5 Lessons From FDA’s First Biosimilar Review

Lisa Mueller, partner in Michael Best’s Intellectual Property and Chair of the Life Sciences and Chemical Practice Groups and Laura Opperman, Ph.D., a Patent Scientist in the Intellectual Property Practice group, gave input for a Law360 article titled, “5 Lessons From FDA’s First Biosimilar Review – Law360,” on January 8, 2015. To view the full article, click here.

Inching Closer to the First Biosimilar Approval in the U.S.

Last week we saw some significant biosimilar activity in the U.S. Specifically, on January 7, 2015, a U.S. Food and Drug Administration (FDA) Advisory Committee (Advisory Committee) voted 14-0 to approve Sandoz Inc.’s (Sandoz) filgrastim biosimilar (referred to as “EP2006”) for all five indications of Neupogen® (the reference product manufactured by Amgen Inc. (Amgen)).  Specifically, the Advisory Committee found EP2006 to be “highly similar” to filgrastim, “notwithstanding minor differences in clinically inactive components,” and that “there are no clinically meaningful differences between EP2006 and filgrastim in terms of [purity], safety, and effectiveness.”  Typically, the FDA follows an Advisory Committee’s recommendation, although it is not required to do so.  Assuming the FDA follows the Advisory Committee’s recommendation, EP2006 would be the first biosimilar approved under the FDA’s 351(k) biosimilar pathway.  Sandoz manufactures a biosimilar version of filgrastim under the brand name Zarzio® in more than 40 countries. For example, Zarzio® was first approved in the European Union in 2009.

As mentioned above, EP2006 received a recommendation for approval in five indications (all of which are somewhat related):  (1) cancer patients receiving myelosuppressive chemotherapy; (2) patients with acute myeloid leukemia receiving induction or consolidation chemotherapy; (3) cancer patients receiving bone marrow transplant; (4) patients undergoing peripheral blood progenitor cell collection and therapy; and (5) patients with severe chronic neutropenia.  Interestingly, because Sandoz provided Phase III data for only one of the five indications, the remaining four indications were awarded by extrapolation.

Extrapolation is highly controversial but viewed as crucial in keeping the research and development costs down for biosimilars.  It will be interesting to see how the FDA handles extrapolation with more complex molecules (such as antibodies), which have been approved for very distinct applications (such as, for example, infliximab and adalimumab, which are approved for such distinct indications such as rheumatoid arthritis, ulcerative colitis and Crohn’s disease).  For example, in Europe, Celltrion Inc. (Celltrion) was able to fully extrapolate to six indications (including psoriasis and digestive disorders) for its biosimilar version of infliximab.  However,  extrapolation was not permitted in Canada where regulators found that differences between Celltrion’s biosimilar and the reference product raised questions about whether the biosimilar infliximab would be suitable for every condition.

Sandoz’ requested approval for EP2006 as a biosimilar to Neupogen® and not as an interchangeable product.  However, switching studies are in process that could support a future interchangeability application.  Publication of the FDA’s guidance document on interchangeability is expected in 2015.

One significant issue not discussed by the Advisory Committee or in its briefing document released prior the meeting was naming.  Will Sandoz’ product have the generic name filgrastim or some variant?  Novartis proposed the brand name, Zarxio for EP2006.  However, this brand name has not yet been approved by the FDA.  Industry is still waiting publication of the FDA’s guidance document on naming.

Despite the good news, significant challenges still remain for Sandoz and its biosimilar product.  On January 6, 2015, the day before the Advisory Board’s vote, Amgen filed a motion for partial summary judgment in its lawsuit filed against Sandoz on October 24, 2014.  Specifically, Amgen urged a California federal judge to find that pursuant to the Biologics Price Competition and Innovation Act (BPCIA) Sandoz was required to provide Amgen with a copy of its 351(k) application for its biosimilar product as well as its manufacturing information no later than 20 days after the FDA notified Sandoz of acceptance of its 351(k) application.  Additionally, Amgen requested that the judge find that Sandoz could not have provided notice of commercial marketing as required under the BPCIA because the FDA had not yet approved Sandoz’ 351(k) application.  Thus, according to Amgen, Sandoz’s conduct violated the BPCIA and this violation represented unfair competition under California law.  Unfortunately, this litigation will likely need to be resolved before EP2006 can enter the marketplace.  Resolution could be years away thus  further delaying entry of the first biosimilar product into the U.S. marketplace.

This post was written by Lisa Mueller.

Be Mindful of Your Claims in Divisional Applications and Patents in South Africa


In September 2014, the Supreme Court of Appeal of South Africa (Supreme Court) issued a decision in Pharma Dynamics (Proprietary) Limited (Pharma) versus Bayer Pharma AG (formerly Bayer Schering Pharma AG) and Bayer (Proprietary) Limited (Bayer Pharma AG and Bayer Limited will be collectively referred to as “Bayer”) relating to Bayer’s South African Patent No. 2004/4083 entitled “Pharmaceutical combination of ethinylestradiol (EE) and drospirenone (DSP)” (the 2004 patent).  A copy of the decision is provided here: DECISION.  The decision is important because the Court held that while it is possible to obtain parent and divisional patents in South Africa having overlapping claims of varying scope, coterminous claims (meaning claims of identical scope) are not permitted.

The claims of the 2004 patent relate to a female contraceptive sold by Bayer under the brand name Yasmin® which is a combination of the DSP and EE.  The 2004 patent is a divisional patent of South African Patent No. 2002/1668 (the 2002 patent).  Claim 1 of the 2004 patent recites:

1.  A pharmaceutical composition comprising:

as a first active agent drospirenone in an amount corresponding to a daily dosage, on administration of the composition, of  from about 2 mg to 4 mg, and

as a second active agent ethinylestradiol in an amount corresponding to a daily dosage of from about 0.01 mg to 0.05 mg,

together with one or more pharmaceutically acceptable carriers or excipients,

wherein at least 70% of said drospirenone is dissolved from said composition within 30 minutes, as determined by USP XXIII Paddle Method II using water at 37ºC as the dissolution media and 50 rpm as the stirring rate.

In contrast, claim 1 of the 2002 patent recites that the drospirenone is in micronized form.

In March 2011, Pharma obtained approval from the Medical Control Council in South Africa to import and sell “Ruby”, a generic version of Yasmin®.  Bayer alleged infringement of claim 1 of the 2004 patent by Pharma and sought judicial relief in the form of an interdict and ancillary relief.  Pharma denied infringement and counterclaimed for revocation of the 2004 patent alleging invalidity.  The lower court, a quo, held that the 2004 patent was valid and infringed by Pharma.  The relief requested by Bayer was granted and Pharma’s counterclaim dismissed.  Pharma appealed.  On appeal, regarding invalidity, Pharma argued that the 2004 patent lacked inventive step and was not a “true” divisional of the 2002 patent and thus lacked novelty in view of the disclosure in the 2002 patent.

In South Africa, divisional patent applications are governed by Section 37 of the Patents Act (Section 37) which provides:

1.  Where at any time after an application has been lodged at the patent office and before it is accepted, a fresh application is made in the prescribed manner by the same applicant in respect of part of the matter disclosed in the first-mentioned application, the registrar may, on application made to him in the prescribed manner before that application is accepted, direct that such fresh application be antedated to a date not earlier than the date on which the first-mentioned application was so lodged.

2.  A patent granted on such fresh application shall not be revoked or invalidated on the ground only that the invention claimed in such fresh application is not new having regard to the matter disclosed in the first-mentioned application.

Pharma made several arguments as to why it believed the 2004 patent was not a “true” divisional.  Specifically, Pharma argued that the “body”and the claims of the 2002 and 2004 patents were the same,  and that Section 37 did not allow for a divisional claim to be broader than the claim of its parent.

The Supreme Court rejected all of Pharma’s arguments. First, the Court noted that the very idea of a divisional patent is that it contains the same text as its parent.  From a practical standpoint, this made sense since the invention disclosed in a divisional and parent was the same and the difference between the two resided in their respective claims.  Next, the Court stated that the claims of the 2002 and 2004 patents were not coterminus (namely, the claims of each did not have identical scope).  Specifically, claim 1 of the 2002 patent was expressly limited to DSP in micronized form.  Claim 1 of the 2004 patent did not recite that DSP was limited to any specific form.  Thus, claim 1 of the 2004 patent was broader than claim 1 of the 2002 patent. Finally, the Court examined previous case law and found that there was nothing that prohibited the claims of a divisional application from being broader than the claims of its parent.  Instead, the Court noted that previous case law stood for the proposition that the claims of a divisional application could not be broader than the invention disclosed in the “body” of its parent.

Under South African patent law, a single invalid claim in a patent renders the entire patent invalid and unenforceable until such invalidity has been cured via an amendment.  Therefore, in view of this recent decision and the fact that patent applications are not formally examined in South Africa, applicants should carefully review the claims of any of their divisional patent applications and patents to make sure that none of the claims is identical in scope (coterminus) with one or more parent applications or patents.

This post was written by Lisa Mueller.

Happy New Year!

Happy New Year from the BRIC Wall Blog!  We would like to take this opportunity to thank our readers for for their interest and support during 2014!!!  We have been taking a short break for the Christmas holidays but will be resuming with a new post starting on January 5, 2015!  Our goal for 2015 is to have more frequent and regular posts.  We would love to receive your comments and suggestions on topics you would like to read about in the new year!

A new list of strategic products creates opportunities for companies in Brazil

On December 17, 2014, the Ministry of Health (Ministry) published a new list of strategic products replacing the previous list established by Ordinance #3089/2013. Interestingly, the Ministry published the list without allowing for any comment and/or suggestion by industry.  The publication of the new list follows the November 13, 2014 publication of the new Productive Development Partnership (PDP) guidelines.

The list contains 11 pharmaceutical drugs and 10 medical devices.  In 2015, these drugs and devices will be the focus of the government for new PDPs partnerships.  Specifically, from January 1st until April 30, 2015, public and private industries will have an opportunity to submit partnership proposals for the PDP program as provided by Article 13 of Ordinance #2531/2014.

Included within the list of pharmaceutical drugs are six biologics which are likely to grab the attention of the industry.  These biologics are:  adalimumab (Humira®), filgrastim (Neupogen®), infliximab (Remicade®), rituximab (Rituxan®), somatropin and L-asparaginase.  Companies developing biosimilars of these biologics can contact a Brazilian public institution in order to discuss the possibility of submitting a PDP proposal (up to April 30, 2015) for approval by the Brazilian government.  The selection of the right public institution coupled with the submission of a well prepared proposal that follows the guidelines established by Ordinance #2531/2014 is of paramount importance in obtaining the government approval needed to start a PDP project.

Please find attached the full text of Ordinance #2531/2014 as well as the new list of strategic products. Ordinance List

This post was written by Lisa Mueller and Roberto Rodrigues of Licks Attorneys.

2014 Year in Review of U.S. Biosimilar Activity

Lisa Mueller, partner and Chair of the Life Sciences and Chemical Practice Groups, and Laura Opperman, Patent Scientist and member of the Intellectual Property Practice group at Michael Best & Friedrich LLP, published an article on Law360 highlighting activity taking place in respect to biosimilars in 2014.

Here is a short excerpt: “This year witnessed significant activity in the U.S. with respect to biosimilars. Highlights include issuance by the U.S. Food and Drug Administration of two new guidances, further debate over the naming of biosimilars, acceptance by the FDA of the first biosimilar application, publication of the “Purple Book” and continued legal wrangling over the so-called patent dance patent resolution provisions added to the Public Health Service Act by the Biologics Price Competition and Innovation Act of 2009…” Click here to read more of Lisa and Laura’s article.

The Breadth of India’s “Bolar Exemption”

Section 107A of the Indian Patents Act, 1970 (Patents Act) is generally referred to as India’s “Bolar exemption”. This section provides a defense for patent infringement in those instances when an invention is used or sold by a third party for purposes related to research and development. Specifically, this section recites:

107A. Certain acts not to be considered as infringement – For the purposes of this Act,—

(a) any act of making, constructing, using, selling or importing a patented invention solely for uses reasonably related to the development and submission of information required under any law for the time being in force, in India, or in a country other than India, that regulates the manufacture, construction, use, sale or import of any product;

(b) importation of patented products by any person from a person who is duly authorized under the law to produce and sell or distribute the product,

shall not be considered as an infringement of patent rights.”

On November 5th, in Bayer Corporation (Bayer) v. Union of India & Ors (NPL), the High Court of Delhi (Court) examined the scope of India’s Bolar exemption. Specifically, the issue to be decided in this case was whether the exportation of an active pharmaceutical ingredient (API) constituted a defense to infringement under Section 107A of the Patents Act.

Case history 

Bayer owns Indian Patent 215758 (the ‘758 patent) that claims sorafenib tosylate (sorafenib) and expires on January 12, 2020. Sorafenib is used to treat patients with advanced kidney and liver cancer and is sold under the brand name “Nexavar”. Sorafenib has been shown to extend the life of patients suffering from kidney cancer by four to five years and six to eight months for those suffering from liver cancer. 

Bayer alleged that NPL was manufacturing a product that infringed the claims of the ‘758 patent and filed a civil suit to restrain NPL from launching, making, using, offering for sale, selling and importing sorafenib, any product containing sorafenib or any other product encompassed by the claims of the ‘758 patent. On March 9, 2012, NPL applied for and received a compulsory license to manufacture pharmaceutical products covered under the ‘758 patent. The compulsory license allowed NPL to manufacture a pharmaceutical product covered by the ‘758 patent under certain terms and conditions. Specifically, the license was “solely for the purpose of making, using, offering for sale and selling the drug covered by the patent for the purpose of treating HCC and RCC in humans within the territory of India(emphasis added). As a result of the compulsory license, NPL has been manufacturing a product under the brand name “Sorafenat”. However, under the terms of the license, NPL is not permitted to export Sorafenat. 

After the compulsory license was granted, Bayer filed an application at the Indian Patent Office seeking termination, revocation/cancellation of the compulsory license. Additionally, during this time, Bayer received information that Sorafenat was being exported by NPL in violation of the terms of the compulsory license. After learning this information, Bayer filed a writ petition with the Court requesting that the product covered under the compulsory license be confiscated and any consignment for export be seized. On March 26, 2014, the Court passed an interim order directing NPL to ensure that no consignment containing Sorafenat covered by the compulsory license was exported. 

In the present case, NPL sought permission to export 1 kilogram of sorafenib to Hisun Pharmaceutical Co. Ltd. (HPCL), a Chinese pharmaceutical company, for the purpose of conducting development/clinical studies and trials. NPL produced a certificate from HPCL stating that the company required the 1 kilogram of sorafenib for the purpose of “formulation R&D purpose and the same was not intended for any commercial purpose”. In addition, NPL filed an affidavit stating that the 1 kilogram of sorafenib was for the purposes of preparing a trial batch of a generic version of the drug. NPL also stated that for purposes of seeking regulatory approval in China, bio-availability, bio-equivalence and stability studies would be required (per the Chinese Rules and Regulations) and that samples from three consecutive batches of production would be needed (each batch required 1 to 2 kilograms of sorafenib).


NPL argued that the 1 kilogram of sorafenib was required for conducting regulatory studies in China and despite the compulsory license, export of the API was exempt pursuant to Section 107A. Bayer argued that the regulatory approvals in China were being sought by HPCL and not by NPL. Bayer contended that the export of 1 kilogram of sorafenib was simply a “commercial transaction” and use by HPCL would not color the transaction. Bayer further argued that exportation of sorafenib was not permitted by the terms of the compulsory license and would not fall within the scope of Section 107A. Bayer stressed that the use by a third party of sorafenib for development purposes did not entitle NPL to infringe Bayer’s patent. Additionally, Bayer argued that because NPL was not conducting any development studies, exportation of sorafenib to HPCL could not be construed to be solely for uses related to the development and submission of information required by any regulatory authority. Finally, Bayer noted that Section 107A did not permit export of Bayer’s product because the word “export” was missing from the section.

The decision

After a review of the facts, the Court accepted that the product NPL sought to export was not for commercial purposes since the amount was only sufficient to make 1000 to 2000 tablets (which was approximately the single trial batch size required by the Chinese Regulatory Authorities). Thus, according to the Court, the only question that had to be addressed was whether Section 107A covered export of a patented product for use by an overseas importer to conduct studies and generate data for the purpose of seeking regulatory approval in that country. 

After reviewing the history of the Bolar exemption in the U.S., India’s accession to the TRIPS agreement, the introduction of Section 107A in the Patents Act in 2002 and its subsequent amendment in 2005, the Court stated that the exclusion to a patentee’s right as provided under Section 107A was wider than the exceptions provided by the laws of the U.S. Specifically, the Court stated: 

“India is one of the largest producers of generic versions of drugs around the world. Given the economic realities of our country, providing cheaper medicines is a necessity. The parliament in its wisdom has, thus couched the exclusion to a patent, as provided under Section 107A, in wide terms. The sweep of the plain language of Section 107A, thus, cannot be restricted in the manner as canvassed on behalf of Bayer. 

…Plainly, Section 107A of the Act takes within its fold any sale of a patented invention which is required for development and submission of information under any law in a country other than India that regulates the manufacture or sale of any product. Indisputably, under the Chinese Law, submission of studies and data related to bio-equivalence and bio-availability of API in a generic version, is required as discussed earlier and the sale of 1 kg. of Sorafenat to HPCL can be reasonably stated to be related to the studies that are required to be conducted by HPCL for obtained the regulatory approvals. 

…[t]he language of Section 107A of the Act is determinative of the question whether export as sought for by NPL is permissible within the exemption of Section 107A of the Act. The use of the expression ‘reasonably related to’ as used in Section 107A of the Act would plainly mean a reasonably nexus. Thus, the only question that needs to be answered is whether there is any reasonable nexus between the sale of Sorafenat by NPL to HPCL and submission of information under the law in force in China. In my view, the answer to this question is clearly in the affirmative. 

…It is also important to note that the language of Section 107A of the Act is materially different from the law as applicable in U.S. Whilst, the US Law restricts the safe harbour to a sale within United States and solely for purposes related to information under a Federal Law, Section 107A of the Act is circumscribed by no such conditions. Thus, a sale even outside India would fall within the sweep of Section 107A, provided it is reasonably related to development and submission of information as required under a law in force in India or outside India.”

The Court also rejected Bayer’s arguments that the language of Section 107A excluded “exports” because this term was not specifically recited. Specifically, the Court stated:

“I am not inclined to accept this contention for the reason that the expression ‘selling’ is wide enough to even include cross border sales (i.e. exports). If the Parliament intended to restrict the exception to only sales within India, the same would have been expressly stated as was done by the US Congress under 35 US Code 271(e)(1).”

Finally, the Court examined the question of whether Section 107A should be read to include only sales made “within” India. The Court answered the question in the negative for three reasons: 

1.  The plain language of the section did not support such an interpretation. Specifically, there were no “words or expressions” that allowed such a restriction to be read into this section. In fact, to the contrary, Section 107A expressly permits use for submission as required by the laws outside of India.

2.  Even if a purposive interpretation of Section 107A is attempted, such an interpretation favors permitting export. According to the Court: 

“[T]he purpose for excluding development activities and uses for regulatory approvals is to ensure that exploitation of patented invention is not restricted beyond the period or sphere of exclusivity granted to the patentee. Thus, although initiative and effort of an inventor must be rewarded, the protection is limited and should not stifle further development and restrict participation beyond the period of exclusivity. There is a strong case for enhancing availability of essential drugs at affordable prices and the safe harbor exception must extend to permit developing overseas sources also.” 

3.  National barriers offer only limited barriers to trade. As a result, confining the exclusion of Section 107A to sales within India would not aid the object of such exclusion. 

This article was written by Lisa Mueller.