An Update on Biosimilar Activity in the U.S.

  1. Developments in Amgen v. Sandoz

Since the Federal Circuit’s July 21, 2015 decision in Amgen v. Sandoz, the biopharmaceutical industry and legal community have been paying close attention to the development of parties’ appeals in this continuing litigation. As anticipated by many, both Amgen and Sandoz filed petition for rehearing en banc on August 20, 2015. Additionally, on August 26, 2015, in an effort to keep Zarxio™ (a biosimilar of Amgen’s Neupogen® (filigrastim) product), off the market after September 2, 2015 (the last day of the 180-day exclusivity period), Amgen filed an emergency motion for an injunction pending en banc consideration. A copy of the petitions filed by Amgen and Sandoz for en banc review and Amgen’s emergency motion can be found here:  Amgen – petition for en banc rehearing (8-20-2015) — 17681771 v1, Sandoz – petition for en banc rehearing (8-20-2015) — 17681773 v1.

Is the “Patent Dance” Optional or Mandatory? 

On the issue of whether it is mandatory that a biosimilar applicant (Sandoz) disclose its biosimilar application (aBLA) and manufacturing information to a reference product sponsor (RPS (Amgen)) under section (l)(2)(A) of the Biologics Price Competition and Innovation Act (BPCIA), thus initiating the information exchange process known as “patent dance,” the panel (with Judge Lourie and Judge Chen forming the majority, and Judge Newman dissenting, on this issue) ruled that Sandoz did not violate the BPCIA by not disclosing its aBLA and manufacturing information. Specifically, the majority ruled that the only remedies available to Amgen under these circumstances were those based on patent infringement (under 42 U.S.C. § 262(l)(9)(C) and 35 U.S.C. § 271(e)). In other words, by the panel’s ruling, a biosimilar applicant may opt out of the initial disclosure requirement to avoid “patent dance” all together and only face patent infringement claims by the RPS without having to worry about BPCIA-based injunctions.

In its petition for rehearing en banc, Amgen emphasizes that the majority’s rule on this issue “is contrary to the plain language of the statute, and Congress’ intent that the BPCIA provide an integrated framework that balances the obligations and benefits of the Applicant and the Sponsor.” (Amgen Petition, at page 2). Specifically, Amgen argues that Congress tied an applicant’s choice to use the 351(k) pathway to providing its aBLA and manufacturing information to the sponsor (i.e. the “shall provide” and “information required” language of 42 U.S.C. § 262(l)(1)(B)(i)).  (Amgen Petition, at pages 3-4). Quoting Judge Newman’s dissenting opinion that the BPCIA “ensure[s] that litigation surrounding relevant patents will be resolved expeditiously and prior to the launch of the biosimilar product,” Amgen argues that the statutory purpose also confirms the obligation of the biosimilar applicant to provide aBLA and manufacturing information. (Amgen Petition, at page 10).

Further, Amgen argues that the patent-based actions are not the exclusive remedies available to the RPS. Specifically, Amgen argues that section 262(l)(9)(C) of the BPCIA only prohibits a non-compliant biosimilar applicant (who chooses not to disclose the aBLA and manufacturing information) from bringing certain kinds of declaratory judgment actions, while that prohibition is lifted for the aggrieved party, namely, the RPS. (Amgen Petition, at pages 11-12). Amgen further argues that patent infringement actions are only “among the tools available to a Sponsor where an Applicant refuses to comply with the BPCIA[,]” and that the RPS and the court should be able to use “broad powers under federal and state laws to remediate the harms to . . . [the] property rights caused by an Applicant’s failure to comply with the BPCIA[,]” as the harms to the RPS are not limited to patent infringement.  (Amgen Petition, at page 15).

Should Marketing Notice be given Pre-marketing or Post-approval?

On the issue of whether Sandoz may provide the 180-day marketing notice under section (l)(8)(A) only after obtaining U.S. Food and Drug Administration (FDA) approval of the biosimilar product (as opposed to any time that is at least 180 days prior to actually marketing), the panel (with Judge Lourie and Judge Newman forming the majority and Judge Chen dissenting, on this issue) held that the applicant may only give effective notice of commercial marketing after the FDA approval. Thus, for Sandoz (who failed to provide its aBLA and the required manufacturing information to the Amgen by the statutory deadline), the 180-day post-approval requirement is mandatory. Therefore, Sandoz may not market its biosimilar product until 180 days after March 6, 2015 (when post-approval notice was given to Amgen), i.e., September 2, 2015.

In its petition for rehearing en banc, Sandoz emphasizes that the BPCIA’s “notice provision simply calls for 180 days’ notice before an expected product launch. It does not require that the notice be after FDA approval.”  (Sandoz Petition, at page 2, emphasis original).  Sandoz argues that the panel’s interpretation of the pre-marketing notice provision distorts the statutory scheme of the BPCIA , which in effect “gives the  sponsor an ‘extra-statutory exclusivity windfall’ – ‘a 180-day injunction beyond the express twelve-year statutory exclusivity period’.”  (Sandoz Petition, at page 6, quoting Judge Chen’s dissenting opinion).  Specifically, Sandoz argues that majority on this issue “reached that erroneous conclusion by focusing on the word ‘licensed’ in subsection (l)(8)(A).”  (Sandoz Petition, at pages 3, 9-10).  Sandoz also argues that the majority ruling “will frustrate Congress’s goal of having patent disputes resolved early so that biosimilars can be available to patients as soon as possible[,]” because its means that “in every situation where the parties participate in the patent exchange process, any not-yet-litigated patent disputes cannot even begin until after FDA approval.” (Sandoz Petition, at pages 7-8, emphasis original). Further, Sandoz argues that the majority erred by creating its own remedy (“a private right of action for an automatic, bondless injunction”), which is conflict with the BPCIA, because “[t]he only mechanisms in the BPCIA for enjoining commercial marketing are patent-based remedies.”  (Sandoz Petition, at pages 10, 13). In addition, Sandoz argues that the majority also erred by enjoining Sandoz without regard to traditional equitable factors, despite the district court’s findings of no irreparable harm[,]” and that the injunction is “overly broad . . .  going beyond marketing and . . .  restricting the ability of Sandoz to import product[.]”  (Sandoz Petition, at pages 13-14).

Emergency Motion

FDA approved Zarxio™ on March 6, 2015 for the same five indications approved for Neupogen®. On April 17, 2015, Amgen filed an emergency motion for an injunction pending appeal before the Federal Circuit, which the Court granted. In its decision on July 21, 2015, the Court ordered that the injunction extend only through September 2, 2015.

The emergency motion filed by Amgen on August 26th requests that the Federal Circuit enter a temporary injunction to preserve the status quo, namely, prevent Sandoz from launching its biosimilar product Zarxio™, while the Court considers whether to grant Amgen’s petition for rehearing en banc, and if granted, while the en banc Court decides the appeal.

Specifically, Amgen alleges that the full scope of its requested remedy cannot be considered or awarded by the district court if Sandoz launches its biosimilar product, and that Sandoz’s launch will fundamentally and permanently alter the market, causing irreparable harm to Amgen if the en banc Court ultimately decides the issues in favor of Amgen. Accordingly, Amgen argues that the en banc Court’s ability to grant Amgen the relief it seeks (namely, remand to the district court to fashion a remedy for Amgen, including injunctive relief) requires that the status quo be preserved beyond September 2 through the full pendency of this appeal.  Of note, Sandoz’s response to Amgen’s petition for rehearing en banc is due by September 8, 2015.

2.  First IPR Institution Decisions for Biosimilars 

In July 2015, the Patent Trial and Appeal Board (PTAB) instituted two inter partes review (IPR) proceedings filed by Boehringer Ingelheim (Boehringer) concerning patents relating to Rituxan® (rituximab). Specifically, on July 14th and July 17th the PTAB instituted IPR proceedings in U.S. Patent Nos. 7,976,838 (IPR2015-00417) and 7,820,161 (IPR2015-00415), respectively. Additionally, on July 13th, the PTA denied institution on a third rituximab IPR petition filed by Boehringer concerning U.S. Patent No. 8,329,172 (IPR2015-00418). A copy of these decisions can be found here:  IPR-2015-00415-Institution-of-IPR, IPR2015-00417_Institution-of-IPR- , IPR2015-00418_Decision-Denying-Institution-of-IPR.

On August 12, 2015, Boehringer filed a request for rehearing of the PTAB’s decision to decline institution of the IPR concerning U.S. Patent No. 8,329,172 (IPR2015-00418). A copy of the request for rehearing can be found here:  BI-IPR2015-00418-Request-for-Rehearing

Finally, on August 14 and 17th, Celltrion, Inc. (Celltrion) filed petitions for IPR of U.S. Patent Nos. 7,976,838 and 7,820,161 along with motions to join the two instituted IPR proceedings for these patents (namely, IPR2015-00417 and IPR2015-00415). A copy of these petitions and motions can be found here:  IPR2015-01733-U.S.-Patent-No.-7976838-Rituximab_Celltrion-Petition, IPR2015-01733-U.S.-Patent-No.-7976838-Rituximab_Celltrion-Motion-for-Joinder, IPR2015-01744-U.S.-Patent-No.-7820161-Rituximab_Celltrion-Petition, IPR2015-01744-U.S.-Patent-No.-7820161-Rituximab_Celltrion-Motion-for-Joinder.

3.  FDA Provides Guidance on the Naming of Biological Products 

On August 27, 2015, FDA published a draft guidance containing its much anticipated views on the nonproprietary naming of biological products. According to the guidance, FDA’s current thinking is that shared nonproprietary names are not appropriate for all biological products and “[t]here is a need to clearly identify biological products to improve pharmacovigilance and, for the purposes of safe use, to clearly differentiate among biological products that have not been determined to be interchangeable.”

As a result, FDA proposes designating a proper name for all biological products, including reference biological products and biosimilar products. The proper name will include: (1) a core name; and (2) a designated suffix. According to FDA, application of this naming convention for all biological products is intended to: (1) encourage routine use of designated suffixes in ordering, prescribing, dispensing, and recordkeeping practices; and (2) avoid inaccurate perceptions of the safety and effectiveness of biological products based on their licensure pathway. FDA intends to apply this naming convention to both newly licensed and previously licensed biological products (for previously licensed biological products, FDA is considering the most effective regulatory approach for implementing this naming convention and intends to provide more information in the future).

Proposed Framework for Designating the Proper Name of a Biological Product

The guidance provides a framework for designating a proper name of a biological product. Specifically, the core name will be the name adopted by the USAN Council for a drug when it becomes available (such as filgrastim, epoetin alfa, etc). The designated suffix will comprise four lowercase letters that will be added to the core name of each product and will be attached with a hyphen. Applicants will be required to conduct their own due diligence and propose a suffix for their product (sponsors of full BLAs should propose a suffix during the IND phase and biosimilar applicants, at the time of licensure). A proposed suffix should be: (1) four lowercase letters; (2) unique; and (3) devoid of any meaning. FDA cautions that a proposed suffix should not: (1) be promotional (namely, make any representations regarding safety or efficacy); (2) include abbreviations commonly used in clinical practice that might be misinterpreted; (3) contain or suggest any drug substance name or core name designated by the USAN Council; (4) look similar to or be mistaken for the name of a currently marketed product; and (5) be too similar to any other product’s suffix designation.

According to FDA, the use of a shared core name will indicate a relationship among products. FDA felt that with the identifier being placed as a suffix, rather than a prefix, the biological products with the same core name will be grouped together in electronic databases to help healthcare providers identify these products. The guidance provides the following examples of products having shared core names:

  1.  replicamab-cznm

replicamab-hixf

2.    putonastim alfa–jnzt

putonastim alfa-kngx

According to the guidance, the designated suffix will be different for each product, except for interchangeable products. The guidance states that FDA is considering two alternative approaches for the naming of interchangeable products: (1) a unique suffix for interchangeable products; (2) the same core name and suffix as the reference product. FDA is requesting comments on these alternative approaches for the name of interchangeable products.

Finally, the guidance does not apply to biological products for which a proper name is provided in the regulations (such as in 21 CFR part 640) or to certain categories of biological products for which there are well-established, robust identification and tracking systems to ensure safe dispensing practices and optimal pharmacovigilance (ISBT 128 for cord blood products).

This post was written by Lisa Mueller and Wei Yan.

A Global Review of the Patentability of Polymorphs

This is a follow-up to our post of August 12, 2015, where we wrote about the new guidelines issued by the Israeli Patent and Trademark Office regarding the examination of polymorph and salt patents. As a result of this post, we at the BRIC Wall Blog thought it would be helpful for our readers to review the patentability requirements of polymorphs in a number of different countries. The result of our efforts is shown in the following table:  POLYMORPHSGLOBALSTUDY.

We look forward to receiving your comments on this table. Additionally, we thank the many law firms listed at the end of the table that so kindly provided the information that forms basis of this table.

New Guidelines for the Examination of Polymorph and Salt Patents Issued by the Israeli Patent and Trademark Office

In May 2015, the Israeli Patent and Trademark Office (IL PTO) issued new working guidelines relating to the examination of patent applications claiming crystal and salt forms of known compounds. The guidelines reflect a significantly more restrictive approach than previously enunciated by the IL PTO regarding the patentability of polymorph and salt patents. Specifically, according to the guidelines:

  1. Novel crystal and salt forms of known compounds are prima facie obvious unless a “substantial advantage” is demonstrated over the prior art. The guidelines state that a “high level of proof” is required to rebut a showing of prima facie obviousness.
  2. A skilled person would appreciate that most pharmaceutical compositions can crystallize in more than one crystal form which will have different properties such as stability, solubility, hygroscopicity, etc. Thereupon, it would be obvious to try to crystallize known compounds with a reasonable expectation of success. In other words, according to the IL PTO, screening does not require any type of “creative sophistication”. Similarly, claims to a process for making crystalline or amorphous compounds will only be found to be inventive if the claimed process recites “special” or “unique” reaction conditions or parameters.
  3. Not every advantage over the prior art will be sufficient to establish inventive step. An advantage will only be regarded as a “substantial advantage” satisfying inventive step when the benefits are not recognized and well-known in the art.
  4. Claims to new crystal forms must include the highest intensity X-ray powder diffraction (XRPD) peaks which conclusively characterize the crystal form (such as eight, ten, etc. of the highest intensity peaks). Claiming the crystal form with a small number of peaks will be considered to be insufficient to distinguish the claimed crystal form from other forms. There is no indication yet from the IL PTO regarding the “minimum” number of peaks to be recited in a claim. For example, a “small” number of peaks (such as 2-4) could be granted if it is established that these peaks conclusively characterize the crystal form.
  5. Claims to processes for making a crystal form must identify the solvent and recite the specific process parameters such as solvent ratios, temperature, heating or cooling rate, etc.
  6. The following lack inventive step:
    1. A polymorph obtained spontaneously due to conversion from another crystal form.
    2. Obtaining a single crystal form using several crystallization procedures that utilize several solvent systems (there is no inventive step because of the high likelihood that a skilled person would have obtained the claimed form).
    3. When crystallization attempts lead to several new forms having satisfactory properties (there is no inventive step because several polymorphs were found to be suitable).

Interestingly, the guidelines presume that research for novel salts and crystal forms to be nothing more than a routine exercise. The guidelines make no reference to the complexity of the research, the lack of predictability as to which forms can be made and their respective properties or provide any flexibility for any serendipity that might be involved. Instead, the guidelines raise the threshold for patentability for novel salt and crystal forms to be higher than that for other types of inventions. Thus, it appears that novel salts and crystal forms will be subject to an automatic “obvious to try” test. Moreover, the guidelines raise doubts whether only “exotic” advantages, which are ordinarily not found will be sufficient to establish patentability.

As mentioned previously, the guidelines are overly restrictive and inconsistent with Israeli case law. There is no basis in Israeli case law for applying a different, more stringent patentability requirement to salt and polymorph patents. In fact, the “obvious to try” test sometimes used by the IL PTO has not been accepted by the Israeli Courts. Moreover, the Supreme Court of Israel has recognized the difficulties involved in the development of a new salt form amenable to pharmaceutical formulation and stated that the development of a novel salt entails a genuine and substantive research program.

Please continue to watch the BRIC Wall Blog for further postings on the patentability of crystal and salt forms.

This post was written by Lisa Mueller and Liad Whatstein of Liad Whatstein & Co.

Can the Minimum Period of 5 years Established by NAFTA for Regulatory Data Exclusivity be Extended in Mexico for Biological Medical Products?

In Mexico, there is no specific body of legislation governing data protection exclusivity (DPE), also known as regulatory exclusivity, for chemical drugs, biological medical products and new indications. The authority responsible for enforcing the regulatory framework for drugs, biological medical products and medical devices, is the Federal Commission for Protection against Sanitary Risks (COFEPRIS), which is part of the Ministry of Health.

In 2012, in an attempt to provide guidance on DPE, COFEPRIS issued internal guidelines that provided a 5 year-term of data protection for new chemical entities only. The guidelines did not address DPE for biological medical products and new indications. Moreover, the reliability and legal value of these guidelines remains uncertain. However, up to now, these internal guidelines have not been challenged or contested by any generic companies.

Based on the interpretation of international treaties (namely, NAFTA and TRIPS), along with the Mexican legislation specifically related to approval of new molecules, innovator companies have successfully obtained regulatory data exclusivity of 5 years through litigation for new chemical entities, formulations and new indications.

Regarding the length of DPE protection, NAFTA states that it should be for at least 5 years. However, for biological medical products, some countries such as United States, Canada, the European Union, among others, grant a greater length of protection of regulatory exclusivity. 

Article 222 bis of the Mexican General Health Law defines a “biologic product” as any substance that has been manufactured by molecular biotechnology; has therapeutic, preventive or rehabilitative effects; is provided in a dosage form; and is identified as such by its pharmacological activity and physical, chemical and biological properties.

At the end of 2012, Janssen Cilag (Janssen) requested DPE for a biological medical product. Based on an interpretation of International Treaties, International Comparative Law and Mexican regulations for biological medical product approval, protection beyond the minimum period of 5 years established by NAFTA was requested. This request was ignored by COFEPRIS, which was understood as a tacit negative response. As a result of this reaction, at the beginning of 2013, the tacit negative response was challenged before the Federal Court for Tax and Administrative Affairs (FCTA). On November 2014, the FCTA confirmed the denial to grant the protection holding that the minimum period of 5 years established by NAFTA had already expired. The FCTA also concluded that foreign legislation was neither applicable nor mandatory and that the plaintiff failed to prove that considerable efforts were involved in the generation of data and information to prove the safety and efficacy of the biological medical product.

As a result of an appeal, in June 2015, a Federal Circuit Court issued a decision ordering the lower FCTA court to issue a new, accurate decision on the merits, providing certain guidelines as to how to decide the time of protection for clinical data of a biological medical product. In a complying decision issued in July 2015, the FCTA concluded that Janssen had demonstrated that the generation of data and information aimed to prove the safety and efficacy for the biological medical product involved considerable efforts. The FCTA also concluded that COFEPRIS did not accurately analyze the case. As a result, at that point of time, FCTA was unable to assess the applicable provisions in NAFTA, which established a possibility of granting a longer period of protection than the minimum period of 5 years. For this reason, FCTA held that it could not act as an administrative authority. Therefore, it ordered COFEPRIS to issue an accurate decision determining whether to expressly recognize a longer period of protection than the minimum of 5 years established by NAFTA. The FCTA’s decision is awaiting further action by COFEPRIS.

This case is very important because for the first time ever the Mexican courts are contemplating the possibility of having the minimum period of 5 years established by NAFTA as a minimum period of protection and not the only established period of protection for clinical data.

This post was written by Lisa Mueller, Mauricio Sámano and Ingrid Ortiz of Olivares.