In an earlier post, we discussed the patent linkage system implemented in the Fourth Amendment to the Chinese Patent Law, which will come into effect on June 1, 2021.  Another important change in the amendment is the introduction of Patent Term Extension (PTE) for pharmaceutical patents.

The new PTE provision is in the 3rd paragraph of Article 42 in the amended Chinese Patent Law, which reads and is translated as follows: “In order to compensate for the time taken for regulatory review and approval of a new drug in China, the Patent Administration Department of the State Council, at the request of a patentee, may extend the term of an invention patent related to the new drug that has received regulatory approval for marketing in China.  The patent term extension should not exceed five years, and the total remaining term of the patent after the regulatory approval should not exceed fourteen years.”

Specific rules for implementing PTE will be provided in the amended Implementing Regulations of the Chinese Patent Law (“Regulations”).  Draft amendments to the Regulations (“draft Regulations”) were released on November 17, 2020.  A final version of the amended Regulations has not been promulgated.

Below is a summary of the PTE rules according to the amended Chinese Patent Law and the draft Regulations.

Eligibility

The amended Chinese Patent Law provides that PTE may be available for an invention patent related to a new drug.  Under Section 85-4 of the draft Regulations, a new drug can be a new chemical drug, biologic drug, or traditional Chinese medicine, and PTE is only available for patents covering the drug, methods of manufacturing of the drug, and medical use of the drug.  Thus, medical device and equipment patents are not eligible for PTE.

The draft Regulations also specify that the patent related to the new drug refers to a patent related to the drug’s active ingredient that receives regulatory approval for the first time in China.  However, it is not clear whether the active ingredient only includes the active moiety or also includes the salts, ester, or crystal forms of the active moiety.

Timing

The draft Regulations provide limitations on the timing of filing a request for PTE.  Under Section 85-7 of the draft Regulations, a request for PTE must be filed within three months from the date when a new drug receives regulatory approval.  The request should be filed with the Patent Administration Department of the State Council (i.e., China National Intellectual Property Administration (CNIPA)).

Thus, under the current version of the draft Regulations, drugs approved prior to March 1, 2021, will not be eligible for PTE.  Some pharmaceutical companies have submitted their concerns on this requirement to the CNIPA.  In particular, they asked for a “transition period” to include some drugs approved before March 1, 2021.  They argued that drugs approved since April 2018 should be eligible for PTE consideration since the Chinese State Council executive meeting decided in April 2018 to provide up to 5 years’ term extension for patents related to drugs for which regulatory approval was simultaneously applied in China and abroad.

Another limitation on the timing is that a PTE request must be filed at least six months prior to the patent’s expiration date (without PTE).  Since the amended patent law will come into force on June 1, 2021, it appears that patents expiring before December 1, 2021, will not be eligible for PTE considerations.  No retrospective remedy is provided in the current version of the draft Regulations.

Calculation

The calculation of PTE under the amended Chinese Patent Law is different from PTE calculation in the U.S. and is more similar to that of the supplementary protection certificate (SPC) in the European Union.  Section 85-5 of the draft Regulations provides that the extended term under PTE is the time period between a patent’s filing date and the date when the drug receives regulatory approval, reduced by five years.  The total time period of PTE is also subject to limits under Article 42 of the amended patent law as discussed above.

Limitations

Section 85-7 of the draft Regulations further provides the following requirements and limitations on the request for PTE:

  • when there are multiple patents related to a new drug, PTE may only be requested for one of the patents;
  • when a patent covers multiple drugs, the term of the patent may only be extended under PTE for one drug;
  • the patent has never received a PTE; and
  • the remaining term of the patent (without PTE) is no less than six months (discussed above).

Also, under Section 85-6 of the draft Regulations, during a patent’s extended term under PTE, the scope of the patent is limited to the new drug and the approved indication(s) of the drug.

Conclusion

Along with other amendments, the introduction of PTE will strengthen IP protection for pharmaceutical patents in China.  The real impact of the amendments will depend on the finalized Regulations, CNIPA’s examination guidelines, and future judicial interpretations.  We will provide more updates on any further clarifications and amendments.

On May 6, 2021, the Brazilian Supreme Court determined that the minimum ten-year patent term set forth in Article 40 of the Brazilian Intellectual Property Statute (Law No. 9,279) was unconstitutional (ADI 5529), and, on May 12, 2021, retroactively reduced the terms of granted pharmaceutical and medical device patents that are valid only due to the ten-year patent term provision to 20 years from the filing date.  The terms of granted patents in fields other than pharmaceuticals and medical devices did not have their terms retroactively reduced, i.e., they maintain their ten-years from grant date terms.

Historically, patent applicants before the Brazilian Patent and Trademark Office (BRPTO) experienced some of the longest pendency times in the world. In 2015, the average pendency of a patent application was eleven years with some applications taking more than twenty years to grant as a patent. This meant that some Brazilian patents were granted only after their 20-years from filing date term had already expired.  Due to the extremely long pendency periods, the Brazilian legislature enacted the minimum ten-year patent term.

In the Brazilian Supreme Court’s May 6 decision, nine of the eleven Justices issued opinions stating that the ten-year patent term, even in view of a backlog of patent applications, violated the Brazilian Constitution.  The reasoning underlying the decision included the fact that the extension was automatic, could be subject to gamesmanship by the applicant, and was not sufficiently limited to prevent evergreening.

The Justices decided that the general provision of twenty years from the date of filing provided a sufficient term of protection for patent owners, and the minimum term constituted a “term extension” that undermined the temporary nature of a patent as provided by the Brazilian Constitution. The Justices highlighted that the term extension finds no parallel in any other country’s patent framework and automatically extends the patent’s life without considering the applicant’s responsibility for contributing to the delay. Furthermore, the Justices emphasized that the minimum term increased pharmaceutical prices in the Brazilian market by creating monopolies and impacted the country’s access to pharmaceuticals.

After the May 6, 2021 decision, several generic companies in Brazil filed lawsuits targeting patents held by pharmaceutical companies.  Specifically, 46 identical lawsuits were filed against 79 patents, including patents directed to Repatha® (evolocumab), Nucala® (mepolizumab), Entyvio® (vedolizumab), Xvega® (denosumab), Brilinta® (ticagrelor), Xarelto® (rivaroxaban), Vyvanse® (lisdexamfetamine), Xalkori® (crizotinib), Latuda® (lurasidone), Ibrance® (palbociclib).

The Brazilian Supreme Court estimated that 11% of patents granted with the extended term are in the pharmaceutical field. With approximately 36,000 total patents granted with the benefit of the patent term extension, the retroactive application of the Brazilian Supreme Court’s May 6, 2021 decision appears to shorten the patent term of approximately 4,000 granted pharmaceutical patents, likely including the 79 patents directed to the major pharmaceutical products noted above.

This decision will have an unprecedented impact on pharmaceuticals in Brazil because many generic and biosimilar manufacturers will be able to launch years before previously anticipated.  It will be interesting to observe the ripple effects of this decision on drug pricing and availability, public health, and patent examination resources and procedures in Brazil in coming years.  Given the Supreme Court’s scrutiny of the limitless and automatic aspects of the provision, it is possible that the Brazilian legislature will consider enacting an alternative framework akin to the patent term extension or supplementary protection certificate regimes employed by the United States and European Union, respectively.

During the first quarter of 2021, multiple companies launched adalimumab biosimilars as a growing number of biosimilar players marketed their versions of the world’s most profitable drug, Humira®, which had sales of about $20 billion in 2020.  While none have launched thus far, at least eight adalimumab biosimilars are due to launch by the end of 2023 in the United States, where Abbvie secured over $16 billion of its Humira® sales revenues in 2020.

On February 11, 2021, the European Commission (EC) granted marketing authorization for Celltrion’s YuflymaTM for use in treating thirteen chronic inflammatory diseases.  This authorization is valid in all EU Member States and the European Economic Area countries Iceland, Liechtenstein, and Norway.  According to Celltrion, YuflymaTM is the first adalimumab biosimilar with a high concentration, low-volume, and citrate-free formulation.

On February 16, 2021, Sandoz Canada launched its adalimumab biosimilar, Hyrimoz®, in Canada.  Hyrimoz® was authorized for sale in Canada by Health Canada on November 4, 2020.  This biosimilar is approved for nine indications, including rheumatoid arthritis, polyarticular juvenile idiopathic arthritis, psoriatic arthritis, ankylosing spondylitis, adult Crohn’s disease, ulcerative colitis, hidradenitis suppurativa, psoriasis, and adult uveitis.  According to Sandoz Canada, the company has completed the pan-Canadian Pharmaceutical Alliance (pCPA) negotiations for Hyrimoz®, which is the first step in securing public reimbursement.

On February 18, 2021, Fresenius Kabi Canada announced the launch of IDACIO® in Canada.  IDACIO® received marketing authorization from Health Canada on October 30, 2020.   IDACIO® is approved for treating all indications of the reference drug Humira® in the areas of rheumatology, gastroenterology, and dermatology.  IDACIO® is the first biosimilar product introduced into North America by Fresenius Kabi.

On March, 23, 2021, LG Chem announced in a public filing that it obtained approval from Japan’s Health Ministry for its adalimumab biosimilar called Adalimumab BS MA.  LG Chem is partnering with Mochida, which obtained exclusive sales and marketing rights over the biosimilar in Japan.  Adalimumab BS MA is approved for nine indications, including rheumatoid arthritis, psoriasis vulgaris, psoriatic arthritis, pustular psoriasis, ankylosing spondylitis, polyarticular juvenile idiopathic arthritis, intestinal Behcet’s disease, Crohn’s Disease, and ulcerative colitis.

In addition, Samsung Bioepis recently launched its adalimumab biosimilar in multiple markets.  On February 18, 2021, it launched the adalimumab biosimilar HadlimaTM in Canada, in partnership with Merck Canada.  In Canada, HadlimaTM is approved for the treatment of rheumatoid arthritis, polyarticular juvenile idiopathic arthritis, psoriatic arthritis, ankylosing spondylitis, adult Crohn’s Disease, ulcerative colitis, hidradenitis suppurativa, plaque psoriasis, and adult and pediatric uveitis.  On March 29, 2021, the company launched HadlimaTM in Australia in partnership with MSD Australia (Merck).  In Australia, HadlimaTM is approved for treating rheumatoid arthritis, juvenile idiopathic arthritis, psoriatic arthritis, ankylosing spondylitis, adult and pediatric Crohn’s disease, ulcerative colitis, hidradenitis suppurativa, and plaque psoriasis.  On March, 15, 2021, Samsung Bioepis agreed with Yuhan Corp. to sell its adalimumab biosimilar under the name AdalloceTM in Korea.  Samsung Bioepis obtained the local license for AdalloceTM in 2017 and plans to launch the product in the first half of 2021.

AbbVie has been using various life cycle extension strategies to maintain as much market share as possible.   In addition to a “patent thicket,” which is the subject of a pending lawsuit, AbbVie has pushed for a shift to a new formulation that causes less pain, offered a wide range of doses for different types of patients, and obtained approval of new indications.  However, in October 2018, with the launch of adalimumab biosimilar products in Europe, the sales of Humira® dropped by 30 percent in the following year.  Thus, evidence from Europe suggests that biosimilar companies are likely to take a significant portion of Humira®’s market share with aggressive discounting.

Two bills were signed into law on April 23, 2021, with the aim of increasing access to and education regarding generic and biosimilar medicines.

The Ensuring Innovation Act was passed with the aim to “lower the price patients pay for their prescriptions,” according to Senator Bill Cassidy, one of the co-sponsors for the bill.  The bill also “ensures affordable life-saving medicine while preserving innovation for cutting-edge medicine,” per comments by Senator Roger Marshall, another of the bill’s co-sponsors. Representative Kurt Schrader, a co-sponsor of the House companion bill, stated that the bill would close “another loophole to prevent drug companies from gaming the system and holding back competition in the marketplace.”

For all these ambitious goals, the bill makes relatively narrow changes to the Federal Food, Drug and Cosmetic Act (the “FD&C Act”). Specifically, the bulk of the changes in the bill replace the term “active ingredient” with the term “active moiety” in certain portions of the FD&C Act, as well as inserting similar terms relating to biologics.  The majority of these changes deal with New Chemical Entity exclusivity and Orphan Drug exclusivity. These exclusivities allow for a period where the first company to meet the requirements for exclusivity may market the medicine without generic competition, regardless of any related patent coverage.

This change to “active moiety” is intended to restrict these exclusivity periods to the FDA’s narrower definition of “the molecule or ion… responsible for the physiological or pharmacological action of the drug substance,” which explicitly excludes changes such as salts, complexes or chelates. This addresses a perceived issue where a company currently selling a drug protected by some form of exclusivity could attempt to receive a new exclusivity period by introducing a product with a new active ingredient but the same active moiety.

Whether these changes will achieve the goals described by the bill’s sponsors remains to be seen. The FDA has, for well over 20 years, interpreted the statute with the “active ingredient” language to require a new “active moiety” to receive exclusivity. 21 C.F.R. § 314.108 (1994).  That said, drug companies have found at least some success in convincing courts that this interpretation was impermissible, see Amarin Pharms. Ireland Ltd. v. Food & Drug Admin., 106 F. Supp. 3d 196, 208–09 (D.D.C. 2015), so the Act cannot be said to have no effect.

The Advancing Education on Biosimilars Act of 2021 was similarly intended to “help lower the cost of health care” by providing education to health care providers and patients about biosimilars, according to Senator Maggie Hassan, one of the bill’s co-sponsors. This effort to educate the public about biologics and biosimilars traces back to at least 2019, when similar bills were introduced by Sen. Hassan and others. Now-retired Senator Mike Enzi, a co-sponsor of the 2019 version of the bill, stated the intention was to “drive down drug costs by increasing confidence in cheaper prescription drug alternatives like biosimilars.”

The Act authorizes the Secretary of Health and Human Services to operate a website providing educational materials regarding biologics and biosimilars, including definitions and the review and approval processes for those products. Should this and other efforts increase the adoption of biosimilars, reports have indicated reductions in health care costs of up to $7 billion annually could be achieved by an increased share of the market going to biosimilars.

On February 25, 2021, the U.S. Court of Appeals for the Seventh Circuit heard oral arguments in UFCW Local 1500 Welfare Fund v. AbbVie Inc. (Case No. 20-2402), a case appealed from the U.S. District Court for the Northern District of Illinois by a group of Humira buyers (including consumer groups, drug wholesalers, and unions) accusing AbbVie of using “patent thicket” around Humira® to block biosimilars from entering the market, in violation of antitrust laws.

The alleged Humira “patent thicket” includes over 130 patents (resulting from about 250 patent applications) covering the adalimumab molecule and other aspects of the technology such as formulations and manufacturing methods. According to the suit, AbbVie also entered into agreements with several biosimilar makers (including Amgen, Samsung Boepsis, and Sandoz) under which the biosimilar makers received access to the European market in October 2018 but will stay out of the U.S. market until 2023. In this case, the Humira buyers are attempting to get a judgement that would allow biosimilars to enter the U.S. market earlier than the date set forth in the agreement.

Humira (adalimumab) is one of world’s most valuable biologic drugs and was approved for treatment of a variety of autoimmune disorders including rheumatoid arthritis, Crohn’s disease, and plaque psoriasis. In 2019, Humira’s sales were $14.9 billion (increased from $13.7 billion in 2018) in the U.S. where no biosimilar was on the market, while sales were $4.3 billion (decreased from $6.3 billion in 2018) in Europe where biosimilars had launched.

In 2019, the group of Humira buyers filed a complaint in the district court alleging, inter alia, that AbbVie “applied for, obtained, and asserted patents to gain the power it needed to elbow its competitors” out of the U.S. market, and “created a thicket of intellectual property protection so dense that it prevented would-be challengers from entering the market with cheaper biosimilar alternatives” in violation of the Sherman Act.

In June 2020, the district court dismissed the complaint without prejudice.  The court evaluated whether AbbVie’s alleged conduct is protected by the Noerr–Pennington doctrine, under which a party’s application for patents before the USPTO is protected against antitrust liability unless the application is “objectively baseless,” i.e., there is no reasonable expectation of success on the merits. The court found that “AbbVie’s rate of success with its patent applications—more than half (53.4%)” supported that AbbVie’s patent applications were not objectively baseless, and thus there was no violation of antitrust law under the Noerr–Pennington doctrine. The court also found that the Humira buyers did not “plausibly allege the existence of an agreement that restrained competition.”

In July 2020, the Humira buyers appealed the decision to the 7th Circuit.  During the oral argument in February 2021 before a panel consisting of Circuit Judges Frank H. Easterbrook, Diane P. Wood, and Thomas L. Kirsch II, the Appellants argued that there was “widespread, objective baselessness in the patent minefield erected by AbbVie.”

Judge Easterbrook asked the Appellants whether they were prepared to prove that each of the patents in the alleged thicket is invalid. The Appellants contended that, instead of showing that all the patents are invalid, they only needed to show that at least one biosimilar maker would have prevailed in a challenge to Humira’s exclusivity if not for the patent thicket. The Appellants further stated that AbbVie only asserted about 60 to 80 patents against would-be biosimilar makers and thus, they only needed to focus on those asserted patents. Judge Easterbrook also questioned the Appellants’ assertions that there was no presumption of the patents’ validity, and noted that the likelihood of proving that all the patents in the entire thicket are invalid is “astoundingly small.”

Judge Wood appeared to agree with the Appellants that it would not matter whether the patents not asserted by AbbVie are invalid. She asked AbbVie why they would agree to the biosimilars’ entry in 2023, years before their patents’ expiration in the 2030s, and whether this agreement is “a signal of tremendous weakness” of the patents.  AbbVie responded that the later-expiring patents in the alleged thicket are generally narrower than earlier-expiring ones, and thus the date set forth in the agreement is a “perfectly appropriate compromise” between AbbVie and the biosimilar makers.

Concerning the consequences of the case’s outcome, Judge Kirsch asked the Appellants how a brand company could enter a global agreement with biosimilar makers without subjecting itself to antitrust lawsuits in the U.S. The Appellants responded that if a company decides to combine settlements in different markets, they need to make sure that they are settling, not trading off one market against another. The Appellants contended that AbbVie’s agreement with the biosimilar makers is a “sweetheart deal in Europe” but “terrible deal” in the U.S.

Overall, the oral arguments provide insights into the court’s views on the antitrust implications of creating a “patent thicket” around a drug, and on global settlement agreements involving entry into different markets.  We will provide additional updates as the case proceeds.

The Federal Circuit has affirmed Bayer’s patent infringement victory related to Baxalta’s biologic product, Adynovate.  Bayer Healthcare LLC v. Baxalta Inc., No. 2019-2418, 2021 WL 771700 (Fed. Cir. Mar. 1, 2021).  At the district court, the jury found the claims of Bayer’s U.S. Patent No. 9,364,520 (“the ’520 patent”) enabled and infringed, and awarded a reasonable royalty of 17.78%.  The appeal raised a variety of issues, including infringement, enablement, damages, and willfulness.  The Federal Circuit affirmed the results of the lower court on all issues.

The ’520 patent is directed to recombinant forms of human factor VIII, a protein useful in the treatment of hemophilia A.  The recombinant forms at issue involve a more specific PEGylation of the protein’s B-domain as compared to the random modifications in the prior art.  The accused product, Adynovate, is a human factor VIII protein with PEGylated amine sites, such as lysine.

Enablement

The question of enablement of the ’520 patent raised an interesting factual scenario.  Baxalta challenged the ’520 patent’s enablement of amine or lysine PEGylation because the specification only provided detailed instructions for practicing the claimed invention using cysteine PEGylation.  In response, Bayer relied on expert testimony to demonstrate that other modifications, such as lysine PEGylation, would have been known at the time of the invention, and the accumulated knowledge of 150 years of protein chemistry would allow one in the field to understand how some amino acids would be more or less amenable to modification.  Despite contrary testimony from Baxalta’s expert, the Federal Circuit held that substantial evidence supported the jury’s verdict.  Baxalta had also challenged the district court’s reliance on the knowledge of a person of ordinary skill as a substitute for the lack of disclosure in the specification.  Both the district court and Federal Circuit rejected this challenge, noting that a specification does not need to disclose each embodiment to enable the full scope of the claims.

Damages

On the issues of damages and the reasonable royalty rate evidence presented at trial, the Federal Circuit found no abuse of discretion in allowing Bayer’s expert testimony on the reasonable royalty rate.  Prior to trial, the district court excluded part of Bayer’s expert testimony on the hypothetical negotiation to determine a reasonable royalty rate.  The district court found that using the midpoint of the bargaining range as a reasonable royalty rate was not tied to the facts of the case, but allowed the expert to testify on his proposed bargaining range of 5.1% to 42.4%.  Ultimately, the jury determined a reasonable royalty rate of 17.78%.  The Federal Circuit found support in the expert report to allow the expert’s discussion of the proposed bargaining range, and noted that Baxalta had the opportunity to fully cross-examine the expert on his theories.  Furthermore, the expert provided ample guidance for the jury to determine the royalty rate, including discussion of the hypothetical negotiation and the Georgia-Pacific factors.  Therefore, the jury could evaluate his opinions and adopt a rate within the proposed range, as it did.

Claim Construction

Baxalta challenged several of the district court’s claim constructions, but the Federal Circuit found adequate support for them.  The court recognized that several of the arguments presented close questions, but the statements in the prosecution history and specification did not rise to the levels of disclaiming certain types of PEGylation as Baxalta had sought.

Infringement

Similarly, the Federal Circuit found substantial evidence to support the jury’s finding that Adynovate met the claim limitations in its infringement analysis.  In particular, the court noted Baxalta’s letter representing to the U.S. Food and Drug Administration that Adynovate includes a controlled and targeted chemical addition of PEG conjugates to the human factor VIII B-Domain.  Combined with supporting expert testimony from Bayer’s expert, there was adequate support for the jury’s determination of infringement.

Additional Issues Raised

The Federal Circuit affirmed the district court’s judgment as to issues raised by the parties regarding supplemental damages and willful infringement.  The district court’s award of supplemental damages was within the court’s discretion and did not constitute an impermissible additur.  Because the jury had determined the royalty rate, applying that rate to the undisputed actual infringing sales base was an appropriate method for the court to award supplemental damages.  Finally, the Federal Circuit agreed that awareness of the ’520 patent was insufficient for a finding of willful infringement, and Bayer failed to present sufficient evidence of the necessary state of mind.  The evidence only showed knowledge of the patents and Baxalta’s direct infringement, but it did not rise to the level of deliberate or intentional infringement required.

The Standing Committee of the 13th National People’s Congress, China’s top legislature, adopted the Fourth Amendment to the 1984 Chinese Patent Law on October 17, 2020. The Fourth Amendment follows a series of amendments that were last adopted in 2008 and will become effective on June 1, 2021. Among the provisions is Article 76, establishing a new pharmaceutical patent linkage system modeled after the U.S. Hatch-Waxman Act. Article 76 of the Fourth Amendment was implemented in accordance with Article 1.11 of the Economic and Trade Agreement Between the Government of the United States of America and the Government of the People’s Republic of China.[1]

Key provisions of Article 76 of the Fourth Amendment include:

  • Establishment of a platform for registering patent information for marketed drugs (similar to the U.S. FDA’s Orange Book), where a holder of a drug marketing approval or patentee of a chemical drug, biological preparation, or traditional Chinese medicine can register information such as relevant patent number, status, and assignee.
  • A requirement for an applicant seeking market approval for a generic drug to submit a non-infringement statement (Type I-IV), similar to Paragraph I-IV certifications made by ANDA applicants in the United States.
  • A resolution mechanism in which a patentee objecting to the non-infringement statement can file an opposition at the People’s Court or the China National Intellectual Property Administration (CNIPA) within 45 days from when the National Medical Product Administration (NMPA) publishes the drug marketing authorization application, initiating an automatic 9-month stay of the generic drug regulatory approval.
    • For non-infringement statements under Type I-III, the NMPA will make an administrative ruling based on a technical examination of a drug. For non-infringement statements under Type IV, the NMPA will make an administrative ruling based on a technical examination of a drug further in consideration of the decision made by the CNIPA or the People’s Court.
    • The automatic stay period does not stop the NMPA’s technical examination of the drug. The NMPA will issue an administrative ruling when the People’s Court or the CNIPA: 1) determines the drug does not fall within the scope of the patent, 2) declares the patent invalid, 3) finds the parties to have settled and reached an agreement, or 4) fails to reach a verdict within the 9 months.
  • 12-month market exclusivity from the date of marketing authorization for the first generic applicant entrant filing a Type IV non-infringement statement and receiving the marketing authorization.

There are several key differences between the U.S. Hatch-Waxman system and the new Chinese law.  China’s patent linkage system is not limited to small molecules and also includes biologics and traditional Chinese medicine. Further, China provides a much shorter stay period of only 9 months.  This 9-month stay period only applies to small molecules and excludes biologics or traditional Chinese medicine.  The market exclusivity period for first generic entrants (12 months), however, is far longer than that of the United States (180 days).

The patent linkage system for pharmaceutical patents in China is just developing, and the resolution mechanism for patent disputes under Article 76 of the Fourth Amendment currently lacks detail for both generic market entrants and patentees.  One notable piece of information missing in the current legislation is whether there is an obligation for the generic market entrants to notify the patentee of the non-infringement statement.  In this regard, stay tuned for updates on finalized draft rules, which are expected to provide further guidance on China’s new patent linkage system.

[1]The text of the Phase One Trade Agreement with China (2020) is available at: https://ustr.gov/sites/default/files/files/agreements/phase%20one%20agreement/Economic_And_Trade_Agreement_Between_The_United_States_And_China_Text.pdf. Article 1.11 begins on page 1-6 on Chapter 1 (page 7 of the PDF).

Updated March 8, 2021

  • FDA has not approved any biosimilars in 2021 after only approving three in 2020.
  • EMA approves second Novolog® (insulin aspartate), fifth Avastin® (bevacizumab), eighth Neulasta® (pegfilgrastim), and twelfth Humira® (adalimumab) biosimilars, and withdraws approval of an adalimumab biosimilar and a pegfilgrastim biosimilar.
  • 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 $81 billion in 2019[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 ten biosimilar approvals in 2019 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 76 applications have been approved in Europe.  Ten of the authorizations have been withdrawn post-approval (Table 1).  Most recently, market authorization holders for Halimatoz® (adalimumab) and Udenyca® (pegfilgrastim) requested that their marketing authorizations be withdrawn due to commercial reasons.  There are eleven other approved adalimumab biosimilars and seven other approved pegfilgrastim 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, 28 other biosimilar drugs have gained U.S. approval to date (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 2020 and the first two months of 2021, however, the FDA has only approved three biosimilar products, whereas the EMA has approved fourteen biosimilar products.  The COVID-19 pandemic has likely shifted regulatory and industry focus to vaccines and therapeutics, thereby causing delays in biosimilar approvals.  Moreover, given the difficult patent litigation and competitive landscapes, there appear to be fewer biosimilar BLAs than in 2017-2019.

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.  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, twelve 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 February 20, 2020, the FDA redefined the term “biological product” to include all “proteins,” which the rule defines as “any alpha amino acid polymer with a specific, defined sequence that is greater than 40 amino acids in size.” Accordingly, the biosimilar and interchangeable pathways are now open to insulin products in the United States.  The EMA already considered insulin a biologic product.  This change by the FDA is expected to lead to additional biosimilar approvals because there are already many biosimilar insulin products approved in Europe, and those biosimilar insulin manufacturers will likely seek to expand into the U.S. market.  In its press release, the FDA explained that it intends “to balance innovation and competition and facilitate the development and approval of biosimilar and interchangeable products. Getting safe and effective biosimilar and interchangeable products approved will help ensure that the market is competitive, and patients may have more affordable access to the treatments they need.”  The FDA approved Mylan’s insulin glargine product SemgleeTM on June 11, 2020 as an equivalent to Sanofi’s Lantus® although it is not considered a biosimilar because approval was under 351(a) of the Public Health Service (PHS) Act (42 U.S.C.. 55. 262(k)).  “We are proud to be the first company, following the reference product, to receive FDA approval on and launch both the vial and pen presentations of an insulin glargine treatment with an identical amino acid sequence to Sanofi’s Lantus,” said Mylan CEO Heather Bresch. She estimated the potential market to be more than 30 million Americans.  In its press release, Mylan stated that it has submitted all necessary documentation to request FDA approval as a biosimilar to Lantus under the 351(k) pathway and “remains confident in seeking an interchangeability designation.”

Table 1. European Medicines Agency List of Approved Biosimilar Drugs (updated March 8, 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 January 6, 2021 and published on January 7, 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 ($19.17B), 2. Keytruda—Merck ($11.08B), 3. Eylea—Aflibercept ($7.54B), 4. Opdivo—Bristol-Myers-Squibb ($7.20B), 5.  Avastin—Roche ($7.12B), 6. Rituxan—Roche ($6.52B), 7. Stelara—Johnson & Johnson ($6.36B), 8. Herceptin—Roche ($6.08B), 9. Enbrel—Pfizer/Amgen ($5.23B), 10. Remicade—Johnson & Johnson/Merck ($4.38B).

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

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

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

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

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

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

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

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

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

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

Impact

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

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

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

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

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

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

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

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

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