 would be a significant barrier to market,” Emmett added.

“FDA anticipates a modest level of funding from these sources initially because only biosimilar biological products that are approved for marketing would be subject to these fees,” the agency said.


Biosimilars and Follow-On Branded Biologics

Promoting Innovation and Access to Life-Saving Medicine Act (H.R.1427, a bill from the first session of the 111th Congress) and the FTC’s report titled Emerging Health Care Issues: Follow-on Biologic Drug Competition are intended to provide the rationale for moving access to biosimilars/follow-on biologics and driving the legislative compromise. Of particular interest is the FTC’s projection of what cost savings (10–30%) will actually be achieved, and that the originator biologic manufacturer may likely retain 90% of its market.

When a new human growth hormone (hGH) product tried to compete with  Genentech’s hGH, physicians hesitated to move patients on to it, so its market was just new patients. If there is only a 10–30% price differential for biosimilar/follow-on biologics and they lack an AB substitutability rating, one would anticipate the same reluctance to switch patients.


FDA’s draft guidance for biosimilars drew mostly good marks from industry at the hearing held May 11. Executives from a dozen biopharma companies, however, pressed for greater flexibility in the definition of proteins, tighter standards in naming and labeling follow-on biologics, as well as more details on moving drugs through agency approvals.

Draft Guidance for Industry and FDA Staff: Technical Considerations for Pen, Jet and Related Injectors Intended for Use with Drugs and Biological Products, April 2009.) The Guidance recognizes that these are innovative approaches to deliver drugs or biologics products that may enhance accuracy and patient compliance.

One major significant issue of this Guidance lies in its application to biosimilars, facilitating their conversion into higher-value follow-on branded products. As an example, Novo Nordisk is now introducing its next-generation FlexPen, a prefilled insulin delivery device that the company reports has a 25–41% lower force than the existing SoloStar and KwikPen devices; diabetic patients prefer lower-force insulin injections since they are less painful.

After obtaining FDA approval to market in the U.S., a first-generation biologic may have little commercial value as a commodity product and have a BX rating (not substitutable), since most biopharma companies have developed a second- or third-generation biologic with an innovative delivery system—a specialty product. It is anticipated that specialty products will command prices near or only 10–20% less than that of the originator product, even though they will not have a BX rating. In this scenario, the initial approval of the first-generation biosimilar is really a strategy to rapidly enter the marketplace, then quickly evolve into a higher-value specialty, often called a follow-on branded product.


CMC Issues and Regulatory Requirements for Biosimilars

Dr. Bao-Lu has exposed very important CMC Issues and Regulatory Requirements for Biosimilars in


Chemistry, Manufacturing and Controls (CMC), preclinical and clinical are three critical pieces in biosimilars development. Unlike a small-molecule generic drug, which is approved based on “sameness” to the innovator’s drug; a biosimilar is approved based on high similarity to the original approved biologic drug. This is because biologics are large and complex molecules. Many functional-, safety- and efficacy-related characteristics of a biologic depend on its manufacturing process. A biosimilars manufacturer won’t be able to exactly replicate the innovator’s process. The traditional abbreviated pathway for generic drug approval through the Hatch- Waxman Act of 1984 doesn’t apply for biosimilars as drugs and biologics are regulated under different laws. New laws and regulations are needed for biosimilars approval in the US. The EU has issued biosimilars guidelines based on comparative testing against the reference biologic drug (the original approved biologic). A full scale CMC development is required including expression system, culture, purification, formulation, analytics and packaging. The manufacturing process needs to be developed and optimized using state-of-the-art technologies. Minor differences in structure and impurity profiles are acceptable but should be justified. Abbreviated clinical testing is required to evaluate surrogate markers for efficacy and demonstrate no immunogenic response to the product.

We anticipate the package for a biosimilars approval in the US will be similar to that in the EU and contain a full quality dossier with a comparability program including detailed product characterization comparison and reduced preclinical and clinical requirements.

Biosimilars Become Inevitable

Biologics developed through biotechnology constitute an essential part of the pipeline for medicines available to patients today. Biologic drugs are quite expensive and many of them are top-selling medicines (see Table 1). Since they come at extremely high prices to consumers, some patients may not be able to afford the use of biologics as the best-available treatments to their conditions. The patent protection on a large number of biologics has expired since 2001. These off-patent biologics include Neupogen, Novolin, Protropin, Activase, Epogen or Procrit, Nutropin, Humatrope, Avonex, Intron A, and Humulin. Traditionally, when a drug patent expires, a generic drug will be quickly developed and marketed. Similarly, generic version of off-patent biologic drugs (also referred to biosimilars or follow-on biologics or biogenerics) represents an extraordinary opportunity to companies that want to seize the potentially great commercial rewards in this unexploited territory. Biosimilars not only benefit the biosimilar manufacturers but also can save patients, and insurance companies, substantial cost and allow patients to gain access to more affordable biologics resulting in market expansion. The government can use biosimilars to reduce healthcare costs. Therefore, development and marketing of bosimilars are supported by both manufacturers and consumers.

Differences between Generic Drugs and Biosimilars

Enacted in 1984, the US Drug Price Competition and Patent Term Restoration Act, informally known as the “Hatch-Waxman Act of 1984” standardized US procedures for an abbreviated pathway for the approval of small-molecule generic drugs. The generic drug approval

is based on “sameness”. In comparison to the innovator’s drug, a generic drug is a product that has the same active ingredient, identical in dose, strength, route of administration, safety, efficacy, and intended use. For approval, the generic companies can go through the Abbreviated

New Drug Application (ANDA) process with reduced requirement in comparison to approval for a new drug entity. The generic drugs need to show bioequivalence to the innovator drugs typically based on pharmacokinetic parameters such as the rate of absorption or bioavailability in 24 to 36 healthy volunteers. No large clinical trials for safety and efficacy are required. The generic companies can rely on the FDA’s previous findings of safety and effectiveness of the innovator’s drugs.

However, the abbreviated pathway for generic drugs legally doesn’t apply to biologics as small-molecule drugs and biologics are regulated under different laws and approved through different pathways in the US (Table 2). Small-molecule drugs are regulated under the Food, Drug and Cosmetic Act (FD&C) and require submission of a New Drug Application (NDA) to FDA for drug review and approval. Biologics are regulated under the Public Health Service Act (PHS) and require submission of a Biologic License Application (BLA) to FDA for review and approval. The Hatch-Waxman Act of 1984 doesn’t apply for biosimilars. New laws are needed to establish a pathway for biosimilar approval.

There are some crucial differences between biologics and small-molecule drugs. Small-molecule drugs are made from chemical synthesis. They are not sensitive to process changes. The final product of a small-molecule drug can be fully characterized. The developmentand production of generic drugs are relatively straightforward. Biologics are made from living organisms so that its functional-, efficacy- and safety-related properties depend on its manufacturing and processing conditions. They are sensitive to process changes. Even minor modifications of the manufacturing process can cause variations in important properties of a biological product. Thus it is believed that a biologic product is defined by its manufacturing process. Biologics are 100- or 1,000-fold larger than small-molecule drugs, possess sophisticated three-dimensional structures, and contain mixtures of protein isoforms. A biological product is a heterogeneous mixture and the current analytical methods cannot characterize these complex molecules sufficiently to confirm structural equivalence with the reference biologics.

Laws and Regulatory Pathways for Drug Approval in the US

Law/Application             Small-molecule            Drug Biologics                     

Law             Food, Drug and Cosmetic Act (FD&C)             Public Health Service Act (PHS)

Drug application   New Drug Application (NDA)   Biologic License Application (BLA)

Generic application   Abbreviated New Drug Application(ANDA)   NEW pathways beyond BPCIA, 2009

Differences between small-molecule drugs and biologics

Product characteristics

Small-molecule generics Small, simple molecule

(Molecular weight: 100-1,000 Da)

Biosimilars   Large, complex molecules, Higher order structures, Post-translational, modifications

(Molecular weight: 15,000-150,000 Da)


Small-molecule generics Produced by chemical synthesis

Biosimilars  Produced in living organisms

Analytical testing

Small-molecule  Well-defined chemical structure, all its various components in the finished drug can be determined

Biosimilars  Heterogeneous mixture, difficult to characterize, some of the components of a finished biologic may be unknown

Process dependence

Small-molecule   Not sensitive to manufacturing process changes. The finished product can be analyzed to establish the sameness.

Biosimilars   Sensitive to minor changes in manufacturing process. The product is defined by the process

Identity and purity

Small-molecule Often meeting pharmacopeia or other standards of identity (e.g., minimums for purity and potency)

Biosimilars   Most have no pharmacopeia monographs

immunogenicity issues prior to 1998. When J&J made a change in the Eprex formulation by replacing human serum albumin (HAS) with polysobate 80 and glycine in response to the

request from European health authorities, some patients developed pure red-cell aplasia (PRCA), a severe form of anemia. Eprex induced antibodies neutralize all the exogenous rHuEPO and cross-react with endogenous erythropoietic proteins. As a result, serum EPO is undetectable

and erythropoiesis becomes ineffective. Upon investigation, J&J found that polysorbate 80 might have caused uncoated rubber stoppers in single-use Eprex syringes to leach plasticizers, which stimulated an immune response that resulted in PRCA. Replacing with Teflon coated stoppers resulted in 90% decrease in PRCA by 2003 [3,4]. The effect of neutralizing antibodies has not always resulted in serious clinical consequences. Three interferon beta products, Betaseron, Rebif and Avonex, are marketed by three different companies. These products induce neutralizing antibodies in multiple sclerosis patients from 5 to 50% after one year treatment. Although these antibodies might be associated with loss of efficacy of treatment resulting in some patients to withdraw from the treatment, it seems no other severe adverse effects were detected [5,6].

Regulatory Landscape

The US, the EU and Japan are the three cornerstonemembers of the International Conference on Harmonization (ICH), which intends to harmonize the regulatory requirements for drug or biologic approval in these three regions. With the other two members, the EU and Japan, already have established biosimilar approval procedures (see below), the US lags behind in the biosimilar race. There are no formal approval pathways for biosimilars in the US. Congress needs to establish a legal framework in order for FDA to develop guidelines. Legislation has been under discussion in Congress since 2007. The legislative debate is centered on patient safety and preserving incentives to innovate with introduction of biosimilars. Two bills introduced in March 2009 deserve attentions [7,8]. The Waxman bill (H.R. 1427) proposes 5 years of market exclusivity to the innovator companies and requires no clinical trials for biosimilar development. The Eshoo bill (H.R. 1548) proposes 12 years of market exclusivity to the innovator companies and requires clinical trials for biosimilar development. Obama administration appears to favor a 7-year market exclusivity [9]. Once a legal framework is established for biosimilars, the FDA will likely take a conservative approach using the comparability as an approval principle. Clinical proof of efficacy and safety will be required, probably in reduced scale.

In the EU, the European Medicines Agency (EMEA) issued regulatory guidelines for approving biosimilars in 2005 (Figure 1) [10-16]. These include two general guidelines for quality issues [11] and non-clinical and clinical issues [12] and four class-specific annexes for specific data requirements for Granulocyte-Colony Stimulating factor (G-CSF) [13], Insulin [14], Growth hormone [15] and Erythropoietin [16]. In addition, a concept paper on interferon alpha [17] is also available. So far, there are eleven biosimilar products which received market authorization in the EU and they are biosimilar versions of human growth hormone, Epoetin and filgrastim. It is estimated six to eight years on average for a biosimilar to be developed [18].

The EMEA treats a biosimilar medicine as a medicine which is similar to a biological medicine that has already been authorized (the “biological reference medicine”) in the EU, The active substance of a biosimilar medicine is similar to the one of the biological reference medicine.

A biosimilar and the biological reference medicine are used in general at the same dose to treat the same disease. A biosimilar and the biological reference medicine are not automatically interchangeable because biosimilar and biological reference medicine are only similar but not identical. A physician or a qualified healthcare professional should make the decision to treat a patient with a reference or a biosimilar medicine. Since the biosimilar may contain different inactive ingredients, the name, appearance and packaging of a biosimilar medicine differ to those of the biological reference medicine. In addition, a pharmacovigilance plan must be in place for post-marketing safety monitoring.

Japan’s Ministry of Health, Labor and Welfare (MHLW) issued guidelines for follow-on proteins or biosimilars approval in March 2009. The first biosimilar, Sandoz’ growth hormone Somatropin, was approved in June 2009. The MHLW’s guidelines consider biosimilars drugs which are equivalent and homogeneous to the original biopharmaceuticals in terms of quality, efficacy and safety. Biosimilars are also requested to be developed with updated technologies and knowledge. Biosimilars need to demonstrate enough similarity to guarantee the safety and efficacy instead of absolute identity to the original biologics. Biosimilars’ regulatory approval applications will be categorized separately from conventional generic drugs. In general, the applications should be submitted, as the new drug applications, with data from clinical trials, manufacturing methods, long-term stability and information on overseas use. The MHLW will assess the data on absorption, distribution, metabolism and excretion (ADME) on a case-by-case basis. The applications do not need to provide data on accessory pharmacology, safety pharmacology and genotoxicity.

Biosmilars are already thriving in Eastern Europe and Asia, where regulatory and intellectual property (IP) standards for biosimilars are more liberal. Biosimilars developed in these regions are primarily sold domestically. These markets are considered less controlled. The quality of the biosimilars may not be in full compliance with ICH guidelines although they are often developed through comparative quality testing and clinical trials against the biologics which are already approved in Western countries

 Comparability Demonstration

 A comparability exercise based on the ICH guideline [22] needs to be performed to demonstrate that the biosimilar product and the reference biologic product have similar profiles with respect to product quality, safety, and efficacy. This is accomplished by comparative testing of the biosimilar product and the reference biologic product to demonstrate they have comparable molecular structure, in vitro and in vivo biological activities, pre-clinical safety and pharmacokinetics, and safety and efficacy in human patients. Comparison of quality attributes between the biosimilar and the reference biologic product employs physicochemical and biological characterization. Comparability on physical properties, amino acid sequence, high order structures, post-translationally modified forms are evaluated by physicochemical tests. In vitro receptor-binding or cell-based (binding) assays or even the in vivo potency studies in animals need to be performed to demonstrate comparable activity despite they are often imprecise. Levels of product related impurities (aggregates, oxidized forms, deamidated forms) and process related impurities and contaminants (host cell proteins, residual genomic DNA, reagents, downstream impurities) need to be assessed and quantified. Stability profiles of the biosimilar product and the reference biologic product also need to be studies by placing the products under stressed conditions. The rate of degradation and degradation profiles (oxidation, deamidation, aggregation and other degradation reactions) will be compared. If unknown degradation species are detected, they need to be studied to determine if they affect safety and efficacy. If differences on product purities and stability profiles are present between the biosimilar product and the reference biologic product, these differences need to be justified using scientific knowledge or preclinical or clinical studies. Changes in the impurity profile should be justified as well.

The demonstration of comparability in quality attributes does not necessarily mean that the biosimilars and the reference biologics are identical, but that they are highly similar. In many cases, the relationship between specific quality attributes and safety and efficacy has not been fully established. For example, physicochemical characterization cannot easily predict immunogenicity and slight changes in manufacturing processes or product composition can give rise to unpredicted changes in safety and efficacy. Changes in bioavailability, pharmacokinetics, bioactivity bioactivity, and immunogenicity are the main risks associated with the manufacturing of biosimilars. In vivo studies should be designed to measure the pharmacokinetics and pharmacodynamics relevant to clinical studies. Such in vivo studies should be designed to detect response differences between the biosimilar and the reference biologic not just responses per se. In vivo studies of the biosimilar’s safety in animals may be used to research any concerns into the safety of the biosimilar in human patients. Although extensive clinical testing is not necessary for biosimilars, some degree of clinical testing is needed to establish therapeutic comparability on efficacy and safety between the biosimilar and the reference biologic product [23,24]. This includes using surrogate markers of specific biologic activity as endpoints for demonstrating efficacy, and showing that patients didn’t develop immunogenic responses to the product. In general, the approval of biosimilars will be based on the demonstration of comparable efficacy and safety to an innovator reference product in a relevant patient population. Clinical data requirement for each individual product will be different and will be determined on a case-by-case basis.

Small-molecule Generics versus Biosimilars


  • Approval based on “sameness”


  • Approval based on “high similarity”


  • Replicate the innovator’s process and product and perform a bioavailability study demonstrating similar pharmacokinetic properties


  • Full CMC development with comparative testing, conduct substantial clinical trials for efficacy and safety including immunogenicity


  • Abbreviated registration procedures in Europe and US


  • Regulatory pathway is defined in EU on “Comparability” status, no pathway yet in US under BLA


  • Therapeutically equivalent, thus interchangeable


  • Lack of automatic substitutability


  • $1 to $5 million to develop


  • $100-$200 million to develop


  • Brand-to-generic competition


  • Brand-to-Brand competition


The patent provisions of the Biosimilar Act, 2009 establish demanding and time-sensitive disclosure requirements. ObamaCare upheld by the Supreme Court is a victory for future development of pathways for biosimilar regulatory approval and eventually biosimilar generic drugs.

Biosimilars are defined as biological products similar, but not identical, to the reference biological products that are submitted for separate marketing approval following patent expiration of the reference biological products. As one of the ICH members, the US needs to catch up with the EU and Japan as those two countries have already issued regulatory guidelines for biosimilars. 2009 and 2012 represent milestones in the regulatory provisions for biosimilars in the US.

Once Congress establishes a legal framework, FDA is expected to set up a biosimilar approval pathway which will be similar to those in the EU and Japan and harmonized under ICH. The biosimilar will need a full CMC development package plus demonstration of comparable quality attributes and comparable efficacy and safety to the innovator’s product. Table 5 provides a comparison summary between small-molecule generics and biosimilars. It will take a much bigger effort to develop a biosimilar than a generic drug. Automatic substitution between the innovator product and a biosimilar is not appropriate as a biosimilar is not a generic version of the innovator product and is approved based on comparability to the innovator product.


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