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 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.

On August 3, 2021, the China National Intellectual Property Administration (CNIPA) released the Draft Revised Patent Examination Guidelines (“Draft Guidelines”) for comments.  The revisions in the Draft Guidelines reflect the recently amended Chinese Patent Law that came into effect on June 1, 2021, and the Draft Revised Implementing Regulations (“Draft Regulations”) of the Chinese Patent Law.  This article summarizes selected provisions in the Draft Guidelines that are relevant to pharmaceutical products.

Patent Linkage System

In an earlier post, we discussed the patent linkage system implemented in the 4th  amendment to the Chinese Patent Law.  On July 4, 2021, the National Medical Products Administration (NMPA) of China and CNIPA jointly issued Measures for the Implementation of Early Resolution Mechanisms for Drug Patent Disputes (Interim) (“Measures”), which became effective on the same day.  The Measures provide details on how the Chinese patent linkage system will work.

According to the Measures, when a generic applicant submits its application for marketing authorization in China, it must make one of the four declarations below based on relevant patent information of the corresponding brand drug listed on the registration platform for drugs marketed in China.

  • Type 1: There is no relevant patent on the platform.
  • Type 2: There is a relevant patent on the platform. However, the relevant patent has expired or has been declared invalid, or the generic applicant has a license from the patentee.
  • Type 3: There is a relevant patent on the platform but the generic/biosimilar applicant will not sell its product before expiration of the patent.
  • Type 4: There is a relevant patent on the platform, but the patent should be declared invalid, or the generic product does not fall into the scope of the patent.

If the patentee or interested party has objections to the Type 4 declaration of a generic applicant, they may, within 45 days from the publication date of the generic application, file a lawsuit in a court or request the CNIPA to make an administrative ruling as to whether the generic product’s technical specifications fall into the scope of a relevant patent.

The first generic applicant who has (1) successfully challenged a brand drug’s patent and (2) is first approved to enter the market in China, can enjoy a 12-month market exclusivity period.  During this period, NMPA may still review but will not approve other generic drug applications (except for co-challengers).

The Draft Guidelines provide that a generic applicant should make the Type 4 declaration before they submit their petition to invalidate the relevant patent before the CNIPA.  If the CNIPA receives multiple petitions for invalidating the same patent, the petitions will be processed by the order of the petition dates.

Patent Term Adjustment (PTA)

In accordance with the amended Chinese Patent Law, the Draft Guidelines provide that PTA may be available for a patent granted over four years from its filing date and three years after the date of request for examination.  The PTA must be requested by the applicant within three months from the issue date with the payment of a fee.

The Draft Guidelines further clarify that, for a Chinese national stage application from a PCT application, the filing date of the national stage application is used for PTA calculation.  Also, for a divisional application, PTA is calculated based on the filing date of the divisional application rather than the parent application.  The Draft Guidelines also state that the date of requesting for examination is the mailing date of the notice of entering examination.

The PTA is calculated as the unreasonable delays by the CNIPA subtracted by applicant delays.  The Draft Guideline give some examples of applicant delays, including:

  • Failure to respond to a CNIPA communication within the specified time period;
  • For applications entering the Chinese national stage before the 30-month date, failure to expressly request examination to start prior to the 30-month date;
  • Filing a requesting for deferred examination
  • Adding inadvertently omitted elements disclosed in priority application in a PCT stage by incorporation by reference of the priority application.

Of notes, according to a publication released by CNIPA on May 27, 2021, PTA is only available for invention patents issued on or after June 1, 2021, and any request for PTA will only be processed after the Regulations are finalized.

Patent Term Extension (PTE)

We have discussed PTE in an earlier post.  The Draft Guidelines provide further clarifications on PTE regulations.

Regarding the type of drugs whose patents are eligible for PTE, the Draft Guidelines provide that PTE is available for patents of “innovative new drugs” and some “improved new drugs,” as defined in the Drug Registration Regulations and related guidelines issued by the National Medical Products Administration (NMPA) of China.  According to the Draft Guidelines, for “improved new drugs” (i.e., class 2 drugs, which are improved drugs having not been marketed in or outside China), only some kinds of drugs in this category are eligible for PTE.  Such class 2 drugs include “class 2.4 drugs” (drugs that contain known active ingredients but are used for a new indication), “class 2.2 prophylactic biologics” (improved vaccines), and “class 2.2 therapeutic biologics” (biologics that contain known active ingredients but are used for a new indication).  Thus, according to the Draft Guidelines, patents related to drugs that have already been marketed outside China are not eligible for PTE.

According to the Draft Regulations, PTE is only available for patents directed to active ingredients, manufacturing methods, and medical uses.  The Draft Guidelines specify that PTE only applies to the claim scope correlating to the NMPA-approved active ingredients, manufacturing methods, and medical uses.

The Draft Guidelines also set forth some limitations on the request for PTE (some have been included in the draft Regulations):

  • PTE must be requested by the patentee within three months from the drug’s approval date. If the patentee is different from the drug marketing authorization holder, the patentee must have the permission from the holder to request the PTE.
  • The patent must be granted prior to the drug’s approval date.
  • The patent must be alive when PTE is requested.
  • There must not be previous PTE granted to the patent.
  • When there are multiple patents related to a drug, PTE can only be requested for one patent.
  • When a patent covers multiple drugs, the term of the patent can only be extended under PTE for one drug.

Also, the Draft Guidelines provide that if the patentee has requested both PTA and PTE for a patent, the CNIPA should determine on the PTE request after the PTA is determined.  If the patentee has not requested PTA but the 3-month time limit for requesting PTA has not expired, the CNIPA should wait until the expiration of the three month limit to determine the PTE (unless patentee expressly waives the request for PTA).  Thus, these provisions in the Draft Guidelines suggest that a patent can receive both PTA and PTE.

According to the publication released by CNIPA on May 27, 2021, PTE is only available for patents related to drugs approved on and after June 1, 2021.  Also, Similar to PTA, any request for PTE will only be processed after the finalized Regulations take effect.

15-Day Mail Delay Grace Period

Another update in the Draft Guidelines relevant to U.S. applicants is that electronically filed applications will no longer be entitled to the 15-day mail delay grace period when calculating deadlines to respond to CNIPA communications.


Since the amended Patent Law came into effect, only the Measures related to the patent linkage system have been finalized so far.  The impacts of the amended Patent Law on other aspects of the Chinese patent system will depend on the finalized Regulations and Guidelines, which have not been promulgated yet.  We will provide further updates when the finalized versions of the Regulations and Guidelines are available.

The recently enacted “Purple Book Continuity Act of 2019” went into effect as of June 25, 2021.  The FDA must proactively update the Purple Book information every 30 days with an alphabetical list of licensed biologics, including the date of marketing application approval and the marketing/licensure status.  Additionally, there is now a potentially higher price for reference product sponsors for biologic drugs to enter the patent dance under the BPCIA and assert their patents against potential competitor biosimilar manufactures.

Prior to enactment of  H.R. 1520, the “Purple Book Continuity Act of 2019,” the FDA published the “Purple Book” reference guide for biologic drugs under section 351(a) or 351(k) of the Public Health Service Act (PHS) with information on whether biologic drug products have been determined by the FDA to be biosimilar to (or interchangeable with) the reference biological product and the date a biological product was licensed for marketing under section 351(a) or 351(k) of the PHS.  The Purple Book also indicated the date of expiration of applicable exclusivity if the FDA evaluated the biological product for reference product exclusivity under section 351(k)(7).  The Purple Book was only updated periodically by the FDA.

The recent enactment now adds a new layer of complexity for parties strategizing how to enter the patent dance under the BPCIA.  The reference product sponsor must provide the FDA with the expiration dates of all patents listed in the patent list sent to the subsection (k) applicant pursuant to 42 U.S.C. § 262(l)(3) and any supplemental lists pursuant to 42 U.S.C. § 262(l)(7) within 30 days of providing the subsection (k) applicant with such lists.  The FDA will then publish the patent expiration dates on the searchable Purple Book database in its recurring monthly updates.

The new regulation will likely ensure that the Purple Book listing will be closely watched by parties looking to develop their own biosimilar versions of licensed biologics.  As a result, a reference product sponsor may choose to forgo asserting some or all of their patents in order to avoid publication of expiration dates in what would amount to an easily accessibly compilation of the relevant patent estate.  This prospect could change the calculus for reference product sponsors in terms of the number and type of patents that they assert.  For example, a reference product sponsor may want to limit the number of patents asserted against a party in order to avoid revealing their hand to follow on competitors that may implement a design around strategy.  It remains to be seen whether the new regulation will have an impact on the desire to wield the better part of expansive portfolios against competitors, for example AbbVie’s recent challenge to Alvotech reported here.

As of the date of this post, the Purple Book lists patents and expiration dates in connection with AbbVie’s Humira® product and Genentech’s Avastin® and Lucentis® products.  Notably, most of the listed patents relate to methods of manufacturing rather than formulations, treatment methods, and other aspects relevant to biosimilar manufacturers.

Despite progress, there is still room to improve on the new regulations from the viewpoint of public transparency.  For instance the Purple Book counterpart for small molecule drugs, “The Orange Book”, requires NDA applicants and holders to provide the patent number and expiration date of any patent which claims the drug or method of using such drug and which a claim of patent infringement could reasonably be asserted (21 U.S. Code § 355(b)).  Recent changes to the Orange book came through the Orange Book Transparency Act of 2020.  NDA holders are now required to notify the FDA of invalidation of a patent within 14 days so the Orange Book listing can be amended as necessary.

The trend for both the Purple Book and Orange Book is moving towards increased public transparency.  The major impetus for the new regulations is to increase the number of lower cost drug options on the market, for example by shedding more light on the patent mine field that awaits some would-be competitors trying to enter the market.  However, it may take several years to see any impact, if at all, on the number of generic drugs and biosimilars entering the market.

On June 21, 2021, the Federal Circuit denied Amgen’s petition for en banc review of the court’s February 2021 decision in Amgen Inc. et al. v. Sanofi, Aventisub LLC, et al., 987 F.3d 1080 (Fed. Cir. 2021), which found that Amgen’s two patents covering the cholesterol-lowering antibody drug Repatha® are invalid for lack of enablement.  For more details on the February 2021 decision, please see our previous post here.

The court did not provide detailed comments in its order.  However, Judge Lourie, joined by Judges Prost and Hughes, wrote a separate opinion on the denial of Amgen’s petition.

Amgen had argued that the court’s February 2021 decision announced a new test for the enablement requirement, under which “enablement is evaluated by the ‘time and effort’ required ‘to reach the full scope of claimed embodiments,’” rather than focusing on “whether it would require undue experimentation.”  The Amici supporting Amgen’s petition also argued that the court had “adopted a ‘numbers-based standard’ to evaluate enablement asking not whether experimentation is undue but how long it would take to make and screen every species.”  In denying the petition, the Federal Circuit stated the argument “mischaracterizes our law.”  The court argued that “[w]hat is new today is not the law, but generic claims to biological materials that are not fully enabled.”  The court further reasoned that “[t]he problem was not simply that the claimed genus was numerous—it was that it was so broad, extending far beyond the examples and guidance provided.  Likewise, it was not that it would take a long time to collect the full set of each and every embodiment—it was that the narrow and limited guidance in the specification made far corners of the claimed landscape that were particularly inaccessible or uncertain to make unenabled.”

Amgen further argued that the court should overrule case law that holds enablement is a question of law.  Although acknowledging that one can reasonably ask why enablement is a question of law while written description is not, the court argued that they are bound by their longtime precedent and Amgen’s arguments “provide no compelling reason to introduce such a seismic shift.”

The court also rejected Amgen’s argument that the February 2021 decision will “threaten innovation” and “devastate the incentives to invest in drug discovery.”  The court argued that “if one considers that one has invented a group of compositions defined by a genus but does not know enough to fully enable that genus, one would suppress innovation if one were able to claim such a broad genus, not enhance it.”  Invoking a consolation prize to urge that the sky is not falling, the court noted that Amgen has a patent protecting Repatha®, which is U.S. Patent No. 8,030,457 claiming CDRs in the anti-PCSK9 antibody.  Thus, taking a post hoc view, the court cited Amgen’s good fortune in later obtaining a narrower patent on its antibody as a reason why Amgen should not complain about having its earlier, broader patent invalidated.

Amgen has not yet indicated whether it will take further actions, such as filing a petition for a writ of certiorari to the Supreme Court.  We will keep monitoring this case and report on future developments.

In the most recent of a series of litigations by AbbVie against manufacturers seeking to market biosimilar versions of Humira®, the world’s most profitable drug, AbbVie initiated an action against Alvotech in the district court for the Northern District of Illinois on April 27, 2021, after Alvotech requested approval of its biosimilar, AVT02, a biosimilar to the high-concentration 100 mg/ml formulation of adalimumab (Humira®). Alvotech stated that it believes AVT02 will be the first biosimilar to the citrate-free, 100 mg/ml formulation of Humira® approved in the United States. AbbVie initially stated in its “3C” statement (under 42 U.S.C. § 262(l)(3)(c)) that it reasonably believed that Alvotech would infringe 63 patents out of purportedly more than 100 total patents covering Humira®, although it subsequently removed one from that list. The 62 patents allegedly infringed by Alvotech are listed in the table below.

Alvotech responded that only four of the 62 patents should be the subject of the action pursuant to 42 U.S.C. § 262(l)(6), specifically U.S. Patent Nos. 8,420,081; 8,926,975; 8,961,973; and 9,085,619. The ’081 and ’619 patents are directed to self-buffering formulations, for example, for the 100 mg/ml formulation of Humira®.  The ’975 and ’973 patents are directed to methods of treating ankylosing spondylitis and Crohn’s disease using adalimumab, respectively. Although AbbVie asserted that litigating only the four patents selected by Alvotech would not resolve all of the infringement issues, Alvotech disagreed, stating that “invalidation of these four patents should pave the way for market entry of AVT02.” Consequently, on April 27, 2021, AbbVie asserted the four patents selected by Alvotech (NDIL-1-21-cv-02258). Alvotech has moved to dismiss that action for failure to join a necessary party (Alvotech USA) for which venue is improper in Illinois.

On May 11, 2021, Alvotech filed a Declaratory Judgment Action in the Eastern District of Virginia (EDVA-1-21-cv-00589; EDVA-2-21-cv-00265) asserting non-infringement, invalidity, and unenforceability due to inequitable conduct and unclean hands.  Notably, Alvotech asserted that AbbVie sought to “systematically and artificially inflate the size of the Humira® portfolio,” including patenting purported inventions that AbbVie does not use for Humira®, by seeking multiple patents on the same invention without informing the USPTO of pending applications in other patent families, seeking patents for prior art Humira®, by obtaining patents through inequitable conduct, and seeking patents on inventions that AbbVie did not invent. Alvotech alleged that the foregoing actions were taken to create what Alvotech described as a “minefield of IP,” which AbbVie’s CEO stated in a 2013 earnings call would be the very obstacle that would face biosimilar manufacturers.  Alvotech asserted that as a result of these activities, AbbVie has been able to garner $10 billion to $20 billion in revenue per year despite the fact that patents covering the Humira® product expired in 2016.

Subsequently on May 28, 2021, AbbVie filed a second complaint in the Northern District of Illinois (NDIL-1-21-cv-02899) asserting the other 58 patents that AbbVie alleged to be infringed by Alvotech. Alvotech has noted in its declaratory judgment action that there has never been a case in U.S. history where 60 or more patents were litigated to final judgement. Yet, AbbVie contends that all 62 must be litigated to resolve the dispute.

In the most recent example of aggressive patent litigation tactics, AbbVie continues to bury its competition in infringement claims while continuing to enjoy monopoly profits on the world’s most lucrative drug for nearly two decades.

We previously reported on AbbVie’s patent portfolio around Humira® (here). AbbVie is not the first and only company to create what has been termed a “patent thicket” around its products. For example, Amgen/Immunex’s Enbrel® (etanercept) and Roche’s Rituxan ® (rituximab) are also protected by large portfolios. However, the expansiveness of AbbVie’s Humira® portfolio, and AbbVie’s apparent willingness to wield their IP against would-be competitors, has heightened the focus on AbbVie’s practices as reported here. As discussed in our earlier post, this prompted an unprecedented antitrust suit against AbbVie in which the district court judge ultimately sided with AbbVie, but which is currently on appeal in the 7th Circuit.

As noted in the table below, challenges to AbbVie’s patents have not garnered much success to-date. As a result, the sheer size and scope of the portfolio continues to present a daunting barrier to market entry for biosimilars to AbbVie’s Humira®. As discussed here, while biosimilar versions of Humira® have launched in numerous countries around the world, AbbVie® continues to thwart biosimilar competition in the United States, where it secured over $16 billion of Humira® sales revenues in 2020.

We will continue to monitor the progress of the battles between AbbVie and Alvotech, as well as new challenges to the patents AbbVie asserted against Alvotech.

Previously challenged patents are noted as follows:

* Pending; ¥ Settled/voluntarily dismissed; # Institution denied