The Center for Biosimilars Staff

The US Court of Appeals for the Federal Circuit today 

 Amgen’s appeal of a previous district court ruling that denied its motion to compel discovery from Hospira in a Biologics Price Competition and Innovation Act (BPCIA) litigation.

In appealing the decision, Amgen had argued that, unless it was provided discovery of Hospira’s manufacturing process for epoetin alfa (Epogen), its right to sue over the cell-culture patents it holds for the drug would be thwarted. It alternatively sought a writ of mandamus, which would compel discovery.

The court, however, said that it lacked jurisdiction over the district court’s order, and found that Amgen failed to satisfy the prerequisites necessary for such a writ, calling it “a drastic remedy reserved for the most ‘extraordinary causes,’” in which the party has no other means of relief, and has demonstrated that it has a legal right to the writ by “clear and indisputable” means.

The court took the position that, barring an injunction under federal law (which the Supreme Court’s ruling in 

rendered unavailable), Amgen could have sought relief under state law (though it did not), sued for patent infringement, or coerced information from Hospira by bringing suit on its cell-culture patents. Moreover, the decision indicated, the Supreme Court appears to have provided for the possibility of the sponsor’s filing suit upon an applicant’s failure to disclose information.

The court stated that “the denial of discovery in this case does not undermine the purpose of the BPCIA," and that the district court was correct in its decision to deny Amgen’s motion.

Articles

The US Court of Appeals for the Federal Circuit today dismissed Amgen’s appeal of a previous district court ruling that denied its motion to compel discovery from Hospira in a Biologics Price Competition and Innovation Act (BPCIA) litigation.

Federal Circuit Dismisses Amgen's Appeal

FDA Commissioner, Scott Gottlieb, MD, has created a new FDA working group of senior agency staff who will investigate ways to increase generic drug competition.

The agency has already taken steps to address what Gottlieb calls “gaming” of the regulatory system by some drug makers who seek to delay the approval of generic drugs. Thus far, the agency has begun work on a Drug Competition Action Plan, held a public 

 on the administration of the Hatch-Waxman Amendments, published a list of off-patent branded drugs that do not yet have approved generics, announced upcoming publication of 2 new documents designed to help generics companies navigate the Abbreviated New Drug Application process, and announced a new policy to expedite the review of generic drug applications.

The new initiative, Gottlieb said on Twitter, will expand upon the goals of the agency’s Action Plan:

The working group will also develop proposals to address ongoing difficulties in administering the Hatch-Waxman Amendments:

Yet the new initiative also seeks to move beyond those current efforts, and to identify new ideas and approaches that will improve access to generic drugs:

 that the working group’s membership includes Elizabeth Dickinson, JD, an FDA attorney in the Office of the Chief Counsel; Grail Sipes, JD, director of the Office of Regulatory Policy at the agency’s Center for Drug Evaluation and Research (CDER), and Maryll Toufanian, JD, deputy director of CDER’s Office of Generic Drug Policy.

The formation of the new working group follows Gottlieb’s recent congressional 

, during which he highlighted barriers to competition in the pharmaceuticals marketplace. Among the barriers Gottlieb identified were restricted distribution systems and access to drugs for bioequivalence testing; single, shared systems for risk evaluation and mitigation strategies (REMS); citizen petitions, drugs not yet addressed under the 2006 Unapproved Drugs Initiative; and so-called “pay-for-delay” agreements, in which generics companies resolve patent disputes by agreeing to delay market entry in exchange for a sum of money.

Since his confirmation as FDA Commissioner in May, Gottlieb has made drug pricing a focus of the agency’s attention, and the formation of the working group suggests that these efforts to increase competition and drive down drug costs will only continue.

FDA Commissioner Gottlieb Forms FDA Working Group Focused on Generic Competition

 led to industry speculation that biosimilar applicants could lack incentive to participate in the information exchange process with reference product sponsors, or the so-called “patent dance,” provided for under the Biologics Price Competition and Innovation Act (BPCIA).

Yet as Patterson Belknap Webb & Tyler attorneys Irena Royzman and Nathan Monroe-Yavneh 

following the steps of the patent dance still holds significant benefits for biosimilar developers. According to Royzman and Monroe-Yavneh, one of the most compelling benefits of the patent dance is that it allows a biosimilar applicant to limit the scope of patents that can be addressed by the first wave of BPCIA litigation.

Under the BPCIA, the reference product sponsor and the biosimilar applicant engage in patent litigation in 2 stages: the first stage begins with a negotiation over which patents to litigate. While the reference manufacturer may hope to bring all of the patents it wants to assert in the first wave of litigation, the biosimilar applicant can cap the number of patents that it wants to challenge during the initial period. The parties then exchange lists of patents, with each list capped at the number determined by the biosimilar developer, and concur on the final range of patents that are then litigated.

AbbVie and Boehringer Ingelheim’s (BI) recent litigation over adalimumab (Humira) illustrates the benefits of the information exchange for the biosimilar developer: while AbbVie 

 that BI will infringe on 74 of its patents, and proposed a single phase of litigation for all of them, BI was able to limit the patent list for the first wave to 8.

Royzman and Monroe-Yavneh also point out that following the steps of the BPCIA gives applicants control over the timing of litigation. The second wave of patent litigation, during which all remaining patents that the reference product sponsor wishes to assert can be litigated, commences after a biosimilar developer files its 180-day notice of commercial marketing. That trigger leaves the timing of the second, and potentially more extensive, litigation period in the hands of the biosimilar applicant.

However, as Ha Kung Wong of Fitzpatrick, Cella, Harper and Scinto told The Center for Biosimilars

, those benefits may not be compelling for biosimilar applicants currently seeking to launch products. “We’ve already seen that some biosimilar applicants would prefer to forego the patent dance entirely,” said Wong. “Currently, the biosimilars in late-stage development are for blockbuster drugs that have been on the market since the 1990s. And because they’ve been on the market for so long, many are covered by only a handful of unexpired patents. So under those circumstances, biosimilar applicants may not see any incentive to participate in this dance.”

That trend could change, however, as biosimilar developers shift their focus to newer biologics. According to Wong, “biosimilar applicants will begin targeting newer drugs not long after data exclusivity expires. Under those circumstances, with larger patent portfolios and longer expiration dates, the certainty that the patent dance provides could be valuable to biosimilar applicants.”

However, the Federal Circuit has not yet clarified a lingering question of the 

 ruling—namely, whether injunctions are available under state law for the failure to provide initial disclosures. The outcome of that question could have bearing on applicants’ willingness to participate in the patent dance. 

 to Wong, “If the initial disclosures under the BPCIA are essentially optional, biosimilar applicants may decide there isn’t enough of an incentive to participate, and may choose to force brand drug makers to operate in the dark as they assert basically all patents at once after they receive notice of commercial marketing.”

For both biosimilar developers and reference product sponsors, Wong says, “There’s still plenty to be concerned about.”

The US Supreme Court’s recent ruling in the case of Sandoz v Amgen led to industry speculation that biosimilar applicants could lack incentive to participate in the information exchange process with reference product sponsors, or the so-called “patent dance,” provided for under the Biologics Price Competition and Innovation Act (BPCIA).

Industry Experts: The Patent Dance Still Has Value, But Uncertainty Lies Ahead

The FDA’s biosimilar pathway has encouraged a robust product pipeline, but the fact that few biosimilar drugs have been approved by the agency thus far, as well as the fact that the FDA has yet to finalize its guidance concerning the demonstration of interchangeability for biosimilars, means that there is still some industry uncertainty on the FDA’s approach to this class of products.

 of agency documents concerning US biosimilar applications, has highlighted lessons learned from the first 4 biosimilars to gain FDA approval: Amgen’s adalimumab (Amjevita), Sandoz’s etanercept (Erelzi), Celltrion’s infliximab (Inflectra), and Sandoz’s filgrastim (Zarxio).

The naming conventions for biosimilars, the review points out, have been a significant challenge for biosimilar applicants. When the FDA 

 its final guidance on the naming of biologics and biosimilars in January 2017, it elected to use a system in which a 4-letter suffix, devoid of meaning, is appended to the reference product’s nonproprietary name. Under the guidance, an applicant is 

 to submit up to 10 proposed suffixes for the drug, in order of the applicant’s preference, with accompanying supportive information about the merits of those suffixes.

As Pharma Intelligence points out, biosimilar applicants should be prepared to undergo a rigorous, data-driven vetting of their proposed suffixes to demonstrate that their choices do not create confusion or pose a risk of errors. However, the agency may be willing to consider flexibility with respect to which meaningless suffix is appended to a biosimilar’s name; just as Amgen was able to convince the FDA that its suffix of choice (-atto) was preferable to other options for its adalimumab product, future biosimilar developers may also attempt to provide persuasive rationales for their suffixes of choice.

Labeling, too, has proven to be a challenging area for biosimilar applicants. The review notes that the FDA has been wary of allowing a biosimilar product’s label to diverge from that of its reference. Celltrion, the authors note, failed in its attempt to include data on adverse events, pharmacokinetics, and clinical studies that were specific to its infliximab product and not to the reference Remicade. Sandoz was also prevented from making amendments to its labeling that would allow the company to note differences in its product presentation from that of the reference product.

Finally, the review notes that the FDA’s programs to incentivize the development of pediatric drugs has posed a hurdle—while innovator products may hold waivers concerning pediatric studies, biosimilar products may still be required to conduct such studies. Sandoz, for example, was asked by the FDA to provide data from pediatric studies with etanercept. The agency eventually demonstrated what the review calls “a degree of regulatory flexibility,” however, and allowed the biosimilar etanercept’s label to indicate that efficacy and safety of the product in the treatment of pediatric psoriasis had not been established.

As the next wave of biosimilar manufacturers file their abbreviated Biologics License Application, the experience of biosimilar developers thus far could prove particularly useful. With only a 40% approval rate for first-cycle applications, the industry has room to learn from—and improve upon&mdash;its growing body of experience.

The FDA’s biosimilar pathway has encouraged a robust product pipeline, but the fact that few biosimilar drugs have been approved by the agency thus far means that there is still some industry uncertainty on the FDA’s approach to this class of products.

Review Highlights Lessons Learned from 4 Biosimilar Approvals

A recent survey of 588 Canadian patients 

 that many patients had serious concerns about biosimilar substitution. 

A recent survey of 588 Canadian patients revealed that many patients had serious concerns about biosimilar substitution. 

Infographic: Patient Concerns With Biosimilar Substitution

AbbVie is engaged in new litigation over its blockbuster adalimumab (Humira). This week, the drug maker 

 suit against Boehringer Ingelheim (BI) in a Delaware federal court, saying that BI will infringe on 74 of its patents for adalimumab in its development of a biosimilar product, BI 695501.

AbbVie earned $16.08 billion on sales of Humira in 2016, and seeks to defend its sales against biosimilars in development by asserting its numerous patents for the drug. The patents at issue in this case vastly outnumber those litigated in a previous suit against Amgen over its own biosimilar; in that case, AbbVie 

“While AbbVie has spent vast resources over decades developing Humira, Boehringer seeks to copy AbbVie’s work and ignore AbbVie’s patents,” the drug maker said in its complaint. “But while the Biosimilar Price Competition and Innovation Act (BPCIA) gives Boehringer an abbreviated regulatory pathway for its biosimilar version of Humira, it does not give Boehringer license to infringe AbbVie’s patents.”

The complaint indicates that AbbVie will assert 8 of those 74 patents in its initial wave of litigation, and will undertake a second wave when BI provides 180-day notice of commercial marketing, as BI did not consent to AbbVie’s proposal of a single stage of litigation for all 74 patents.

The patents that AbbVie has chosen to assert in this litigation include composition, methods of treatment, methods of administration, use of anti-tumor necrosis factor antibodies, and methods of production, among others. Among the patents on AbbVie’s list is the so-called “‘135 patent” for a method of treating rheumatoid arthritis. Five claims of that patent were struck down by the US Patent and Trademark Office’s Patent Trial and Appeal Board (PTAB) after a challenge from BI. The same claims were also invalidated by the PTAB in a previous inter partes review proceeding concerning Coherus BioScience’s CHS-1420.

Last week, BI announced that it had enrolled its first patient in a 

 to demonstrate interchangeability of its BI 695501 molecule with Humira. The results of the study—which will compare pharmacokinetics and clinical outcomes in 240 patients with moderate to severe chronic plaque psoriasis, and include safety, efficacy, and immunogenicity data&mdash;are expected in the second half of 2019. 

AbbVie is engaged in new litigation over its blockbuster adalimumab (Humira). This week, the drug maker filed suit against Boehringer Ingelheim in a Delaware federal court, saying that BI will infringe on 74 of its patents for adalimumab in its development of a biosimilar product, BI 695501.

AbbVie Files Complaint Against BI in New BPCIA Litigation Over Humira

Hi, I’m Kelly Davio for The Center for Biosimilars

, your resource for clinical, regulatory, business, and policy news in the rapidly changing world of biosimilars. 

Here are the top 5 biosimilars articles for the week of July 31. 

Number 5: A recent survey of Canadian patients

 highlights serious concerns about automatic substitution of biosimilars for reference products. 

Number 4: Biosimilar developer Coherus has 

moved for a stay of discovery in its BPCIA litigation over pegfilgrastim,

 citing the company’s need to preserve its resources. 

The FDA Reauthorization Act of 2017 was passed by the Senate on Thursday.

 The must-pass bill reauthorizes user fees for biosimilar applicants.

Number 2: It was a busy week for trastuzumab biosimilars, with

 biologics license applications filed by Amgen and Allergan as well as Celltrion and Teva.

Brian Lehman takes a close look at the potential impact of Merck’s launch of Renflexis at a 35% discount

 off the list price of the reference, Remicade, in the US marketplace. 

Finally, last week, our newsletter asked you to share your thoughts on how great a discount payers are expecting for biosimilar products. To view results of the poll, 

To sign up for our weekly newsletter or to read these articles and more, visit www.centerforbiosimilars.com.

The Center for Biosimilars recaps the top 5 stories in biosimilars news for the week of July 31, 2017.

The Top 5 Biosimilars Articles for the Week of July 31

The Senate today passed the FDA Reauthorization Act of 2017 (FDARA) in a roll call vote.

The bill, which reauthorizes user fees for biosimilar product applications, among other provisions, will ensure funding for the continued operations of the FDA. The Senate voted on the bill following Senate Majority Leader Mitch McConnell’s (R-Kentucky) Tuesday 

 of a cloture motion (limiting consideration of a pending bill to 30 additional hours) on the bill to proceed.

Despite the fact that the FDARA had broad, bipartisan support and had been passed by the House on July 13, the Senate’s consideration of the bill was delayed by contentious debate over Republican efforts at healthcare reform. The act also faced pressure from Senator Ron Johnson (R-Wisconsin), who had vowed to block the legislation’s passage unless it included an amendment comprising his “right-to-try” legislation.

 that sources close to the Senate say that Johnson agreed not to hold up the timely passage of the FDARA in exchange for the swift consideration of his legislation in a separate vote. The Senate 

, the “Trickett Wendler, Frank Mongiello and Jordan McLinn Right to Try Act of 2017,” just hours before the vote on FDA reauthorization. Johnson’s sponsored legislation will allow patients who are terminally ill to access experimental treatments that are under investigation, though not yet approved, by the FDA.

While Senator Johnson eventually supported the bill, Senator Bernie Sanders (I-Vermont) cast the sole vote in opposition. Sanders, who had demanded that the FDARA include provisions for the importation of cheaper drugs from other countries, had previously voted against advancing the bill out of committee.

Now that the FDARA has passed both houses, it faces one last potential hurdle: the Trump Administration. On July 12, the White House released a 

 asserting that Congress should provide for 100% of FDA program funding through user fees. While the statement indicated that the administration was in support of the goals of the act, it remains to be seen whether that support will extend to the fee structure agreed upon by Congress. 

FDARA Passed by Senate, Senator Johnson Gets Vote on "Right to Try"

 for a stay of discovery in Biologics Price Competition and Innovation Act (BPCIA) litigation concerning its proposed pegfilgrastim biosimilar, CHS-1701, referenced on Amgen’s blockbuster drug Neulasta.

In the motion filed last week, Coherus told the court that it believes the recent regulatory delay of CHS-1701 justifies a stay in litigation; in June, the company received a complete response letter (CRL) from the FDA with respect to the biosimilar product. The agency asked Coherus to reanalyze a subset of samples with a revised immunogenicity assay. It also requested that the drug maker provide additional manufacturing-related process information, though it did not request a clinical study of CHS-1701 in oncology patients or indicate that additional process qualification lots would be needed. 

On the heels of the CRL and the subsequent delay of the product, Coherus 

 approximately 30% of its workforce, or 51 employees, in an attempt to cut its operational costs by $10 million. Coherus suffered another setback when Daiichi Sankyo, the company’s partner in the development of an investigational etanercept biosimilar, CHS-0214, terminated its relationship with the biosimilar maker.

In light of its new financial outlook, Coherus told the court in its motion for a stay that “Preservation of resources is especially important to Coherus—a new start-up biosimilar company that has no products and, because of a recent FDA rejection of its drug application, will have no revenue until its anticipated mid-2018 launch of the product at issue in this case,” and claimed that “Amgen can use its vast resources to bankrupt Coherus with unnecessary litigation expenses before Coherus can launch [CHS-1701].”

The ongoing BPCIA litigation began when the California-based biosimilar developer filed a Biologics License Application for its biosimilar product in October 2016, initiating an information exchange process, or the so-called “patent dance,” with Amgen. Subsequently, Amgen filed its initial 

 in May 2017, claiming that Coherus had infringed on one of its patents—Coherus then moved to dismiss Amgen’s complaint.

Coherus claims that discovery in the case should not proceed while its motion to dismiss is pending before the court.

 the parties to comply with a July 18 order to submit case management documents to court by August 17, 2017. After it receives the required documents, the court will hear oral arguments on Coherus’ motion to stay litigation.

Coherus BioSciences has moved for a stay of discovery in BPCIA litigation concerning its proposed pegfilgrastim biosimilar, CHS-1701, referenced on Amgen’s blockbuster drug Neulasta.

Coherus Seeks Stay in BPCIA Litigation, Cites "Preservation of Resources"

 today that the companies have submitted a Biologics License Application (BLA) for ABP 980, a proposed trastuzumab (Herceptin) biosimilar.

The companies’ BLA submission includes data from a phase 3 comparative efficacy, safety, and immunogenicity study conducted in adult female patients with HER2-positive early breast cancer. The partnership also 

 for approval of the product with the European Union’s European Medicines Agency in March of 2017.

"The submission of ABP 980 for FDA review is an exciting milestone and speaks to our joint commitment with Allergan to deliver quality oncology biosimilars to patients," said Sean E. Harper, MD, executive vice president of research and development at Amgen. "Approval of ABP 980 would provide more patients access to a high-quality therapy with a proven safety and efficacy profile. We look forward to further discussions with the FDA."

Allergan’s chief of research and development, David Nicholson, added, "We're proud of the progress we've made so far and look forward to continuing our work to bring more biosimilars to market."

US-based Amgen and Ireland-based Allergan are collaborating on 4 biosimilar products, including ABP 980, for oncology indications. In July, the partnership received a unanimous recommendation for approval from the FDA’s Oncologic Drugs Advisory Committee (ODAC) for another of those products, ABP 215, a proposed bevacizumab (Avastin) biosimilar. The FDA’s decision on ABP 215 is expected in September.

The Amgen—Allergan partnership’s filing comes just 1 day after Celltrion and Teva 

 a trastuzumab biosimilar BLA of their own. The Celltrion—Teva product, CT-P6, also relies on data from a phase 3 equivalence trial in patients with HER2-postive early breast cancer.

However, the first biosimilar trastuzumab product expected to penetrate the US market is Mylan and Biocon’s trastuzumab, MYL-1401O, which has a Biosimilar User Fee Act date of September 3, 2017. The product recently received a unanimous ODAC recommendation for approval. The Mylan—Biocon product is expected to be the first biosimilar challenger to the reference Herceptin after Mylan entered a global 

 with the reference product’s sponsor, Genetech, in March. The settlement has provided Mylan with a global license to commercialize MYL-1401O after approval.

Amgen and Allergan announced today that the companies have submitted a Biologics License Application for ABP 980, a proposed trastuzumab (Herceptin) biosimilar.