Last week, a federal court in Delaware unsealed an opinion supporting its grant of summary judgment that U.S. Patent No. 7,033,590 (“the ’590 Patent”) is invalid for lack of enablement.[1] The ’590 Patent is owned by Baxalta Inc. (“Baxalta”), a subsidiary of Takeda Pharmaceutical Co. Ltd (“Takeda”).

As we previously discussed, Baxalta sued Roche’s subsidiary Genentech Inc. (“Genentech”), alleging that that the blockbuster drug Hemlibra, made by Genentech, infringes Baxalta’s ’590 patent. Genentech denied Baxalta’s allegations and alleged, inter alia, that claims 1–4, 19, and 20 of the ’590 patent were invalid for lack of enablement.[2]

The ’590 patent is entitled “Factor IX/Factor IXa Activating Antibodies and Antibody Derivatives” and was issued on April 25, 2006. Its patent application, filed on September 14, 2000, claimed priority to a foreign application filed on September 14, 1999. At issue are claims 1–4, 19, and 20 of the ’590 patent, which cover a genus of antibodies that bind to factor IX/factor IXa, thereby increasing the procoagulant activity of FIXa and restores blood clotting process in hemophilia A patients.

Claim 1 of the’590 patent recites:

  1. An isolated antibody or antibody fragment thereof that binds Factor IX or Factor IXa and increases the procoagulant activity of Factor IXa.

The litigation related specifically to infringement of the ’590 patent’s claims by Genentech’s Hemlibra (emicizumab), which was approved by the FDA for treatment of hemophilia A on October 4, 2018.[3] Baxalta itself has never commercialized a treatment for hemophilia A based on any of the antibodies covered by this patent.[4]

In his memorandum opinion, visiting Circuit Judge Timothy Dyk, who normally sits on Federal Circuit, held that the relevant claims of Baxalta’s patent were invalid for lack of enablement after applying the test articulated in In re Wands,[5] because undue experimentation would be required for a person skilled in the art to make and use the claimed invention.[6] The court found that neither the accused claims themselves nor the specification of the ’590 patent provided sufficient “guidance as to how to identify which antibodies will satisfy the claim limitations, nor [does it] describe what structural or other features of the disclosed antibodies cause them to bind to Factor IX/IXa or to increase the procoagulant activity of Factor IXa.”[7]

More specifically, based on the Wands factors, the Court cited to the following as supporting its finding of lack of enablement: (1) large amount of experimentation was needed because the number of candidates identified in the ’590 patent “number in the millions;” (2) there was no guidance as to how to identify the antibodies other than by trial and error; (3) the patent provided a very limited amount and variety of working examples; (4) the field of art (antibodies) was unpredictable; and (5) the breadth of the claims were too broad.[8] The Court concluded that “where, as here, there are a large number of potential candidates, few working examples disclosed in the patent, and no guidance in the specification as to how to practice the full scope of the invention except to use trial and error to narrow down the potential candidates to those satisfying the claims’ functional limitations—the asserted claims are not enabled.”[9]

The Court identified several Federal Circuit cases to support its finding that the asserted claims were not enabled as to their functional limitations.[10] For example, the Court points to Amgen Inc. v. Sanofi, Aventisub LLC, which we previously discussed here, where the Federal Circuit noted that where the patent at issue contained claims with broad functional language, the hurdles for fulfilling the enablement requirement were high.[11] There, the Federal Circuit found a lack of enablement on grounds that the claims were “far broader in functional diversity than the disclosed examples, [and] the only ways for a person of ordinary skill to discover undisclosed claimed embodiments would be through either trial and error… or by discovering the antibodies de novo.[12] Judge Dyk also compared this case to Idenix Pharms. LLC v. Gilead Scis. Inc.,[13] Wyeth & Cordis Corp. v. Abbott Labs.,[14] and Enzo Life Scis., Inc. v. Roche Molecular Sys., Inc.,[15] to analogize the situation “where the inventors had identified a small number of compounds within the scope of the claims and the court found the claims were not enabled given the breadth of the claims and the lack of sufficient guidance in the specifications.”[16]  We discussed several of these cases here.

The Court also found that the functional scope of the ’590 patent was not sufficiently represented by working examples.[17] Rather, the Court concluded that the ’590 patent merely “disclose[d] a starting point for further research.”[18] For example, the ’590 patent did not provide any working examples of two of the four Markush-group members cited in its asserted claims, nor provide any guidance in its specification for one skilled in the art to identify those isotopes.[19]

Finally, the Court also held that the ’590 patent “does not remotely enable” the accused product, emicizumab. “None of the 11 disclosed antibodies in the specification increase the procoagulant activity of factor IXa more than 3.75%,” while emicizumab increases procoagulant activity by approximately 10%.[20] Furthermore, emicizumab was a bispecific humanized antibody and the ’590 patent provided no working examples of either a bispecific or humanized antibody.[21] Baxalta’s expert conceded that the patent’s language about the covered antibodies and their therapeutic utility was merely “aspirational”[22] and the Court concluded that it could not “allow Baxalta to provide a starting point for further research and then claim someone else’s solution to the problem.”[23]

Potential Impact

This decision follows the Federal Circuit’s judgment as a matter of law for lack of enablement in Amgen Inc. v. Sanofi, Aventisub LLC, for which a petition for a writ of certiorari has been filed as discussed here.  That petition raises the question of whether enablement is “a question of fact to be determined by the jury . . . as [the Supreme] Court has held,” or whether it is “a question of law that the court reviews without deference . . . as the Federal Circuit holds.”  Here, Judge Dyk held that “no reasonable jury could find the full scope of the asserted claims of the ’590 patent are enabled.”[24]

In view of the trend toward higher standards for written description and enablement for antibody claims and claims reciting broad functional language, patent drafters will be well-advised to provide more working examples in general, working examples for every Markush group, and more guidance in the patent specification for how to identify candidates within the claimed group. We will continue to follow further developments including a potential appeal of this decision and the Supreme Court’s decision on Amgen’s petition.

[1] Memorandum Op. at 1, Baxalta Inc. v. Genentech, Inc., No. CV 17-509-TBD (D. Del. Jan. 13, 2022).

[2] Id.

[3] Memorandum Op., supra note 1, at 8, 19.

[4] Id. at 16.

[5] 858 F.2d 731, 737 (Fed. Cir. 1988).

[6] Memorandum Op., supra note 1, at 5.

[7] Id.

[8] Id.at 29 to 31.

[9] Id at 31.

[10] Id.

[11] 987 F.3d 1080, 1087 (Fed. Cir. 2021).

[12] Id. at 1088 (internal quotations omitted).

[13] 941 F.3d 1149, 1155–56, 1162 (Fed. Cir. 2019)

[14] 720 F.3d 1380, 1385–86 (Fed. Cir. 2013).

[15] F.3d 1340, 1346–47 (Fed. Cir. 2019).

[16] Memorandum Op., at 37.

[17] Memorandum Op., supra note 1, at 38-42.

[18] Id. at 42.

[19] Id.

[20] Id. at 45.

[21] Id. at 45.

[22] Id.

[23] Id. at 47 (internal citations omitted).

[24] Id. at 7.

On January 4, 2022, the District Court for the District of Delaware granted Hikma Pharmaceuticals USA Inc.’s (“Hikma”) motion to dismiss Amarin Pharma Inc.’s (“Amarin”) infringement claims, finding that Hikma’s “skinny label” for its generic heart drug, icosapent ethyl, did not induce infringement of Amarin’s three patents. This decision comes on the heels of the Federal Circuit’s recent decision in GlaxoSmithKline LLC v. Teva Pharms. USA, Inc., 7 F.4th 1320, 1338 (Fed. Cir. 2021) and is a victory for generic manufacturers who raised concerns about the future of the generic industry and the use of “skinny labels.”

State of Federal Circuit Law on “Skinny Labels”

As we have previously reported, the generics industry has been concerned with infringement liability for selling drugs with labels that carve out patented uses (aka “skinny labels”) after the Federal Circuit twice ruled in favor of GlaxoSmithKline (“GSK”) in their case against Teva Pharmaceuticals. USA (“Teva”). First, in October of 2020, the Federal Circuit found that substantial evidence, i.e. Teva’s marketing of its drug as equivalent to the brand drug and physicians’ knowledge that brand drug could be used to treat the indication, supported the jury’s finding that Teva was liable for induced infringement for the patented indication it carved out of its skinny label.  However, the Federal Circuit’s opinion left several questions unanswered and raised several concerns about whether listing a generic drug as AB-rated meaning that it is therapeutically equivalent (displaying bioequivalence and pharmaceutical equivalence) to a brand drug could establish inducement and whether ANDA filers that carve out patented uses under section viii of 21 U.S.C. § 355(j)(2)(A) could be liable for infringement. After Teva filed a petition for rehearing which was supported by seven amicus curiae briefs, the original panel vacated its October 2020 ruling and decided to rehear the case entirely.

In August of 2021, after another round of oral arguments, the panel again affirmed the jury’s findings that Teva’s “partial label” induced infringement of GSK’s patent. The Federal Circuit held that substantial evidence demonstrated that “Teva’s partial label did not successfully carve out the patented use, and thus, Teva was selling its generic with a label which infringed the method claim.”[1] Accordingly, Teva’s label was “not a skinny label.”[2] The Federal Circuit also held that Teva’s marketing materials encouraged physicians to prescribe carvedilol in a manner that would cause infringement.[3] In its decision, the panel stated that the laws regarding generic drugs remain intact and quoted the language of an amicus brief to explain the law as follows:

“Generics could be held liable for actively inducing infringement if they marketed a drug with a label describing a patented therapeutic use or if they took active steps to encourage doctors or patients to use the drug in an infringing manner. But generics could not be held liable for merely marketing and selling under a ‘skinny’ label omitting all patented indications, or for merely noting (without mentioning any infringing uses) that FDA had rated a product as therapeutically equivalent to a brand-name drug.”[4]

The Federal Circuit clarified that its holding was a “narrow, case-specific review” and “does not upset the careful balance struck by the Hatch-Waxman Act regarding section viii carve-outs.”[5] According to the Federal Circuit, Teva did not omit all patented indications or note (without mentioning any infringing uses) that the FDA found a product therapeutically equivalent to a brand product.[6]  On October 7, 2021, Teva filed a Petition for Rehearing en banc.  In its Petition, Teva argues that “[t]he panel’s decision contradicts settled precedent, eviscerates the carve-out statute, and throws inducement doctrine into disarray.” [7]  Quoting Judge Prost’s dissent, Teva argues that “[b]ecause ‘the background facts here will seemingly persist in most skinny-label cases,’ the effects of the decision will be seismic.” [8]

After this decision, many generic companies raised concerns about whether this opinion materially altered the “skinny label” regime or at the very least removed it as a viable option for FDA approval.[9]

Aside from raising generic’s concerns, the Federal Circuit panel’s opinion in GlaxoSmithKline LLC v. Teva Pharms. USA, Inc. also raises the appearance of a split in Federal Circuit law on inducement of “skinny labels.” For example, previously, in Grünenthal GMBH v. Alkem Labs Ltd., 919 F.3d 1333, 1339-40 (Fed. Cir. 2019), a different panel affirmed the district court’s finding that the defendants’ “skinny labels” did not induce infringement band because neither label was specifically indicated for the patented treatment, or made a reference to the patented indication. The panel found that even though the label was indicated for “[m]oderate to severe chronic pain,” which included both infringing and non-infringing uses, it did “not specifically encourage use” of the generic for the patented “treatment of polyneuropathic pain.” [10] Grünenthal differs from the GSK case in that it did not involve statements by the generic regarding the equivalency of its drug to the branded drug. However, the panels’ competing views on inducement demonstrate a clear split and one that will continue to create uncertainty and concerns for the lower courts until its resolution.

Amarin Pharma, Inc. v. Hikma Pharms. USA, Inc.

The most recent decision addressing these concerns came on January 4, 2022. In Amarin Pharma, Inc. v. Hikma Pharms. USA, Inc., No. 20-1630 (D. Del.), Judge Richard G. Andrews of Delaware issued an opinion dismissing Amarin’s induced infringement claims against Hikma. The three patents-at-issue in the litigation relate to methods of using icosapent ethyl for the reduction of cardiovascular risk. Amarin sued Hikman, alleging that Hikma had induced doctors to infringe the patents by encouraging them to prescribe the generic for patent protected indications. Amarin also sued Health Net, LLC (“Health Net”), alleging that its formulary placement induces infringement by encouraging Hikma’s generic for the patented use.

Amarin’s brand product, Vascepa® (icosapent ethyl), is used in the treatment of hypertriglyceridemia and cardiovascular risk reduction. Amarin’s patents only cover using icosapent ethyl to treat cardiovascular risk reduction. Hikma had received FDA approval to sell its generic version of icosapent ethyl for use in the non-patented indication of hypertriglyceridemia under the “skinny label” regime. Amarin argued that the label used by Hikma to sell its generic was “not-skinny-enough” and that this label combined with Hikma’s public statements resulted in induced infringement of the patented indication[11]. Specifically, Amarin asserted that Hikma’s label teaches cardiovascular risk reduction because it contains a warning for patients with cardiovascular disease and it does not explicitly state that the product should not be used for the patented indication.

Judge Andrews disagreed with Amarin and found that neither Hikma’s label nor its statements teach using the generic in cardiovascular risk reduction. As to the label, Judge Andrews held that the notice regarding side effects is a warning and not an instruction to use icosapent ethyl to reduce cardiovascular risk. Relying on Takeda Pharms. U S.A., Inc. v. W-Ward Pharm. Corp., 785 F.3d 625, 632 n.4 (Fed. Cir. 2015), Judge Andrews also found that the label’s silence regarding cardiovascular risk reduction does not plausibly amount to inducement because generic labels do not need to contain a statement discouraging use of the patented indication.[12] Judge Andrews further found that Hikma’s press releases and website did not support accusations of actual induced infringement. The fact that Hikma’s press releases described icosapent ethyl as the “generic equivalent” of Vascepa® was not sufficient to establish inducement. With respect to the website, Judge Andrews relied on Grünenthal GMBH v. Alkem Labs Ltd., 919 F.3d 1333, 1339-40 (Fed. Cir. 2019), and held that without more, the mere fact that Hikma advertises its product as “AB rated” in a therapeutic category that includes both patented and non-patented uses does not amount to specifically encouraging use for the patented treatment.[13]  In light of these facts, Judge Andrew granted Hikma’s motion to dismiss.

By contrast, Judge Andrews denied Health Net’s motion to dismiss the induced infringement claims. Judge Andrews found that formulary selection and the prior authorization process could amount to affirmative acts of induced infringement. Judge Andrews found that “Health Net’s prior authorization form supports an inference of specific intent because it lists the patented indication on the generic icosapent ethyl capsules form” and that its “placement of generic icosapent ethyl on a preferred tier encourages the substitution of the generic for the branded drug, including for the patented indication.”[14] Ultimately, Judge Andrews agreed with the recommendations of the Magistrate Judge that Amarin had pled enough to survive the motion to dismiss stage.

Conclusions

The decision in favor of Hikma provides some reassurance to generic companies that the “skinny label” regime remains alive and well and that the Federal Circuit’s decision in GlaxoSmithKline LLC v. Teva Pharms. USA, Inc., was narrowly tailored to a specific set of facts.

However, the conversation continues as to the future of skinny-labeled generics and whether the language of press releases, web pages and other marketing materials requires more scrutiny. Additionally, the liability of insurance companies is coming into the spotlight. Amarin was able to defeat the motion to dismiss filed by Health Net, which suggests that we may see more cases against insurance companies in the future. It will be interesting to see whether other brand companies target not only insurers, but other companies in the supply network.

We will continue to provide updates on the evolving skinny-label landscape including the Federal Circuit’s decision on Teva’s en banc petition as well as any appeals of the Amarin decision.

 

[1] GlaxoSmithKline LLC v. Teva Pharms. USA, Inc., 7 F.4th 1320, 1338 (Fed. Cir. 2021).

[2] Id. at 1328.

[3] Id. at 1336-38.

[4] Id. at 1326.

[5] Id.

[6] Id.

[7] GlaxoSmithKline LLC v. Teva Pharms. USA, Inc., No. 18-1976, Dkt. 195 at 10 (Fed. Cir. Oct. 7, 2021).

[8] Id.

[9] See GlaxoSmithKline LLC v. Teva Pharms. USA, Inc., No. 18-1976, Dkt. 213 (Fed. Cir. Oct. 25, 2021) (Amicus Brief of Apotex, Inc.); see also Dkt. 217 (Amicus Brief of Mylan Pharmaceuticals Inc.).

[10] Id.

[11] Amarin Pharma, Inc. et al v. Hikma Pharms. USA Inc., No. 20-1630, slip op. at 6-7 (D. Del. Jan. 4, 2022).

[12] Id. at 7.

[13] Id. at 9.

[14] Id. at 11.

At the end of last month, three amicus curiae briefs were filed following the petition for a writ of certiorari in the Amgen, Inc. v. Sanofi, Inc. case. We previously discussed the petition for a writ of certiorari in detail here.

The first amicus brief was submitted by the Association of University of Technology Managers (AUTM), Biogen, Bristol-Myers Squibb, Corning, Merck Sharp & Dohme, and St. Jude Children’s Research Hospital, collectively. Amici began the brief by noting that they “also are competitors, and have been directly adverse to one another in litigation over their innovations and patent rights. Yet despite their diverse interests and disagreements on many issues, amici have joined a common brief in support of the petition for certiorari in this case to urge that the Court review and reverse the Federal Circuit’s decision below.” Amici argue that the Federal Circuit’s decision “threatens to disrupt the patent bargain,” because it replaces the former statutory enablement standard – that the disclosure be sufficient to enable any person skilled in the art to make and use the invention – with a new “special, atextual” rule for genus claims.

According to amici, this new rule allows for invalidation of the patent if practicing the “full scope of the claimed embodiments” requires “substantial time and effort.” Amici argue that if this law is not reversed, innovators will be compelled to divert time and resources away from additional discoveries. Instead, the innovators will need to spend their resources on testing additional examples of their invention and “adding information already known to skilled artisans to their patent applications.” Finally, amici note they practice in “fast-paced fields of research,” where fast-paced patent filings are needed to protect innovator’s rights. If innovators with limited resources, such as universities and non-profits, must spend more time and money generating additional examples, those innovators might choose to forego their patent rights altogether in order to focus on new discoveries.

Finally, Amici argue that the Federal Circuit’s decision that enablement is a question of law is an error. They note that the same court has ruled that written description, which is in the same sentence in 35 U.S.C. § 112(a), is a question of fact to be decided by a jury.[1] They argue that the Federal Circuit’s habit of “routinely set[ting] aside jury verdicts confirming the validity of patents against enablement challenges – as it did twice in this case – lead[s] innovators to doubt whether they will have reliable patent protection for their inventions even after prevailing at trial.”

GlaxoSmithKline, PLC (“GSK”) submitted the second amicus brief. Although GSK does not consider the issue of whether enablement is a question of fact to be decided by a jury, it makes multiple arguments why the Federal Circuit’s decision should be reversed. First, it argues that the Federal Circuit has created a new rule for genus claims that could devastate the chemistry and biotechnology fields. If the law is not reversed, GSK argues, innovators will be forced to draft narrower claims to avoid invalidation of their patents, even though “known techniques could permit competitors to circumvent the literal scope of a narrow claim by making insubstantial changes to a chemical compound or a biological molecule.” GSK argues that a genus claim is generally commensurate with the innovator’s discovery, and that “[a]llowing for a wide breadth of protection based on a genus is, as a practical matter, the only means to ensure that an inventor in these arts actually receives a commercially meaningful period of exclusivity contemplated by our patent system.” If these innovators cannot receive the full patent protection that they deserve, GSK argues, then the innovators may choose trade secret protection over patent protection and disclosure.

Additionally, GSK argues the Federal Circuit’s standard for genus claims is undesirable for innovators because “it would ‘force an inventor seeking adequate patent protection to carry out a prohibitive number of actual experiments’ and ‘discourage inventors from filing patent applications in an unpredictable area.’”[2] GSK notes that the Patent Act does not limit the number of species that a claim can have, “nor does the Patent Act require different, elevated tests for enablement for certain types of claims.”

Finally, GSK lists reasons why the “full scope” enablement test “erects a formulaic, inflexible requirement that tends toward a predetermined outcome: invalidating genus claims.” It argues the rule gives additional power to judges to set aside expert testimony and “real-world facts showing that artisans were able to exploit the invention following its teachings.” GSK notes that this test is similar to other rigid, atextual tests that the Supreme Court has previously rejected.[3]

The final amicus brief was submitted from intellectual property professors throughout the United States. Like GSK, these amici did not address whether enablement is a question of fact to be decided by a jury. Amici state, “The Federal Circuit has changed the law dramatically in recent years, to the point where it is no longer possible to have a valid genus claim in the chemical and biotechnology industries.” They note that the previous standard of providing enough information to allow one of ordinary skill in the art to make and use the invention is no longer enough for genus claims, and that the Federal Circuit is now rejecting the genus claims as invalid if “the genus contains thousands or millions of possible chemicals, unless the patent itself identifies exactly which of those myriad species will work.” This leaves one of two options for innovators: (1) spend extra time and resources identifying all the possible species, or (2) draw narrow claims that will be avoided by “minor modification.”

Amici emphasize that what constitutes “undue experimentation” should be decided on a case-by-case basis by examining the facts in the case. Additional experimentation is not automatically “undue experimentation,” but “is a common part of the PHOSITA’s work.” They state, “as long as the specification provides some working examples, that disclosure can give PHOSITAs sufficient guidance to enable the full scope of the genus claims.”

The petition for a writ of certiorari and the three amicus curiae briefs were distributed last week for Conference taking place on January 21. The Court asked Sanofi for a response by February 10, 2022, but Respondents have asked for a 30-day extension of time to file this response. We will continue to watch this case and post updates on any advancements.

[1] PIN/NIP, Inc. v. Platte Chem. Co., 304 F.3d 1235, 1243 (Fed. Cir. 2002).

[2] In re Angstadt, 537 F.2d 498, 502-03 (C.C.P.A. 1976).

[3] KSR Int’l Co. v. Teleflex Inc., 550 U.S. 398, 421 (2007); see also Octane Fitness, LLC v. ICON Health & Fitness, Inc., 572 U.S. 545, 553 (2014); Halo Elecs., Inc. v. Pulse Elecs., Inc., 579 U.S. 93, 104 (2016).

Last week, Coherus BioSciences, Inc. (“Coherus”) announced that the United States Food and Drug Administration (“FDA”) approved YUSIMRY™, an adalimumab biosimilar. YUSIMRY™ is a tumor necrosis factor blocker approved as a subcutaneous formulation. It is indicated for plaque psoriasis, psoriatic arthritis, rheumatoid arthritis, juvenile idiopathic arthritis, ankylosing spondylitis, Crohn’s disease, and ulcerative colitis. This is the seventh biosimilar to be approved for AbbVie’s blockbuster immunosuppressant Humira® (adalimumab).

“We are excited that Coherus has received FDA approval for YUSIMRY, our second approved product, and we are grateful to the patients and investigators who participated in our clinical trials and for the dedication of employees across all functions at Coherus,” said Denny Lanfear, CEO of Coherus. “Growth and diversification of our biosimilar portfolio is a high priority for Coherus — first and foremost as it enables greater patient access to important medicines — and because revenue from these products will fund the continued investment in our innovative pipeline programs that will drive our future growth.” As we previously discussed, AbbVie’s Humira® is the world’s most profitable drug with sales reaching close to $20 billion in 2020, over $16 billion of which were U.S. sales revenue. In 2021, AbbVie reported with an increase in sales of Humira® in the U.S., but as predicted, a decrease of sales internationally due to biosimilar competition in other parts of the world.

Humira® was first approved in December 2002 and has enjoyed exclusivity in the U.S. market for the last 19 years, even though multiple adalimumab biosimilars have been approved by the FDA starting in 2016. As we previously discussed, this exclusivity was due to AbbVie’s patent thicket hindering biosimilar competition. After a series of patent lawsuits and settlements, including with Coherus, biosimilar versions are slated to launch in the U.S. starting in 2023. Coherus’ press release indicates that it will launch YUSIMRY™ in the U.S. on or after July 1, 2023, per the terms of its agreement with AbbVie.

Disclaimer: The information contained in this posting does not, and is not intended to, constitute legal advice or express any opinion to be relied upon legally, for investment purposes or otherwise. If you would like to obtain legal advice relating to the subject matter addressed in this posting, please consult with us or your attorney. The information in this post is also based upon publicly available information, presents opinions, and does not represent in any way whatsoever the opinions or official positions of the entities or individuals referenced herein.

As we have previously discussed, on February 11, 2021, the Federal Circuit decided Amgen Inc. et al.  v. Sanofi, Aventisub LLC, et al. The Federal Circuit affirmed the district court’s grant of JMOL that Amgen’s Repatha® patents (U.S. Patent Nos. 8,829,165 and 8,859,741) were invalid for lack of enablement. The claims at issue cover a genus of monoclonal antibodies that bind to the proprotein convertase subtilisin/kexin type 9 (“PCSK9”) enzymes. This binding blocks PCSK9’s degradation of low-density lipoprotein (“LDL”) receptors, allowing the LDL receptors to continue regulating LDL cholesterol. The specification discloses amino acid sequences for twenty-six antibodies, including evolocumab (the antibody marketed as Repatha®). Before the district court granted Sanofi’s JMOL for lack of enablement, two separate juries had found that Sanofi failed to prove that the asserted claims were invalid for lack of written description and enablement.

The Federal Circuit affirmed the JMOL ruling, first citing its precedents holding that the enablement requirement under 35 U.S.C. § 112 is a question of law to be reviewed without deference. Then, the Federal Circuit concluded that practicing the full scope of the claims requires undue experimentation given the breath of the functional claim limitations, the guidance in the specification, and the unpredictability of the antibodies that would be produced. The Federal Circuit explained that it was not concluding “that the effort required to exhaust a genus is dispositive. It is appropriate, however, to look at the amount of effort needed to obtain embodiments outside the scope of the disclosed examples and guidance.”

Amgen petitioned for en banc review, which was denied on June 21, 2021, as we previously discussed. Subsequently, on November 18, 2021, Amgen filed a petition for a writ of certiorari asking the Supreme Court to overturn the Federal Circuit’s ruling. The petition presents two questions for review:

  1. whether enablement is “a question of fact to be determined by the jury . . . as [the Supreme] Court has held,” or whether it is “a question of law that the court reviews without deference . . . as the Federal Circuit holds.”
  2. whether enablement is governed by the statutory requirement that the specification teach those skilled in the art “to make and use” the claimed invention, or whether it must enable those skilled in the art “to reach the full scope of claimed embodiments” without undue experimentation – i.e. “to cumulatively identify and make all or nearly all embodiments of the invention without substantial time and effort.”

For the first issue, Amgen points to Supreme Court decisions holding that “enablement” is “a question of fact to be determined by the jury.”[1] Amgen notes that Federal Circuit cases that have held the opposite.[2]  Interestingly, in a separate opinion on the denial of the petition for Federal Circuit en banc review, Judges Lourie, Post, and Hughes had stated, “[o]ne can reasonably ask, as Amgen does, why enablement is a question of law.”[3] However, these judges went on to say that they saw no reason to revisit this issue because its precedent is “long in the tooth.”  Amgen proceeds to point out that the Supreme Court’s precedent is even older than the Federal Circuit, and either way the Supreme Court’s precedent is binding on the Federal Circuit.  Finally, Amgen argues that the Federal Circuit’s decision that enablement is a question of law invades the role of the jury.

On the second issue, Amgen argues that the Federal Circuit created a new “hurdle” to the enablement requirement, especially for genus claims.  Amgen emphasizes that the Federal Circuit’s requirement that the specification teach the skilled artisan “to reach the full scope of claimed embodiments” means that the patent must teach how to make all or nearly all the embodiments of the invention without “substantial time or effort.”  Amgen argues that it is impossible to specify every conceivable implementation of the invention in a patent.  It believes this new “hurdle” will be particularly harmful to the biotech and pharmaceutical innovations, since the Federal Circuit may tend to invalidate claims based merely on the size of the genus they encompass.

Amgen claims that its patents include a step-by-step “roadmap,” which employs methods routine in the art, for making additional antibodies to PCSK9.  Amgen claims that the Federal Circuit did not identify any actual embodiment that could not be made by following this “roadmap,” and thus improperly held the claims invalid.

Potential Impact:

It will be interesting to see whether the Court will grant Amgen’s petition for certiorari to examine whether the Federal Circuit has strayed from prior Supreme Court decisions holding that enablement is a question of fact to be decided by the jury.  The Supreme Court has shown a willingness to overturn longstanding Federal Circuit precedent where it perceives a conflict with the Court’s prior holdings.[4]  This is a decision to watch, as whether enablement is a question of law to be decided by a judge or a question of fact to be decided by a jury will affect both challengers’ and a patentees’ litigation strategies.  If enablement questions must be decided by a jury, they may, in practice, become a less powerful means of challenging arguably overbroad patent claims due to the expense of reaching a jury determination.

[1] Wood v. Underhill, 46 U.S. (5 How.) 1, 4 (1846).

[2] See Raytheon Co. v. Roper Corp., 724 F.2d 951, 960 n.6 (Fed. Cir. 1983).

[3] Amgen Inc. v. Sanofi, Aventisub LLC, 850 F. App’x 794 (Fed. Cir. 2021).

[4] See MedImmune, Inc. v. Genentech, Inc., 549 U.S. 118 (2007); see also TC Heartland LLC v. Kraft Foods Grp. Brands LLC, 137 S. Ct. 1514 (2017).

The U.S. Patent and Trademark Office (USPTO) recently instituted two of Mylan’s petitions seeking Inter Partes Review of Regeneron’s U.S. Patent No. 9,669,069 B2 (the “’069 Patent,” subject of IPR2021-00880) and U.S. 9,254,338 B2 (the “’338 Patent,” subject of IPR2021-00881), finding that Mylan (now part of Viatris) established a reasonable likelihood in prevailing in showing unpatentability of at least one claim in each patent.  Regeneron markets Eylea® (aflibercept), a recombinant VEGF-binding fusion protein, for treatment of retinal diseases.  This is the latest development in a series of battles over Eylea®, which has been marketed in the United States since 2011, has enjoyed $8.36 billion in revenues in 2020, and is the third highest grossing biologic product in the world as reported here. We recently reported on Regeneron’s battle with Novartis over a pre-filled glass syringe for injecting a VEGF-antagonist such as aflibercept into the eye.

Both of Regeneron’s patents claim treating an angiogenic eye by “sequentially administering to the patient a single initial dose of a VEGF antagonist, followed by one or more secondary doses of the VEGF antagonist, followed by one or more tertiary doses of the VEGF antagonist” and further recite “wherein each secondary dose is administered 2 to 4 weeks after the immediately preceding dose.” The ’069 patent specifies that “each tertiary dose is administered on an as-needed/pro re nata (PRN) basis,” while the ’338 Patent specifies that “each tertiary dose is administered at least 8 weeks after the immediately preceding dose.”

The Patent Trial and Appeal Board (the “Board”) instituted both petitions on all grounds asserted by Mylan.  Mylan cited several references in each of its petitions as being anticipatory references, but the respective parties’ arguments and the Board’s focus centered substantially on the Dixon reference. Dixon was relied upon both as an anticipatory reference and as a primary reference for the obviousness grounds in each petition in combination with (IPR2021-00881), or optionally in combination with (IPR2021-00880), Regeneron’s earlier publications (“Papadopolous” and “Dix” references).

Regeneron urged the Board to apply its discretion to deny institution as Dixon or other references that “were before the Examiner and considered during prosecution” constitute “substantially the same art that was already considered by the Examiner.” See IPR2021-00881 at pp. 9-11; see also IPR2021-00880 at pp. 10-13. However, reviewing the prosecution of the ’069 patent (IPR2021-00880), the Board found that only a single page of the Dixon reference was filed in an information disclosure statement (IDS). The Board found that based on the single page of Dixon, “[i]t would consequently have been impossible for the Examiner to analyze the limitations of the challenged claims.” IPR2021-00880 at pp. 12-13.  While Regeneron also argued that a 2008 press release provided to the Examiner in an IDS in connection with ’338 Patent disclosed the same teachings of the cited prior art in the petition, the Board disagreed.  See IPR IPR2021-00881 at pp. 9-14.  In particular, the Board found that the disclosed press release failed to provide the additional disclosures relied upon by Mylan, including that “VEGF Trap-Eye and aflibercept (the oncology product) have the same molecular structure,” and therefore the same sequence. Id. at p. 14.

Interestingly, while the Board agreed with Regeneron that the claim preamble “method for treating an angiogenic eye disorder in a patient” was limiting, the Board was not persuaded by Regeneron’s arguments that the claims require a certain level of efficacy because the specification merely stated that “[t]he amount of VEGF antagonist administered to the patient in each dose is, in most cases, a therapeutically effective amount” and a therapeutically effective amount means “detectable improvement in one or more symptoms or indicia of an angiogenic eye disorder, or a dose of VEDF [sic] antagonist that inhibits, prevents, lessens, or delays the progression of an angiogenic eye disorder.” See IPR2021-00881 at p. 20 (emphasis in original) (citing ’338 Patent at 6:48–50 and 6:50–55).

The Board was also unpersuaded by Regeneron’s arguments that the claimed “tertiary dose” requires maintaining efficacy gained by the claimed “initial” and “secondary doses,” even in light of Regeneron’s alleged showing during prosecution that “less frequent, tertiary dosing ‘once every 8 weeks’ was surprisingly efficacious.” See IPR2021-00881 at p. 22.  Instead, the Board found that the specification clearly indicated that the terms “initial dose,” “secondary doses,” and “tertiary doses,” merely refer to the temporal sequence of administration of the VEGF antagonist.  See id. (citing ‘338 Patent at 3:31–38).

In the Patent Owner’s Preliminary Response to each petition, Regeneron argued that Dixon fails to disclose the amino acid sequences required by the challenged claims. Regeneron argued that Dixon fails to disclose the amino acid sequence of the VEGF antagonist described by the reference and the evidence of record failed to show that the amino acid sequence of VEGF Trap-Eye taught in Dixon was known to be the same as the amino acid sequence of aflibercept. See IPR2021-00880 at pp. 28-29 and IPR2021-00881 at p. 30. Regeneron also argued that the prior art used varying nomenclature referring to different VEGF-trap proteins and also reported VEGF-Trap Eye with varying molecular weights. See id.  The Board disagreed and found that the evidence of record stated sufficient facts to support institution. The Board noted that Dixon expressly teaches that VEGF Trap-Eye and aflibercept (the oncology product) have the same molecular structure, but there are substantial differences between the preparation of the purified drug product and their formulations. See IPR2021-00880 at p. 36. The Board also found that that VEGF-Trap Eye was taught in prior art references, including a 2002 publication (“Holash”) disclosing that VEGF-TrapR1R2 was created by fusing the second Ig domain of VEGFR1 with the third Ig domain of VEGFR2, and an earlier and now expired Regeneron patent (“Papadopoulos”), which expressly disclosed “VEGFR1R2-FcΔC1(a) encoded by the nucleic acid sequence of SEQ ID NO: 1,” as recited in dependent claim 12” and this fact was not disputed by Regeneron. See id.at pp. 36-37. The Board did, however, acknowledge an apparent discrepancy concerning the molecular weight of aflibercept and VEGF Trap-Eye in the prior art, but did not find this discrepancy to be sufficient to deny institution given the identical structures.  The Board credited expert testimony that the sequence of the VEGF antagonist which is marketed as aflibercept “was disclosed well before January 2011” and that numerous references demonstrated that “aflibercept, VEGF Trap (R1R2), and VEGF Trap-Eye, among other terms, were understood by a person of ordinary skill in the art to refer, interchangeably, to the same drug.”  IPR2021-00880 at p. 38 (quoting Mylan’s Declarant’s expert testimony).

Regeneron also argued in connection with the ’069 Patent that  Dixon and another cited prior art reference, Heier 2009, failed to disclose the claim feature reciting “wherein each tertiary dose is administered on an as needed/ pro re nata (PRN) basis, based on visual and/or anatomical outcomes as assessed by a physician or other qualified medical professional.” However, the Board disagreed.  The Board found first that Dixon expressly discloses that patients were treated on a “p.r.n. basis.” Secondly, the Board concluded that, while a physician doing an assessment is not expressly mentioned in the cited references, a person or ordinary skill in the art would recognize that the prescription of the appropriate medication would necessarily need to be performed by a physician or other qualified medical professional licensed by the state. See IPR2021-00880 at p. 31. (citing, inter alia, Continental Can Co. USA v. Monsanto Co., 948 F.2d 1264, 1269 (Fed. Cir. 1991) (holding that anticipation requirement that every element of a claim appears in a single reference accommodates situations where the common knowledge of “technologists” is not recorded in a reference, i.e., where technical facts are known to those in the field of the invention).

Thus, the Board found that Mylan had established a reasonable likelihood in prevailing in showing unpatentability of at least one claim in each of the challenged patents.

This is the latest development in a series of challenges to Regeneron’s thicket of patents covering Eylea® including IPR2021-00402 (challenging U.S. Pat. No. 10,464,992, terminated due to settlement), PGR2021-00035 (challenging U.S. Pat. No. 10,828,345, terminated due to settlement), PGR2021-00117 (challenging U.S. Pat No. 10,857,231), IPR2022-00298 (challenging U.S. Pat. No. 9,254,338), IPR2022-00257  (challenging U.S. Pat. No. 9,669,069); IPR2022-00258 (challenging U.S. Pat. No. 9,254,338); Reexamination 90/014,448 (challenging U.S. Pat. No. 10,464,992), and Reexamination 90/014,449 (challenging U.S. Pat. No. 10,406,226).

Regeneron’s Patent Owner’s Response in each case is due by February 2, 2022.  We will keep monitoring these cases and report on future developments.

Updated November 15, 2021

  • FDA and EMA both approve first biosimilar version of Lucentis® (ranbizumab).
  • FDA has approved only two biosimilars in 2021 after only approving three in 2020.
  • EMA approves four more Avastin® (bevacizumab) biosimilars, bringing the total number of approved bevacizumab approvals to nine, but also withdraws approval of two of bevacizumab and one rituximab biosimilars.
  • Given the increasing number of approved biosimilars in Europe, biosimilar manufacturers are increasingly deciding to not market their products due to commercial reasons.

As pharmaceutical drug costs attract increasing media attention and political scrutiny, a growing number of biosimilar drugs are set to enter the U.S. and European markets in the coming years.  Global sales for the top ten branded biologic drugs totaled approximately $85 billion in 2020[1].  In a September 2020 report, the IQVIA Institute for Human Data Science estimated biosimilar sales totaling $80 billion over the next five years compared to $14 billion during the previous five years (2015-2019), and that the availability and use of biosimilar medicines would reduce U.S. drug costs by $100 billion through 2024.

In the FDA’s Center for Drug Evaluation and Research’s (CDER) annual report, the FDA highlighted the three biosimilar approvals in 2020 under the Biologics Price Competition and Innovation Act (BPCIA) of 2009, which was “designed to create competition, increase patient access, and potentially reduce cost of important therapies.”  The FDA’s Biosimilars Action Plan, unveiled in 2018, has been designed to aid the development of a market for biosimilars in order to increase competition for biologic drugs, which make up 40% of U.S. pharmaceutical spending.  Competition in the heavily regulated marketplace for these blockbuster therapeutics is expected to substantially impact the pharmaceutical industry and national health systems.  To date, the U.S. has considerably lagged behind Europe’s expansion of biosimilar drug options.

Since 2005, the biosimilar regulatory framework in Europe has been implemented through the Committee for Medicinal Products for Human Use (CHMP) under the European Medicines Agency (EMA).  The CHMP provides initial assessments for marketing authorization of new medicines that are ultimately approved centrally by the EMA.  Since Sandoz’s somatotropin biosimilar, Omnitrope®, was first authorized on April 12, 2006, an additional 81 applications have been approved in Europe.  Fourteen of the authorizations have been withdrawn post-approval (Table 1).  Most recently, market authorization holders for Equidacent® (bevacizumab), Lextemy (bevacizumab), and Ritemvia® (rituximab) requested that their marketing authorizations be withdrawn due to commercial reasons.  There are seven other approved bevacizumab biosimilars and five other approved rituximab biosimilars.

The U.S. did not implement a regulatory framework for biosimilar evaluation until after enactment of the Biologics Price Competition and Innovation Act (BPCIA) of 2009.  Given that the first U.S. biosimilar drug was approved almost a decade after the first in Europe, the number of authorized biosimilar drugs in Europe far exceeds the number of biosimilars approved in the United States.  Sandoz’s filgrastim biosimilar, Zarxio®, received the first U.S. approval in 2015, whereas nine filgrastim biosimilars have been approved in Europe dating back to multiple authorizations in 2008.  Zarxio® (in the U.S.) and Zarzio® (in Europe) are biosimilar to the reference product Neupogen® marketed by Amgen and originally licensed in 1991.  Subsequent to Zarxio®’s approval, 30 other biosimilar drugs have gained U.S. approval to date including two interchangeable products (Table 2)

As illustrated in the following graph, while the EU’s significant head start led to an imbalance in the number of biosimilar drugs available in the respective markets, the EU’s relatively higher rate of approvals in recent years has widened its lead over the United States, although the U.S. FDA reversed that trend in 2019 with ten approvals.  Through 2021, however, the FDA has only approved two biosimilar products, whereas the EMA has approved eight biosimilar products.  However, given the increasing competition between biosimilar manufacturers in Europe, four EMA-authorized biosimilar products have been withdrawn in 2021.

A recent study of U.S. biosimilar approvals found that most comparative efficacy trials conducted to obtain FDA approval for a biosimilar had a tendency to be larger, longer, and more costly than clinical trials required for originator products. Moreover, the FDA requires animal studies whereas the EMA does not require animal studies to approve a biologic product.  Further, given the difficult patent litigation and competitive landscapes, there appear to be fewer biosimilar BLAs than in 2017-2019, and launches of FDA-approved adalimumab and rituximab biosimilars are delayed due to settlements of patent litigations.  Thus, in addition to the patent litigation landscape, there are regulatory hurdles and costs faced by biosimilar applicants that deter or delay biosimilar products from reaching the U.S. market.

Currently, sixteen biosimilar applications are under review by the EMA for marketing authorization (Table 3).  As an increasing number of patents expire on blockbuster biologic drugs, the number of abbreviated biologics license applications is also increasing.  Biosimilars for more than 28 different original biologics are currently navigating biosimilar pathways or are in late stage development in the U.S. (Table 4).

On September 17, 2021, the FDA approved Samsung Bioepis and Biogen’s ranibizumab ByoovizTM as the first biosimilar to Lucentis® for the treatment of neovascular (wet) age-related macular degeneration (AMD), macular edema following retinal vein occlusion (RVO), and myopic choroidal neovascularization (mCNV).  “In the United States, approximately 11 million people are affected with AMD and the prevalence of advanced AMD is growing due to the aging population. The approval of the first ranibizumab biosimilar in the U.S. is a monumental milestone for people living with retinal vascular disorders in the U.S.,” said Kyung-Ah Kim, Senior Vice President and Development Division Leader, at Samsung Bioepis. “The approval of BYOOVIZ™ underscores our continued commitment to providing valuable treatment options for people who do not have access to life-enhancing biologic medicines around the world,” she added.  “We are very excited to be able to open a new chapter with the approval of BYOOVIZ™ in the U.S. This approval represents a great step toward the advancement of a new therapeutic option addressing debilitating disease progression of patients with retinal vascular disorders in the U.S.,” said Ian Henshaw, Senior Vice President and Global Head of Biosimilars at Biogen. “Biosimilars could help broaden patient access to more affordable treatments and generate healthcare savings to offset rising costs of these complex diseases while ensuring sustainability of healthcare systems.”  EMA also approved ByoovizTM in August 2021 as the first ranibizumab biosimilar in Europe.

Table 1. European Medicines Agency List of Approved Biosimilar Drugs (updated November 15, 2021).

Table 2. U.S. Food and Drug Administration List of Approved Biosimilar Drugs.

Table 3. European Medicines Agency List of Biosimilars Under Evaluation for Marketing Approval (Source: EMA list of applications for new human medicines compiled on November 3, 2021 and published on November 8, 2021). 

Table 4. Biologics having already expired or nearing primary patent expiry in the U.S. and biologics that have biosimilars in the regulatory pipeline.

[1] Based on sales reported by respective manufacturers (1. Humira—Abbvie ($20.39B), 2. Keytruda—Merck ($14.38B), 3. Eylea—Aflibercept ($8.36B), 4. Stelara—Johnson & Johnson ($7.94B), 5. Opdivo—Bristol-Myers-Squibb ($7.92B), 6. Enbrel—Pfizer/Amgen ($6.37B), 7. Avastin—Roche ($5.32B), 8. Trulicity—Eli Lilly ($5.07B), 9. Ocrevus—Roche ($4.61B), 10. Rituxan—Roche ($4.52B).

On October 26, 2021, the Patent Trial and Appeal Board (PTAB) granted Regeneron’s petition to institute an inter partes review (IPR) of Novartis’s patent U.S. Pat. No. 9,220,631 (“the ’631 patent”), which covers a pre-filled glass syringe for injecting a VEGF-antagonist into the eye.  This is the second time the PTAB reviewed Regeneron’s petition to institute an IPR over the ’631 patent.  Last time, the PTAB denied Regeneron’s petition based on an ongoing proceeding at the International Trade Commission (ITC), without addressing the merits.

Regeneron makes Eylea (Aflibercept), a recombinant VEGF-binding fusion protein, and Novartis makes Lucentis (Ranibizumab), a humanized monoclonal antibody fragment binding to VEGF.  Both products have been approved for treating age-related macular degeneration and other retina diseases, and are being sold in pre-filled syringes.

On June 19, 2020, Novartis filed a complaint at the ITC alleging that Regeneron infringed the ’631 patent.  Soon after, Regeneron filed a petition at the PTAB on July 16, 2020 to challenge the validity of the ’631 patent.  The PTAB denied Regeneron’s petition on prudential grounds due to the ITC’s scheduled trial in 2021.  On April 8, 2021, shortly before the ITC trial was set to begin, Novartis unilaterally withdrew its complaint at the ITC but maintained a co-pending infringement action against Regeneron in the U.S. District Court for the Northern District of New York (NDNY).  In NDNY, Judges McAvoy and Suddaby recused themselves and the case was reassigned to Judge Hurd.  A hearing regarding the briefing schedule on Regeneron’s Motion to Stay is scheduled for November 5, 2021.  Regeneron filed this IPR petition on April 16, 2021, renewing the invalidity arguments from its prior petition.  In addition to the IPR and the NDNY action, the parties are in litigation in the U.S. District Court for the Southern District of New York (SDNY), where Regeneron has accused Novartis of violating antitrust laws by using its licensing scheme and patent suits related to the eye disease treatment.

In its opinion, the Board first addressed whether discretion should be exercised to deny the institution of the IPR.  The Board started with analyzing the Fintiv factors[1] and declined to deny the institution under 35 U.S.C. § 314(a).  In particular, the Board found that there are circumstances weighing strongly against denying the institution.  The Board pointed out that its discretionary denial of Regeneron’s prior IPR petition was relied on Novartis’ representation that the ITC would issue a final determination addressing the validity of the ’631 patent.  However, Novartis unilaterally terminated the ITC investigation after the Board denied the petition.

The Board further considered whether discretion under § 314(a) should be exercised in a “serial petition” situation.  Applying the factors provided in General Plastic[2], the Board concluded that discretionary denial is not warranted because Regeneron’s filing of multiple IPR petitions is a unique situation created solely by Novartis’s unilateral termination of the ITC investigation on the eve of trial.

The Board also considered whether it should deny institution under 35 U.S.C. § 325(d), because the same or substantially the same prior art or argument were previously presented.  Applying the two-part framework test provided in Advanced Bionics[3], the Board found that the prior art presented by Regeneron in the IPR petition is not the same or substantially the same as the references considered by USPTO during prosecution of the ’631 patent.  In view of these analysis, the Board refused to exercise its discretion to deny the institution of the IPR.

Next, the Board analyzed the prior art and arguments presented by Regeneron and found that Regeneron has persuasively shown how each element of claim 1 is taught by the combination of the references and provided sound reasoning for combining the references.  However, the Board found no nexus between the objective evidence related to secondary considerations and the claims.  Weighing all information presented, the Board held that there is a reasonable likelihood that Regeneron would prevail in showing at least one claim of the ’631 patent is unpatentable, and instituted the IPR to all claims of the ’631 patent.

According to the scheduling order entered with the institution decision, Novartis will have until January 18, 2022 to file a response to the Petition.  Subsequently, Regeneron will have until April 12, 2022 to file a reply to Novartis’ response.  We will keep monitoring this case and report on future developments.

[1] See Apple Inc. v. Fintiv, Inc., IPR2020–00019, Paper 11 (Mar. 20, 2020) (“Fintiv”).

[2] Gen. Plastic Indus. Co. v. Canon Kabushiki Kaisha, IPR2016-01357, Paper 19 at 15–16 (PTAB Sept. 6, 2017).

[3] Advanced Bionics, LLC v. MED-EL Elektromedizinische Geräte GmbH, IPR2019-01469, Paper 6 at 8 (PTAB Feb. 13, 2020).

On October 15, 2021, the U.S. Food and Drug Administration (“FDA”) approved Boehringer Ingelheim’s Cyltezo® (adalimumab-adbm), the first interchangeable biosimilar to AbbVie’s blockbuster immunosuppressant Humira® (adalimumab).  We previously discussed Boehringer Ingelheim’s 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 approval of Cyltezo® before a decision on the Citizen Petition was a surprising development.  This marks the second interchangeable biosimilar product approved by the FDA after Semglee® (insulin glargine-yfgn), but is importantly the first interchangeable monoclonal antibody to be approved.

In order for a biosimilar to acquire the “interchangeable” designation, in addition to meeting the requirements for a biosimilar (i.e., highly similar to, and no clinically meaningful differences from, an approved reference product), the manufacturer must show that the interchangeable biosimilar product is expected to produce the same clinical result as the reference product in any given patient. For biological products administered more than once to an individual patient, the manufacturer needs to further provide data ensuring that the risk in terms of alternating or switching between use of the interchangeable biological product and its reference product is not greater than the risk of using the reference product without switching.

The benefit of meeting these more extensive requirements is that, just like with a traditional generic drug, an “interchangeable” biosimilar can be substituted for the often pricier reference product by a pharmacist without the prescribing doctor’s intervention or approval (subject to state pharmacy laws).

Cyltezo®, which is one of several adalimumab biosimilars in the United States, was originally approved as a biosimilar to Humira® in August 2017. As we previously reported in this post, Humira® is the world’s most profitable drug, with sales of $20 billion in 2020, over $16 billion of which was U.S. sales revenue. While multiple companies have launched adalimumab biosimilars worldwide, none has launched in the U.S. due to settlements of patent litigations delaying launch until 2023, including Cyltezo®’s planned launch in July 2023.

If the 30 percent drop in sales of Humira® upon the initial launch of adalimumab biosimilar products in Europe is any indication, AbbVie is likely looking at a significant decline in its U.S. market share upon launch of the U.S. adalimumab biosimilars. The availability of an interchangeable version has significant implications for other biosimilar makers. For example, Cyltezo’s “interchangeable” designation will give it a competitive edge over other adalimumab biosimilars because the manufacturer of the interchangeable biosimilar has already proven the safety and efficacy of the cheaper “pharmacy-level substitution,” even in the middle of a course of treatment using the reference product.  Pharmacy benefit managers will likely prefer the interchangeable drug over all others, and place it on their preferred formularies to achieve cost savings and convenient switching of patients.

Depending on Cyltezo®’s level of success, the U.S. landscape for future biosimilar development may transform in at least following ways:

  1. races to obtain interchangeable designations for other biologics becoming the norm;
  2. new strategies and efforts by brand manufacturers to thwart approval of interchangeable products;
  3. changes in how brand manufacturers market their products after approval of an interchangeable given the ease and automation of substitution with an interchangeable at the pharmacy level;
  4. relegation of non-interchangeable biosimilars to racing to the bottom on price; and
  5. a need for newly developed biologics to demonstrate safety and/or efficacy advantages over existing biologics that treat the same indications to convince doctors or pharmacy benefit managers to switch patients to the new, higher priced biologics over the existing approved interchangeable products.

Disclaimer: The information contained in this posting does not, and is not intended to, constitute legal advice or express any opinion to be relied up legally, for investment purposes or otherwise. If you would like to obtain legal advice relating to the subject matter addressed in this posting, please consult with us or your attorney. The information in this post is also based upon publicly available information, presents opinions, and does not represent in any way whatsoever the opinions or official positions of the entities or individuals referenced herein.

On September 16, 2021, eleven congressional leaders (“the Signors”) sent a letter to Andrew Hirshfeld, the acting director of the United States Patent and Trademark Office (“USPTO”), requesting the USPTO to reevaluate the Patent Trial and Appeal Board’s (“PTAB”) view on discretionary denials of petitions for inter partes review (“IPR”).  The Office uses discretionary denials to deny institution of challenges to patents when an upcoming trial in district court would address the patent’s validity on the premise that parallel review would be an inefficient use of the PTAB’s resources. The first signature of the letter is none other than Senator Patrick Leahy (D-VT), one of the two lead sponsors of the America Invents Act. The congressional letter garnered bi-partisan support, with other signors including Senator Elizabeth Warren (D-MA), Congressman Darrell Issa (R-CA), and Senator Richard Blumenthal (D-CT). However, Thom Tillis (R-NC), who has signed previous letters to the USPTO and is an active member of the Senate Judiciary IP Subcommittee, is noticeably absent from the letter.

The Signors emphasized that discretionary denials are contributing to the high price of drugs. As described in the letter, some pharmaceutical companies engage in anti-competitive patent practices that artificially extend the manufacturer’s monopoly on a drug, prevent competitors from entering the market, and drive up the cost of drugs. The letters cites as an example that pharmaceutical companies create “patent thickets” comprising “dozens of questionable, back-to-back patents,” or engage in “product hopping” by transitioning from one branded drug to another very similar drug with a longer patent life.

As noted by the Signors, the IPR process was designed by Congress to provide “a lower-cost and faster alternative to litigation” to allow competitors to challenge weak patents and bring generic or biosimilar products to market sooner. The Signors explained that the IPR system is “one of the few tools available” to serve as a “check against questionable patents” and “help address the root cause of high prescription drug prices.” By denying IPR petitions for “reasons not based on merit” but based on administrative factors “not grounded in statute,” the Signors argued that discretionary denials of IPR petitions have weakened the IPR process.

Particularly, the Signors point to Apple, Inc. v. Fintiv, Inc., IPR2020-00019, Paper 11 (PTAB Mar. 20, 2020, designated as precedential May 5, 2020), which set forth the factors governing the PTAB’s discretion to deny institution of an inter partes review (“IPR”). Since Fintiv, the number of IPR petitions denied for reasons not based on the merit have risen dramatically – from 5% in 2016 to an estimated 19% in 2020.

Currently before the Supreme Court are two petitions for writ of certiorari related to Fintiv as further discussed here. Additionally, various members across the patent community have also weighed in on the Fintiv factors in response to the USPTO’s request for comments on discretionary institutions in 2020 as further discussed in our earlier post found here.

With the additional pressure on the USPTO from Congress, we may see changes to discretionary denials and to Fintiv in the future.