On February 23, 2021, a Federal Circuit panel of Chief Judge Prost, Judge Newman, and Judge Moore reheard oral argument in GlaxoSmithKline LLC v. Teva Pharms. USA, Inc. As discussed in our previous post, on February 9, 2021, the panel issued an order granting Teva’s petition for rehearing, vacating the prior October 2, 2020 judgment and withdrawing the October 2, 2020 opinion. The panel limited the oral argument to the issue of whether there is substantial evidence to support the jury’s verdict of induced infringement during Teva’s “skinny label” period from January 8, 2008 through April 30, 2011.

As we previously reported, in its original opinion the Federal Circuit held that based on the entire trial record there was substantial evidence to support the jury’s finding that Teva induced infringement throughout the term of the patent-at-issue, including during its “skinny label” period. In the vacated opinion, the Federal Circuit noted that “[p]recedent has recognized that the content of the product label is evidence of inducement to infringe” and cited “the FDA labels” as supporting the jury’s infringement verdict, but did not clarify whether those statements referred to Teva’s label during the skinny label period, the period when the label expressly included the patented indication, or both. See GlaxoSmithKline LLC v. Teva Pharms. USA, Inc., 976 F.3d 1347, 1355 (Fed. Cir. 2020). Following the Federal Circuit’s original opinion, Teva and several amici expressed concerns that the opinion could have monumental impacts in threatening the viability of Congress’s “carve out” statute (21 U.S.C. § 355(j)(2)(A)(viii)) and exposing generic companies to infringement liability despite the use of skinny labels.

During the oral argument on rehearing, the panel focused its attention on the specific facts of the case rather than the broader legal issues.  The panel geared its questions towards the labels, the accessibility of Teva’s press releases, and the trial testimony of the parties’ experts. The panel appeared to remain aligned as it did in its original opinion. Chief Judge Prost, who dissented from the majority’s original opinion, focused much of her attention during the oral argument on questioning GSK’s attorney about the wording of the indications in GSK’s label and its declarations to the FDA, while Judge Moore, who joined in the original majority opinion, pressed Teva’s attorney on the accessibility of Teva’s press releases. Judge Newman remained silent throughout much of the rehearing, but questioned Teva’s attorney about how to address the amici’s concerns without discouraging the research and development of new methods of use for older drugs.

In light of the panel’s questions during the oral argument and the concerns expressed by Teva and the amici, it appears that the panel is inclined to issue a more narrowly tailored opinion reaching the same conclusions, but revising its reasoning to focus on the specific facts of the case.

We will provide additional updates on this important case once the Federal Circuit issues its opinion.

In a precedential opinion in Amgen Inc. et al. v. Sanofi, Aventisub LLC, et al., No. 20-1074 (Fed. Cir. 2021) issued on February 11, 2021, the Federal Circuit affirmed the decision of the United States District Court for the District of Delaware granting JMOL that Amgen’s Repatha® patents (U.S. Patent Nos. 8,829,165 and 8,859,741) were invalid for lack of enablement.  The district court’s grant of JMOL overturned a jury verdict finding Amgen’s claims were not invalid for lack of enablement.

The claims at issue cover a genus of monoclonal antibodies that bind a certain epitope of PCSK9 and block binding of PCSK9 to the LDL receptor.  The Federal Circuit ultimately concluded that practicing the full scope of the claims would require undue experimentation given the breadth of the functional claim limitations, the limited guidance and examples provided in the specification, and the unpredictability of antibody generation.

The Federal Circuit applied the Wands factors in its analysis, stating that Wands “did not proclaim that all broad claims to antibodies are necessarily enabled.” The Court found the facts were more akin to those in Wyeth, Enzo, and Idenix, in which the claims at issue—drawn to small molecules, rather than antibodies—had both structural and functional limitations, and in which the specifications failed to teach whether the many embodiments of the broad claims would exhibit the required functionality.[i]

Summarizing the body of enablement law, the Court stated “[w]hat emerges from our case law is that the enablement inquiry for claims that include functional requirements can be particularly focused on the breadth of those requirements, especially where predictability and guidance fall short. In particular, it is important to consider the quantity of experimentation that would be required to make and use, not only the limited number of embodiments that the patent discloses, but also the full scope of the claim.”  While the Court stated that its holding is not that “the effort required to exhaust a genus is dispositive,” it held that “[i]t is appropriate … to look at the amount of effort needed to obtain embodiments outside the scope of the disclosed examples and guidance.”  Thus, while a claim that includes functional language may be enabled, broad functional limitations create “high hurdles” for fulfilling the enablement requirement.

According to the Court, Amgen’s patent disclosures failed to satisfy this heightened bar. As the Court reasoned, making the full scope of the claimed embodiments in the Repatha patents would require “substantial time and effort.” The only ways to discover the undisclosed claimed embodiments would be either through trial and error (i.e., making structural modifications to the disclosed antibodies and then screening the new antibodies for the desired binding and blocking properties), or by discovering the antibodies de novo according to the randomization-and-screening “roadmap” described in the specification. The Federal Circuit agreed with the district court that the small subset of examples of antibodies provided in the specification did not provide sufficient guidance as to how to obtain the full range of working embodiments within the claims.

Impact

The Federal Circuit’s conclusion here was not unexpected, especially after the panel judges made clear during the oral arguments held in December that Amgen faced an “uphill battle” in defending the validity of their antibody genus claims. But how does this decision impact the biologics market and the future of antibody claims? Significantly.

First, it’s now open season not only on antibody patents, but also on patents covering a large genus of molecules in general, particularly those reciting functional limitations. Armed with this decision, patent challengers may now more easily invalidate antibody claims through post-grant review or ex parte reexamination, as well as during litigation.  A search of USPTO records reveals that there may be nearly 25,000 patents granted in the past 20 years that claim antibodies based on the functions of “binding” or “blocking” susceptible to invalidation for lack of enablement.[ii]  And at least some of those patents may cover highly profitable drugs with significant market share or be currently blocking or deterring market entry of other molecules into the pharmaceutical market.  In fact, of the top ten global best-selling drugs forecasted for 2021, five are antibody drugs or antibody fragment drugs, with tens of billions of dollars in annual sales.[iii] By putting broad functionally defined patent claims at serious jeopardy, competing companies may be able to enter the market with molecules that will emerge from under the shadow of such claims.

Second, while the Federal Circuit’s opinion does not provide guidance as to how patent owners should claim a novel genus of antibodies, the decision strongly suggests that purely functional language likely will not suffice. Patent drafters seeking to claim an antibody genus using functional limitations will need to pay close attention to the requisite analysis to enable one of ordinary skill in the art to make and use the claimed scope, e.g., by disclosing sufficient structural features and limitations, a substantial number of examples of antibodies that fall within the genus relative to the genus as a whole, and a crystal clear roadmap that can be used to identify antibodies within the scope of the claim without undue experimentation.  Whenever possible, patent drafters should primarily focus on structural claiming as the first line of defense, e.g., by drafting claims reciting specific complementary determining region (CDR) sequences, or perhaps a high percentage of identity to a specific disclosed amino acid sequence. Functional claiming may still have value as a second line of defense in patent claims, particularly if the drafter carefully considers the breadth of the claims, provides a sufficient amount of direction and guidance, and provides a number of specific working examples demonstrating that species spanning the full scope of the claims achieve the claimed function.

Notably, this decision diverges from European practice, where broad patents to antibodies against a new epitope are the norm, and follow-on applications claiming particular sequences are often rejected as lacking inventive step over the broad patent’s functional disclosures.

Given the cascading repercussions of this decision, Amgen will likely file a petition for writ of certiorari. It  will be interesting to see if a petition is granted in this case, particularly after the Supreme Court refused in January 2021 to consider whether a genus claim is not enabled “as a matter of law” if it encompasses a large number of compounds in Idenix.[iv]

[i] See Wyeth & Cordis Corp. v. Abbott Laboratories, 720 F.3d 1380, 1385–86 (Fed. Cir. 2013); Enzo Life Sciences, Inc. v. Roche Molecular Systems, Inc., 928 F.3d 1340, 1345–48 (Fed. Cir. 2019), cert. denied 140 S.Ct. 2634 (2020); Idenix Pharmaceuticals LLC v. Gilead Sciences Inc., 941 F.3d 1149, 1160–63, 1165 (Fed. Cir. 2019), cert. denied 2021 WL 161021 (Jan. 19, 2021).

[ii] Based on PTO Patent Full-Text and Image Database searches (http://patft.uspto.gov/netahtml/PTO/search-adv.htm) conducted on February 23, 2021 using the query: ACLM/antibody AND (ACLM/bind$ OR ACLM/block$) AND ISD/20000223->20210223.

[iii] https://www.echemi.com/cms/132623.html

[iv] 941 F.3d 1149, 1160–63, 1165 (Fed. Cir. 2019), cert. denied 2021 WL 161021 (Jan. 19, 2021).

A panel of the Federal Circuit agreed on February 9, 2021, to rehear arguments in a case between GlaxoSmithKline LLC (“GSK”) and Teva Pharmaceuticals USA, Inc (“Teva”) regarding Teva’s generic to GSK’s carvedilol product, Coreg®. As discussed below and in our previous post, the three-judge panel previously held in a 2-1 decision in October 2020 that Teva’s carvedilol product induced infringement of a patent covering the treatment of congestive heart failure even during a period in which Teva’s label had “carved out” that indication, resulting in a so-called “skinny label.” The Panel (Judges Prost, Newman, and Moore) is scheduled to rehear arguments on February 23.

Whenever an Abbreviated New Drug Application (“ANDA”) is filed, among the many requirements the Applicant must address are whatever patents the reference drug application holder has registered with the FDA to protect its exclusivity in marketing the drug. For ANDA Applicants, this usually requires filing a certification that I) the application holder did not register patents covering the drug, II) the patent or patents have expired, III) the Applicant does not seek to market the drug until a patent has expired, or IV) the registered patent is invalid or will not be infringed. A certification under the fourth provision—a “Paragraph IV” Certification—typically results in patent litigation.

However, when an Orange Book listed patent covers only certain methods of use, ANDA Applicants may file a “Section viii Statement” asserting that “method of use patent does not claim … a use for which the applicant is seeking approval.” In other words, if a drug is approved for multiple indications, an ANDA Applicant can overcome patents that cover less than all of the approved indications as a regulatory hurdle by submitting a Section viii Statement (potentially avoiding patent litigation under the Hatch-Waxman Act).

Before Teva received approval for its carvedilol product, there were three indications listed for Coreg®: one had no patent protection, one was covered by a soon-expiring patent which Teva opted to wait out, and the third—for congestive heart failure (CHF)—had active patent protection. Teva omitted the CHF indication from its proposed label rather than challenge the CHF patents, creating a skinny label with two indications rather than three. However, Teva eventually reinserted the missing indication after its generic product had been on the market for several years.

The case was tried by a jury, which found that Teva had induced infringement of the CHF patent claims even during the several years that that indication was omitted from Teva’s label. The district court granted Teva’s Motion for Judgment as a Matter of Law, finding no inducement during any time period—including when Teva’s label included the CHF indication.  The split Federal Circuit panel reversed, restoring the jury finding of infringement during all time periods, holding that evidence, including Teva’s marketing of its drug as equivalent to the existing Coreg® and physicians’ knowledge that Coreg® could be used to treat CHF, was sufficient to support the verdict regardless of the label’s stated indications.

Following the panel’s opinion, Teva filed a Petition for Rehearing En Banc arguing generally that the panel’s decision essentially nullified the utility of a Section viii Statement and harmed the doctrine of induced infringement by removing a causation element.  Eight amicus briefs were filed supporting rehearing—seven of which explicitly supported Teva.

On February 9, 2021, the panel issued an order vacating its October 2020 judgment and scheduling a rehearing of the appeal on the merits. The oral argument is scheduled for Tuesday, February 23, and is limited to the question of whether there is substantial evidence supporting induced infringement during the time period that the CHF indication was not present on Teva’s label.

Additional coverage of this case will follow as it develops, including coverage of the oral argument scheduled to take place next week.

On December 9, 2020, the Federal Circuit heard oral arguments on the validity of Amgen’s patents (U.S. Patent Nos. 8,829,165 and 8,859,741) on cholesterol-lowering drug Repatha. Specifically, the question came down to whether the patents, claiming a genus of antibodies by their functional properties, are enabled under 35 U.S.C § 112. The panel consisted of Judges Sharon Prost, Alan D. Lourie, and Todd M. Hughes.  While we are still awaiting the Court’s decision, the oral argument strongly suggested that the Federal Circuit is likely to continue its trend of holding functional genus claims invalid under Section 112.

Claim 1 of Amgen’s ’165 patent, which is representative, recites “an isolated monoclonal antibody, wherein, when bound to PCSK9, the monoclonal antibody binds to at least one of [certain listed amino acid residues], and wherein the monoclonal antibody blocks binding of PCSK9 to LDLR.”  Amgen explains that its claims cover antibodies that bind a certain epitope on the PSK9 protein, and that its inventors discovered that antibodies that bind this “sweet spot” will block PSK9 from binding to LDL receptors, ultimately lowering cholesterol.

Within seconds after counsel for Amgen began his argument, Judge Lourie stepped in and pointed out that the patent claims are composition of matter claims defined by function (in fact, two separate functions – “binding” and “blocking”) rather than structure. Given the breadth of this functional language, and the district court’s finding that “a substantial amount of time and effort” would be required to determine the scope of the claims, Judge Lourie stated that “that sounds like undue experimentation,” making it a “pretty uphill battle” for Amgen to overcome.

Amgen’s counsel responded that the claim is directed to a specific structure, namely the specific arrangement of “sweet spot” binding sites in the form of a 3D structure, which results in the functional “blocking.”  However, Judge Lourie seemed unconvinced that the claims were not purely based on function.

Judge Prost then addressed the issue of “roadmap predictability,” referring to Amgen’s argument that the specification provides a roadmap enabling those skilled in the art to make and use the full scope of antibodies within the claim.  Judge Prost asserted that there was no direction or guidance as to whether a specific antibody will bind, or exactly how to make the 400 distinct antibodies that Amgen argues fall within the claimed genus.  She stated that only 26 of the antibodies were described in the specification, with only nine of those antibodies exhibiting successful binding to the “sweet spot.”  As to the other 384 antibodies, she noted that there was simply no evidence of what those antibodies may be, and that they may very likely cover competitor antibodies whose structures are quite different from those described in the specification.

Counsel for Sanofi continued with this “numbers” argument, questioning whether 400 antibodies was even an accurate scope of the claimed genus. Citing the testimony of a lead inventor and an expert who stated that they didn’t know how many antibodies the genus would cover, and noting the many different permutations based on the dual functionality and the effects of a change of just a single amino acid, he argued that the number is more likely in the millions, or “astronomical.”  Using an analogy to the California gold rush (“the fact that you knew that there were gold in the hills and that you knew you had a pan to find it, doesn’t mean that you’re entitled to gold on every square mile of the California countryside”), he argued that determining the scope of the claims in this case is a classic example of undue experimentation.

Judge Hughes poised an interesting question about why the number of experiments matters if the test being conducted is the same across all samples and is not qualitatively difficult. He also stated that he was having difficulty distinguishing the Wands case from the facts at issue here. Counsel for Sanofi responded that repeated testing, regardless of whether that test is the same each time, is just labor intensive, to such a degree that no scientist would consider doing it. He also argued that the “hit rate” (or amount of antibodies found to be within the genus) was of particular importance – in Wands, the hit rate was nearly 50%, whereas here, he argued, it’s searching for a needle in a haystack.

Overall, the oral arguments provide insight into the Judges’ views and shed some light on the future of antibody genus claims.  The Court seems likely to follow its decisions in Idenix and Wyeth, where functionally-defined claims to a genus of small molecules were held invalid under Section 112, extending this precedent into the antibody field.[1]  The USPTO has already made it difficult for patent owners to obtain claims to a functionally defined genus of antibodies.  We expect that patent owners claiming a novel genus of antibodies will need to recite structural features such as specific complementary determining region (CDR) sequences, or perhaps a percentage of identity to a given amino acid sequence.  Hopefully, the Federal Circuit’s opinion will offer some guidance to this effect, but biotech companies should not expect new support from the Federal Circuit for functional genus claims. Given that the breadth of acceptable claims for antibodies is narrowing, patent attorneys will need to explore other options for drafting enforceable claims to continue to motivate innovation in the field.

[1] Idenix Pharm. LLC v. Gilead Scis. Inc., 941 F.3d 1149 (Fed. Cir. 2019), cert denied 2021 WL 161021 (Jan. 19, 2021); Wyeth & Cordis Corp. v. Abbott Labs., 720 F.3d 1380 (Fed. Cir. 2013).

On January 28, 2021, Bio-Thera Solutions, Ltd., a biopharmaceutical company based in China, announced that the U.S. Food and Drug Administration (FDA) accepted its Biologics License Application (BLA) for BAT1706, a proposed biosimilar to bevacizumab, referencing Genentech’s Avastin®, but excluding indications under orphan drug exclusivity protection.  The FDA has set November 27, 2021, as the decision date for the application.

Bevacizumab is an angiogenesis inhibitor, which suppresses new blood vessel growth in tumors by inhibiting vascular endothelial growth factor A.  Bio-Thera’s BLA seeks approval of BAT1706 for the treatment of metastatic colorectal cancer in combination with fluorouracil-based chemotherapy, non-squamous non–small cell lung cancer, recurrent glioblastoma, metastatic renal cell carcinoma in combination with interferon α, and persistent, recurrent, or metastatic cervical cancer.

Bio-Thera also filed for regulatory approval for BAT1706 in China and the European Union.  In December 2020, Bio-Thera announced a partnership with Brazil-based Biomm for the commercialization of BAT1706 in Brazil.  Bio-Thera has also commercialized a biosimilar of adalimumab, referencing Abbvie’s Humira®, and received marketing authorization in China.  Bio-Thera is also developing additional biosimilar products including tocilizumab, golimumab, ustekinumab and secukinumab, and mepolizumab.

“The FDA’s acceptance of our BLA is a significant achievement that brings Bio-Thera closer to providing cancer patients in the USA with a high-quality, low-cost treatment option,” said Dr. Shengfeng Li, Founder and CEO of Bio-Thera Solutions. “Regulatory filings for BAT1706 have now been accepted by the China National Medical Products Administration (NMPA), European Medicines Agency (EMA) and FDA, demonstrating Bio-Thera’s commitment to developing BAT1706 to global standards so that BAT1706 can be made available to the global cancer patient community.”

In the U.S., two bevacizumab biosimilars have been approved: Mvasi launched by Amgen in July 2019 and Zirabev by Pfizer in January 2020.  The FDA’s acceptance of the BLA added Bio-Thera to a list of biosimilar developers, including Amgen, Pfizer, Samsung Bioepis, Centus, and Mylan, to report the filing of a BLA for a bevacizumab biosimilar.

The COVID-19 relief and spending bill signed into law on December 27, 2020, includes a provision – Division BB, Title III, Subtitle C, Section 325[1] – that adds a new paragraph 9 to 42 U.S.C. §262(k) requiring the U.S. Food & Drug Administration (“FDA”) to provide more information to the public about patented biological products. This information includes:

  1. a list of each biological product, by nonproprietary name, for which a biologics license is in effect;
  2. the date of licensure and the application number;
  3. the licensure status and, as available, the marketing status; and
  4. exclusivity periods.

The FDA has 180 days from the enactment of the paragraph to make this information available to the public in its Database of Licensed Biological Products, or “Purple Book,” and the FDA is required to revise the list every 30 days.  Prior to enactment of this provision, the Purple Book, unlike the Orange Book for small molecules, did not contain any patent information.

As part of the “patent dance” for biosimilar approval, a reference biologic product sponsor provides a biosimilar applicant with patent information regarding the reference product. The new paragraph now requires that the sponsor provide this information to the FDA within 30 days of the date the information is provided to the biosimilar applicant. The FDA is required to include this patent information when it revises the Purple Book every 30 days. The FDA is also required to publish any subsequent or supplemental list of patents provided to a biosimilar applicant.

Notably missing are any consequences for reference sponsors for failure to provide this information to the FDA.  Stay tuned for updates on how FDA implements these new requirements and whether the FDA promulgates any new regulations for providing the information.

 

[1] The text of the bill is available at: https://rules.house.gov/sites/democrats.rules.house.gov/files/BILLS-116HR133SA-RCP-116-68.pdf.  Section 325 begins on page 2125 of Division BB (page 4592 of the PDF).

On December 2, 2020, Boehringer Ingelheim Pharmaceuticals, Inc. (“Boehringer Ingelheim”) submitted a Citizen Petition requesting a change in the FDA’s interpretation of “strength” of biological products under the Biologics Price Competition and Innovation Act (“BPCIA”).  The Citizen Petition is available on regulations.gov under docket number: FDA-2020-P-2247.  Boehringer Ingelheim seeks an interpretation of “strength” to mean total drug content, without regard to concentration.  The Citizen Petition further requests the FDA update its guidance documents to incorporate the new definition, and apply the updated definition to pending and approved applications before the agency.

The proposed change would primarily impact the approval of “interchangeable” biological products.  An “interchangeable” biological product “means that the biological product may be substituted for the reference product without the intervention of the health care provider who prescribed the reference product.” 42 U.S.C. § 262(i)(3). One requirement for the FDA to approve such a product is that the proposed biological product has the same “strength” as the reference product: “the route of administration, the dosage form, and the strength of the biological product are the same as those of the reference product; . . .” Id. § 262(k)(2)(i)(IV).  According to Boehringer Ingelheim, the FDA currently interprets “strength” as encompassing both total drug content and concentration.

In the petition, Boehringer Ingelheim presents three arguments as to why the concentration should not be included when evaluating the strength of the biological product.  First, Boehringer Ingelheim states that the FDA’s interpretation of “strength” conflicts with the BPCIA.  Second, it unnecessarily and unreasonably facilitates anticompetitive practices, such as patent “evergreening” tactics designed to prevent or delay competition from biosimilar and interchangeable products seeking approval.  And third, the interpretation is arbitrary and capricious in violation of the Administrative Procedure Act because it treats injectable solutions differently than similarly situated parenteral products without any reasonable basis.

Boehringer Ingelheim markets Cyltezo® in 20 mg and 40 mg doses, each administered at a 50 mg/mL concentration.  Cyltezo is an approved biosimilar of Humira® at the same concentration.  In addition to the original 50 mg/mL dosage, Humira was later approved for use in a 100 mg/mL formulation.  Boehringer Ingelheim argues that when FDA interprets “strength” to mean concentration, it allows brand manufacturers to manipulate the concentration of their reference products at strategic times during the extended eight to ten-year development period for biosimilars, which unfairly creates a “moving target” for sponsors seeking approval via the 351(k) pathway.  If the FDA modifies its interpretation of “strength” as Boehringer Ingelheim has requested, Boehringer Ingelheim can seek an interchangeability determination of Cyltezo that would apply to Humira’s higher concentration formulation.

On November 20, 2020, the U.S. Food & Drug Administration (“FDA”) released a Q&A-format draft guidance to address four questions regarding the submission of biologics license applications (BLAs) and labeling for interchangeable biosimilar products. 85 FR 74345 (“Draft Guidance”). The Q&As in the Draft Guidance will be finalized by adding them as a revision to the final guidance document, Questions and Answers on Biosimilar Development and the BPCI Act. A biosimilar product is one that is highly similar to the reference product notwithstanding minor differences in clinically inactive components and there are no clinically meaningful differences between the biological product and the reference product in terms of the safety, purity, and potency of the product. Section 351(i)(2) of the Public Health Service Action (“PHS Act”). An interchangeable product is one that is shown to meet the standards described in section 351(k)(4), means that the biological product may be substituted for the reference product without the intervention of the health care provider who prescribed the reference product. Section 351(i)(3). To date, the only known BLA under review for a proposed interchangeable biosimilar product is Boehringer Ingelheim’s BLA for an Adalimumab to be interchangeable with Abbvie’s Humira®. As more applicants file interchangeability BLAs and the FDA gains more experience with interchangeable biosimilars, the FDA intends to provide additional recommendations in future guidance documents.

The four Q&As addressed in the Draft Guidance are summarized as follows:

  1. How may the applicant seek FDA review for licensure for an interchangeable biosimilar, and how does FDA intend to review the application?

To seek FDA review for licensure for an interchangeable biosimilar, the applicant must submit a BLA under section 351(k) of the PHS Act with an affirmative statement in the cover letter indicating that the product meets the standards described in section 351(k)(4) for licensure as an interchangeable biosimilar or clearly requesting “INTERCHANGEABLE-ONLY REVIEW.”

If an applicant includes a statement for 351(k)(4) licensure, the FDA will evaluate the BLA as both an application for licensure of a biosimilar product and an application for licensure of an interchangeable biosimilar. If the application then only supports licensure of the product as a biosimilar product but not an interchangeable biosimilar, the FDA will split the action for administrative purposes. By splitting the action, the FDA could license the product as a biosimilar product and then convey any deficiencies in the application for licensure as an interchangeable biosimilar. The FDA could then make a later determination of interchangeability for the product upon submission of a supplement of additional data.

If the applicant requests interchangeable-only review, the FDA’s complete response letter will address any deficiencies of both interchangeability and biosimilarity because biosimilarity is a condition necessary for approval of a 351(k) BLA as an interchangeable product. However, the response letter will not address whether the application is sufficient to support a demonstration of licensure as a biosimilar product alone, as per the applicant’s request. If the application can support biosimilarity, but not interchangeability, the applicant may choose to amend and resubmit the application to address the deficiencies to support a demonstration of interchangeability or to amend and resubmit the BLA seeking licensure as a biosimilar product.

  1. How should a 351(a) BLA holder proceed if it seeks licensure of its biological product under section 351(k) as biosimilar to or interchangeable with another biological product licensed under section 351(a) (a “reference product”)?

For licensure of a proposed biological product as a biosimilar product, the applicant should submit an original application under section 351(k) of the PHS Act. For licensure of a proposed biological product as an interchangeable biosimilar product, the applicant should submit either an original application under section 351(k) of the PHS Act or a supplement to an approved application submitted under section 351(k) of the PHS Act. An applicant may, however, support a demonstration of biosimilarity or interchangeability under section 351(k) using relevant data and information from the applicant’s own 351(a) BLA for the reference product.

The Draft Guidance clarifies that it is not necessary for the holder of a 351(a) BLA for a biological product licensed or deemed licensed under section 351(a) to seek revocation of its 351(a) license in order to submit a 351(k) application. The 351(a) BLA holder may continue to market the reference product licensed or deemed licensed under section 351(a) while the 351(k) BLA is pending and after licensure of the biological product under section 351(k).

  1. Does FDA have recommendations for labeling of interchangeable biosimilars at this time?

Yes – the Draft Guidance explains that certain principles outlined in the FDA’s July 2018 Guidance for Industry: Labeling for Biosimilar Products (“Biosimilar Labeling Guidance”) also pertain to interchangeable biosimilar products.

Specifically, interchangeable biosimilar product labeling, like biosimilar product labeling, should incorporate relevant data and information from the reference product labeling, including clinical data that supported the FDA’s finding of safety and effectiveness of the reference product. As explained in the Biosimilar Labeling Guidance, labeling should not include a description of or data from clinical studies conducted to support a demonstration of biosimilarity or interchangeability because such studies would typically not be expected to facilitate an understanding of product safety and effectiveness.

Interchangeable biosimilar labeling should meet the content and format requirements of the physician labeling rule (PLR) as described in 21 CFR 201.56(d) and 201.57, as well as the final pregnancy and lactation labeling rule (PLLR) as described in 21 CFR 201.57(c)(9)(i)-(iii). Interchangeable biosimilar labeling should also follow the Biosimilar Labeling Guidance for revising biosimilar product labeling and submitting initial and revised labeling.

The Draft Guidance highlights certain differences between interchangeable biosimilar and reference product labeling. For example, interchangeable biosimilar product labeling conforming to PLR and/or PLLR may deviate from reference product labeling because the reference product labeling may not be required to conform to those requirements at the time of licensure of the interchangeable biosimilar. The interchangeable biosimilar product labeling may also differ from the reference product labeling if an applicant choses to seek licensure of the interchangeable biosimilar for fewer than all of the reference product’s licensed conditions of use.

  1. Does FDA recommend that the BLA-holder of an approved interchangeable biosimilar include a labeling statement on interchangeability?

Yes – a statement should be placed on the line immediately beneath the Initial U.S. Approval in the Highlights of Prescribing Information stating that the product is interchangeable with the reference product.

 

By addressing these questions, the FDA hopes to “enhance transparency and facilitate the development and approval of biosimilar and interchangeable products.” Comments and suggestions regarding the Draft Guidance should be submitted to the FDA by January 19, 2021.

On November 18, 2020, companies Samsung Bioepis Co., Ltd. and Biogen Inc. announced that the United States Food and Drug Administration (“FDA”) accepted for review the Biologics License Application for SB11, a proposed biosimilar referencing Genentech, Inc. product Lucentis® (ranibizumab).  Ranibizumab is an anti-VEGF (vascular endothelial growth factor) therapy for retinal vascular disorders, which are a leading cause of blindness in the United States.  SB11 is one of two opthamology biosimilar candidates jointly developed by Samsung Bioepis and Biogen in the U.S., Canada, Europe, Japan, and Australia, the other being aflibercept (“SB15”).  SB11 was accepted for review last month by the European Medicines Agency.

“The FDA filing acceptance for SB11 brings us a step closer to our goal of being able to offer affordable treatment options for people with retinal vascular disorders,” said Hee Kyung Kim, Senior Vice President and Clinical Sciences Division and Regulatory Affairs Team Leader at Samsung Bioepis.  Ian Henshaw, the Senior Vice President and Global Head of Biosimilars at Biogen, stated that SB11 and other biosimilars, “aim[] to ensure sustainability of healthcare systems by offering broader patient access to effective and more affordable treatment options.”

If approved, SB11 will join a Samsung Bioepis and Biogen biosimilar portfolio that includes three widely prescribed anti-TNF biosimilars in Europe: Benepali® (etanercept), ImraldiTM (adalimumab), and Flixabi® (infliximab).

Mark your calendars – on December 9th, the Federal Circuit is slated to hear oral arguments as to whether two Amgen patents claiming a genus of antibodies meet the enablement requirement of 35 U.S.C. § 112. The court’s decision may have a considerable impact on antibody-based drug development and the scope of patent protection available for antibody innovations.

In one corner, there’s Amgen, backed by amici Bristol-Myers Squibb and Merck. In the other, we have Sanofi and Regeneron, supported by amici Eli Lilly and Pfizer. The tension has been building since 2014, when Amgen sued Sanofi and Regeneron for patent infringement of two patents (U.S. Patent Nos. 8,829,165 and 8,859,741) drawn to a class of drugs called PCSK9 inhibitors (and covering Amgen’s cholesterol-lowering drug Repatha). While the defendants conceded infringement, the validity of the patents was brought into question, and following a years-long legal rollercoaster, Amgen is now challenging U.S. District Judge Richard G. Andrews’s decision invalidating the patents for lack of enablement.

In his August 2019 ruling, Judge Andrews found that the Amgen patents claimed a “vast” class of antibodies, and that it would take “undue experimentation” to practice the full scope of the invention. Specifically, he explained that the claims were directed to a large genus of antibodies (Amgen says the genus comprises about 400 distinct antibodies; Sanofi argues the number is actually in the millions), but the written description only specified a small fraction of the species that fell within that genus. With a substantial gap between the number of potential and actual species, and a lack of significant guidance or direction in the patent to a person of ordinary skill in the art on how to predict whether an antibody will bind to specific PCSK9 residues, Judge Andrews concluded that the claims were not enabled under Section 112.

The question of antibody genus patentability raises unique challenges considering the industry of big pharma and the research and development efforts that goes into antibody-based drugs. On one hand, antibody development has been described as extremely costly, complex, unpredictable, and time-consuming, such that it makes more sense for a company to seek patent protection for the genus as soon as they have a discernible universe of antibody species. But on the other hand, as Sanofi argues, allowing such broad claims to antibodies not actually discovered may be just a strategic means to stifle competition.

Could the outcome of this case ultimately threaten antibody innovation? Or will companies just have to get more creative with patent claims? Stay tuned for a summary of the Federal Circuit oral arguments and predictions about the case moving forward in a follow-on December post.