On April 25, 2019, the U.S. Food and Drug Administration (“FDA”) approved new biosimilar product EticovoTM (etanercept-ykro) by Samsung Bioepis.  Eticovo is a biosimilar to Enbrel® (etanercept), which is marketed by Amgen, Inc. (“Amgen”).  Like Enbrel, Eticovo was approved across five eligible indications for the treatment of rheumatoid arthritis, ankylosing spondylitis, plaque psoriasis, psoriatic arthritis, and polyarticular juvenile idiopathic arthritis.[1]  Eticovo is the 19th FDA-approved biosimilar and the 2nd FDA-approved biosimilar to Enbrel.  Sandoz’s ErelziTM (etanercept-szzs) was approved by the FDA as a biosimilar to Enbrel on August 30, 2016,[2] but Erelzi has yet to launch in the United States due to pending patent litigation.[3]  Sales of Enbrel in the United States last year amounted to $4.807 billion for Amgen.[4]

Samsung Bioepis describes itself as a “biopharmaceutical company dedicated to unlocking the potential of biosimilar medicines.”[5]  According to Samsung Bioepis, its etanercept biosimilar has been approved outside the United States for marketing in 38 countries, including EU member states (January 2016), Canada (August 2016), Brazil (December 2017), Australia (July 2016), and Korea (September 2015),[6] under names such as Benepali and Brenzys.  In the United States, Eticovo is Samsung Bioepis’ second FDA-approved anti-TNF biosimilar, along with Renflexis (infliximab-abda).[7]

On April 30, 2019, directly after the FDA approved Eticovo, a lawsuit was filed in the District of New Jersey against Samsung Bioepis by Immunex Corp. (“Immunex”), Amgen Manufacturing, Ltd. (“AML”), and Hoffmann-La Roche Inc. (“Roche”) (collectively, “the Plaintiffs”).[8]  Immunex and AML are wholly-owned subsidiaries of Amgen.  The case involves five asserted patents that the Plaintiffs allege cover etanercept, methods and materials for manufacture of etanercept, and therapeutic uses of etanercept.  The asserted patents are (i) U.S. Patent Nos. 8,063,182 and 8,163,522, owned by Roche and exclusively licensed to Immunex; and (ii) U.S. Patent Nos. 7,915,225, 8,119,605, and 8,722,631, owned by Immunex.  For each of the asserted patents, Immunex has granted AML an exclusive license or exclusive sublicense.  To note, these are the same plaintiffs and same five patents at issue in the litigation referenced above involving Sandoz and its etanercept biosimilar, Erelzi.

The Biologics Price Competition and Innovation Act (“BPCIA”) provides a framework for patent disputes between biosimilar applicants and reference product sponsors, commonly referred to as the “patent dance.”  According to the Plaintiffs’ complaint, Samsung Bioepis failed to participate in the patent dance because it did not tender the information specified in 42 U.S.C. § 262(l)(2), including a copy of its abbreviated biologics license application (“aBLA”) for Eticovo.  Under the Supreme Court’s decision in Sandoz Inc. v. Amgen, Inc., 137 S. Ct. 1664 (2017), Samsung Bioepis is entitled to decline participation in the patent dance.  However, upon such a failure by the biosimilar applicant to provide the aBLA and information under 42 U.S.C. § 262(l)(2) to the reference product sponsor, the filing of the aBLA can constitute an artificial act of infringement under 35 U.S.C. § 271(e)(2)(C)(ii) and the reference product sponsor is entitled under 42 U.S.C. § 262(l)(9)(C) to bring an action “for a declaration of infringement, validity, or enforceability of any patent that claims the biological product or a use of the biological product.”  Accordingly, the Plaintiffs seek a declaratory judgment that Samsung Bioepis infringed the asserted patents under 35 U.S.C. § 271(e)(2)(C)(ii) by submitting its aBLA for the alleged purpose of obtaining FDA approval to engage in the commercial manufacture, use, or sale of Eticovo prior to the expiration of the patents.  The Plaintiffs also seek a declaratory judgment that Samsung Bioepis has infringed or will fringe the asserted patents under 35 U.S.C. § 271(a), (b), and/or (g).

The complaint also alleges that Samsung Bioepis has not yet provided a notice of commercial marketing pursuant to 42 U.S.C. § 262(l)(8)(A).  That section of the BPCIA states that a biosimilar applicant “shall provide notice to the reference product sponsor not later than 180 days before the date of the first commercial marketing of the biological product.”  Unlike the voluntariness of participation in the patent dance of the BPCIA, the Plaintiffs assert that this notice of commercial marketing is a mandatory requirement that “operates to bar [Samsung] Bioepis from commercial marketing pending, at a minimum, such notice, followed by 180 days.”  The complaint thus seeks a preliminary injunction prohibiting Samsung Bioepis from commercial marketing consistent with the notice period provided by the statute.  The complaint also seeks a preliminary injunction to enjoin Samsung Bioepis from commercial marketing of Eticovo pending a final determination as to infringement, validity, and enforceability of the patents and further seeks a temporary restraining order pending the court’s decision on a preliminary injunction.

We will continue to keep you updated on further developments.

[1] https://www.accessdata.fda.gov/drugsatfda_docs/appletter/2019/761066Orig1s000ltr.pdf; https://www.accessdata.fda.gov/drugsatfda_docs/label/2019/761066s000lbl.pdf

[2] https://www.accessdata.fda.gov/drugsatfda_docs/appletter/2016/761042Orig1s000ltr.pdf

[3] See Immunex Corp. v. Sandoz Inc., 2:16-cv-01118 (D.N.J.)

[4] https://www.amgen.com/media/news-releases/2019/01/amgen-reports-fourth-quarter-and-full-year-2018-financial-results/

[5] https://www.samsungbioepis.com/en/about/about01.do

[6] https://www.samsungbioepis.com/en/newsroom/newsroomView.do?idx=49&currentPage=1; https://www.samsungbioepis.com/en/product/product01.do

[7] https://www.accessdata.fda.gov/drugsatfda_docs/label/2017/761054Orig1s000lbledt.pdf

[8] Immunex Corp. v. Samsung Bioepis Co., Ltd., 2:19-cv-11755 (D.N.J.)

Recently, in Adello Biologics LLC v. Amgen Inc., Case PGR2019-00001 (Paper No. 13) (PTAB Apr. 19, 2019), the PTAB instituted post-grant review of claims 1-30 of U.S. Patent No. 9,856,287 (“the ’287 patent”).  The ’287 patent is the patent at issue in a pending litigation between Amgen and Apotex under the Biologics Price Competition and Innovation Act (BPCIA) in the District Court for the Southern District of Florida.  The ’287 patent, entitled “Refolding Proteins Using a Chemically Controlled Redox State,” contains claims drawn towards methods of refolding proteins expressed in non-mammalian expression systems.  Independent claims 1 and 16 require that the method include “incubating the solution so that at least about 25% of the proteins are properly refolded.”  Independent claims 10 and 26 require that “about 30-80% of the proteins are properly folded.”  Adello Biologics LLC, Apotex Inc., and Apotex Corp. (“Petitioners”) asserted eight grounds of unpatentability for lack of written description support, lack of enablement, anticipation, obviousness and indefiniteness.

In its analysis, the PTAB first determined that the ’287 patent is eligible for post-grant review. Pursuant to the AIA, post-grant review provisions only apply to patents that contain a claim with an effective filing date on or after March 16, 2013. The ’287 patent was filed on Feb. 1, 2017 but claims priority to two applications, one filed in 2009 and another filed in 2010.  Petitioners argued that claims 1-9 and 16-25 were not fully disclosed until they were added by amendment to the claims of the ’287 patent after filing and argued that claims 1-30 are not enabled.  Petitioners argued that the language “at least about 25% of the proteins are properly refolded” does not appear anywhere in the specifications or in the priority applications.  Petitioners equated “at least about 25%” with “25%-100%” and argued that the priority applications fail to provide any disclosure for any percentages of properly refolded proteins over 80%.  Amgen Inc. (“Patent Owner”) argued that the law for written description does not require explicit examples in the specification that cover the entire range of the results disclosed in the claim. The PTAB agreed but noted that “when there is substantial variation with the genus, however, a sufficient variety of species must be described to reflect the variation within the genus.” See Paper 13 at 17. The PTAB then held that the percentages of properly refolded proteins disclosed in the examples of the priority application did not constitute a representative number of species within the genus of “at least about 25%.” The PTAB held that the ’287 patent was eligible for post-grant review and that it is more likely than not that there is inadequate written description support for “at least about 25%” as recited in the claims.

Petitioners further argued that the claims fail to comply with the enablement requirement of 35 U.S.C. § 112(a). For example, Petitioners argued that the claims “recite that the thiol-pair ratio is in the range of 0.0001-100 and do not place a numerical limit on the thiol-pair buffer strength, resulting in a vast number of possible redox conditions” and that the claims do not place a limit on the proteins to be refolded. See Paper 13 at 19. Petitioner argued that due to large number of proteins covered by the claims, the specification fails to provide sufficient guidance to allow a person of ordinary skill in the art to arrive at the claimed ranges of “at least about 25%” or “about 30-80%” of the proteins being properly refolded with undue experimentation.  Patent Owner argued that the Petitioners failed to demonstrate why the experimentation needed would be undue, pointing out that the ’287 patent discloses that optimization of the redox component thiol-pair ratios and thiol-pair buffer strength can be done for each protein. The PTAB rejected these arguments. Instead, the PTAB relied on the unrebutted testimony of Petitioners’ expert who concluded that from the specification, a person of ordinary skill in the art would understand that there is no direct correlation between the thiol-pair ratio and the thiol-pair buffer strength that can be used for all proteins and as a result there is a large number of redox conditions that can tested. The PTAB agreed with the expert that the specification fails to narrow the range of these possible conditions. Thus, the PTAB concluded that it is more likely than not that claims 1-30 are unpatentable for lack of enablement.  Furthermore, in view of the Supreme Court’s recent decision in SAS Inst., Inc. v. Iancu, 138 S. Ct. 1348 (2018), because the PTAB concluded that Petitioners demonstrated more likely than not that claims 1-30 lack enablement and that claims 1-9 and 16-25 failed to provide sufficient written description support, it instituted a post-grant review of all grounds asserted in the Petition.[1]

According to the scheduling order entered with the institution decision, the Patent Owner will have until July 11, 2019 to file a response to the Petition. Subsequently, the Petitioners will have until Oct. 3, 2019 to file a reply to Patent Owner’s response.

[1] The PTAB instituted a post-grant review after its analysis of the written description and enablement grounds. However, the PTAB also made observations in its decision relating to the other asserted grounds as well.

  • FDA approves the second Enbrel® (etanercept) biosimilar—no etanercept biosimilar has launched in the United States to date.
  • FDA approves the fourth Herceptin® (trastuzumab) biosimilar—no trastuzumab biosimilar has launched in the United States to date.
  • European Medicines Agency approves ninth and tenth adalimumab biosimilars and second bevacizumab biosimilar.

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 $71 billion in 2017[1].  In July 2018, Health and Human Services Secretary Alex Azar announced a Biosimilars Action Plan 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.  The RAND Corporation estimates that biosimilar products can save the U.S. health system approximately $54 billion over the next decade, as discussed here.

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 59 applications have been approved in Europe.  Six of the authorizations have been withdrawn post-approval (Table 1).

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, 18 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.

Currently, six 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 at least 23 different original biologics are currently navigating biosimilar pathways or are in late stage development in the U.S. (Table 4).

On April 29, 2019, Samsung Bioepis announced the approval of its etanercept biosimilar EticovoTM.  “The approval of ETICOVO adds to our growing portfolio of anti-TNF medicines in the US, where we believe biosimilars can bring meaningful value to the country’s healthcare system,” said Christopher Hansung Ko, President & CEO of Samsung Bioepis. “Through relentless process innovation and an uncompromising commitment to quality, we remain dedicated to advancing one of the industry’s strongest biosimilar pipelines.”  In addition to the United States, Samsung Bioepis’ etanercept biosimilar has been approved for marketing in 38 countries, namely 28 European Union (EU) member states, the European Economic Area (EEA) member states of Norway, Iceland and Liechtenstein, as well as Switzerland, Canada, Brazil, Australia, New Zealand, Israel, and Korea.

In April 2019, the EMA approved two more adalimumab biosimilars to Abbvie’s Humira® in Europe, bringing the total number of approved adalimumab biosimilars to ten.  In February 2019, the EMA approved Pfizer’s Zirabev, which is the second bevacizumab biosimilar to Genentech and Roche’s Avastin® approved in Europe.

The FDA has recently provided useful guidance as reported here.  Under the leadership of Dr. Scott Gottlieb, the FDA advanced new policies aimed at promoting more competition when it comes to biosimilar products as outlined in Dr. Gottlieb’s December 11, 2018 statement on new actions advancing the agency’s biosimilars policy framework.  However, with Dr. Gottlieb’s unexpected resignation on March 5, 2019, it will be up to the next permanent successor to guide stakeholders in navigating the FDA approval process.

Table 1. European Medicines Agency List of Approved Biosimilar Drugs (updated May 6, 2019).


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 April 8, 2019 and published on April 15, 2019).

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, 2. Rituxan—Roche, 3. Enbrel—Pfizer/Amgen, 4. Herceptin—Roche, 5. Avastin—Roche, 6. Remicade—Johnson & Johnson/Merck, 7. Lantus—Sanofi, 8. Neulasta—Amgen, 9. Avonex—Biogen, 10. Lucentis—Roche/Novartis).

Many factors contribute to the price that consumers pay for prescription drugs and biologics.  These factors include research and development costs, manufacturing costs, terms negotiated by insurance plans, supply and demand, and intellectual property rights.  Intellectual property rights are often viewed as one of the most significant factors driving high drug and biologic prices. In March, a bipartisan group of six senators sponsored the Biologic Patent Transparency Act (BPTA). The BPTA is intended to “help increase patent transparency, promote biosimilar competition, bring needed biosimilar treatments to patients faster, and ultimately, lower drug prices for consumers.” The bill is intended to impose “transparency requirements that are similar to what are required for small molecule drugs under the Hatch-Waxman framework, which has proven successful in promoting the development and use of generic drugs.”

One target of the bill is “patent thickets.”  Patent thickets are described as ranging from dozens to hundreds of patents intended to block competition, and may include invalid or unenforceable patents.  AbbVie’s Humira has been criticized as a patent thicket with about 136 patents. Though the patent on Humira’s main ingredient expired in 2016, some patents directed to processes and techniques required to replicate Humira remain in force until 2034. Biosimilar competition would be blocked until 2023 when settlements will enable several companies to market biosimilars while paying AbbVie a royalty.  Since biologics are typically produced in living cells, the process often requires complex steps with more possible variations which can be patented. Johnson & Johnson’s Remicade is another biologic with more than 100 patents. The BPTA would require companies to disclose all patents that protect their biologics, which could make it easier for competitors to evaluate and develop generic versions. If a patent is not included in the list in a timely manner, no action for infringement of that patent could be brought.

The bill would also make FDA’s Purple Book a publicly available, single, searchable list which would include information on:

  • Patents that claim and relate to FDA-approved biological products, for which a claim of patent infringement could reasonably be asserted by the holder, including manufacturing processes;
  • Official and proprietary name of each biological product;
  • The date of licensure and application number for each product;
  • Information related to determinations of biosimilarity and interchangeability;
  • Information related to marketing status, dosage form, route of administration, reference product, and any periods of exclusivity related to the product and the date that the exclusivity expires; and
  • Approved indications.

Another goal of the bill is to limit patent enforceability of later filed patents by the biologic manufacturer when a biosimilar application has already been filed with the FDA by barring some claims of infringement for patent owners that do not timely disclose their patents. In other words, the bill is intended to discourage patent owners from filing numerous patent applications covering minor variations of the product, processes for making the product, or methods of using the product, long after the patent on the original product has issued. However, the language of the bill does not specifically reference the date that a biosimilar application has been filed.  The language in the bill regarding the restriction on claims of patent infringement only states that patents which are not timely included on the list cannot be used to bring an action for infringement. There is no specific language in the bill which would limit the enforceability of later filed patents by the biologic manufacturer when a biosimilar application has already been filed with the FDA, as long as such patents are disclosed in a timely manner.   Since the language “timely included in such list” is not limited to inclusion on the list before a biosimilar application is filed, an argument could be made that a patent which issues after a biosimilar application has been filed can still be timely disclosed.

Recently, there have been a number of legislative proposals with a goal of reducing drug and biologic product prices. While patents are the focus of the BPTA, other proposals include closing a loophole in the Food and Drug Administration’s Risk Evaluation and Mitigation Strategies (REMS) program which denied generic drug and biosimilar manufacturers access to product samples; prohibiting anticompetitive agreements between drug/biologic and generic/biosimilar manufacturers; allowing Medicare to negotiate prices with pharmaceutical companies; limiting regulatory exclusivities based on price increases; and restricting the price of prescription drugs/biologics in the U.S. based on the median price in Canada, the United Kingdom, France, Germany and Japan.  It is clear that rising drug prices are a concern, however, any public policy on drug pricing must find a balance between providing incentives to manufacturers for developing new medicines and providing affordable drug/biologic prices to consumers.

On April 2, 2019, Eli Lilly and Company (“Lilly”) filed a Petition for Post-Grant Review (“PGR”) of Genentech’s U.S. Patent 10,011,654 (“the ’654 patent”). The ’654 patent, entitled “Antibodies Directed to IL-17A/IL-17F Heterodimers,” has just seven claims, with independent claim 1 drawn to “[a]n isolated humanized monoclonal antibody that binds to an IL-17A-17F heterodimer comprising the polypeptide of SEQ ID NO: 3 and the polypeptide of SEQ ID NO: 4 with or without  their associated signal peptides.” The ’654 patent was issued on July 3, 2018, and within minutes of the issuance, Genentech filed suit against Lilly in the Southern District of California alleging infringement of the ’654 patent by Lilly’s Taltz® (containing ixekizumab as its active ingredient).[1] The case, captioned Genentech, Inc. v. Eli Lilly and Company, Case No. 18-cv-1518, is currently in the discovery stage. The PGR petition is timely filed within one year of that complaint and within nine months of the grant date of the patent.

Lilly’s PGR petition alleges that it is more likely than not that all seven claims of the ’654 patent are unpatentable on the following grounds: (1) claims 1-7 lack written description support under 35 U.S.C. § 112(a); (2) claims 1-7 lack enablement under 35 U.S.C. § 112(a); (3) claims 1-7 are anticipated under 35 U.S.C. § 102(a) by U.S. Publication No. 2010/0266609A1 to Adams et al.; and (4) claims 1-7 are anticipated under 35 U.S.C. § 102(a) by U.S. Publication No. 2013/0315911A1 to Stevens et al. Specifically, Lilly alleges that Genentech’s ’654 patent claims a genus of antibodies defined solely by function- the ability to bind to a particular protein: IL-17A/F. Lilly asserts that this functional characterization, without more, is insufficient to establish written description support for a claimed functional genus. According to Lilly, the appropriate tests for written description support are those set forth by the Federal Circuit in Amgen Inc. v. Sanofi [2] and Ariad Pharm., Inc. v. Eli Lilly & Co.[3], which the USPTO has expressly endorsed in recent guidance to examiners, but which was not available during prosecution of the ’654 patent. Because the ’654 patent ­­– and its asserted priority applications – allegedly fail to disclose a representative number of antibodies falling within the scope of the claimed genus or any structural features common to the members of the genus such that one of skill in the art could visualize or recognize the members of that genus, Lilly asserts that the ’654 patent fails these tests and therefore does not meet the written description requirement. In a similar vein, the PGR petition further alleges that the specification of the ’654 patent (and its priority applications) does not enable those skilled in the art to make and use whole categories of antibodies falling within the claims, without undue experimentation.

Lilly also notes that European Patent No. 1641822B1 (“EP ‘822”), the European counterpart to the ’654 patent and claiming priority to the same U.S. provisional applications, was revoked in its entirety by the EPO on November 24, 2016, on added matter grounds after an opposition proceeding. The High Court of Justice in the U.K., according to Lilly, found the U.K. counterpart to be invalid as well, finding that the claims to the antibody and its uses in treating rheumatoid arthritis were obvious and that the claims directed to the use of the antibodies that bind to IL-17A/F to treat psoriasis were invalid on insufficiency grounds.

Interestingly, Lilly’s petition for PGR comes hot on the heels of another Petition for Post-Grant Review of the ’654 patent filed just a day before, on April 1, 2019, by UCB, Inc. (“UCB”). As in Lilly’s petition, UCB’s petition also alleges that claims 1-7 of the ’654 patent are unpatentable for a lack of written description, with UCB specifically asserting that the ’654 patent does not adequately describe a genus of anti-IL-17A/F humanized antibodies and does not disclose a representative number of species or common structural features, as required by the Federal Circuit case law.

Under 37 C.F.R. § 42.207, if patent owner Genentech wishes to file a preliminary response to the petitions, it must do so no later than three months after the date of the USPTO’s notice according a filing date to the petitions. The PTAB must then determine whether to institute a trial within three months of the earlier of (1) the patent owner’s preliminary response filing and (2) the preliminary response due date.[4]

 

[1] For more details, please see our previous post, “Genentech Files Suit Alleging Eli Lilly’s Taltz® Product Infringes a Newly Issued Genetech Patent, available at https://www.biosimilarsip.com/2018/07/16/genentech-files-suit-alleging-eli-lillys-taltz-product-infringes-a-newly-issued-genentech-patent/.

[2] 872 F.3d 1367, 1378 (Fed Cir. 2017), cert. denied, 139 S. Ct. 787 (2019).

[3] 598 F.3d 1336, 1349 (Fed. Cir. 2010) (en banc).

[4] See Trial Practice Guide, 77 Fed. Reg. at 48757.

Over four years ago, in October 2014, Amgen initiated a patent infringement suit against Sanofi and Regeneron regarding biologics for treatment of high cholesterol.[1]  The case reached an important milestone recently as a jury entered a verdict largely upholding the validity of Amgen’s asserted patents, to the disappointment of Sanofi and Regeneron.  A similar decision had previously been entered in March 2016, but the Federal Circuit then found error and remanded for a new trial.  Based on statements by Sanofi and Regeneron, the most recent decision may be appealed as well.

Amgen’s drug Repatha® (“Repatha”) uses the monoclonal antibody evolocumab to inhibit PCSK9 from destroying low-density lipoprotein (LDL) receptors, which are responsible for extracting LDL cholesterol, or “bad cholesterol,” from the bloodstream.  Repatha and other PCSK9 inhibitors thereby lower a patient’s LDL cholesterol levels and thus aid in the prevention of heart attacks, strokes, and cardiovascular disease.  Amgen began developing Repatha in early 2005 and received FDA approval in August 2015.  Starting in September 2007, Sanofi and Regeneron jointly developed their own drug, Praluent® (“Praluent”), which includes the PCSK9 inhibitor alirocumab as an active ingredient.  The FDA approved Praluent in July 2015.  Sales data demonstrates these companies’ motivation behind the protracted legal battle over Amgen’s patents.  For net sales in the United States in 2018, Amgen reported $358 million for Repatha (up from $225 million in 2017)[2], and Sanofi and Regeneron reported $181.3 million for Praluent (up from $131.4 million in 2017)[3].

The patents at issue are Amgen’s U.S. Pat. Nos. 8,829,165 (“the ’165 patent”) and 8,859,741 (“the ’741 patent”).  The relevant claims cover a genus of antibodies that bind to specific amino acid residues on PCSK9 and block PCSK9 from binding to LDL receptors.  The patents are not limited to claiming Amgen’s Repatha, or any other antibody, by amino acid sequence, and Amgen asserted that the patents are infringed by Sanofi and Regeneron’s Praluent.  Sanofi and Regeneron stipulated to infringement but challenged the validity of the patents.  The parties proceeded to a first trial in March 2016, and the jury returned a verdict finding the asserted claims valid.  Specifically, the jury found that Sanofi and Regeneron failed to prove by clear and convincing evidence that the claims of the ’165 and ’741 patents are invalid for lack of enablement or lack of written description.  In January 2017, following post-trial motion practice, the district court entered a final judgment in favor of Amgen and granted a permanent injunction enjoining sales of Praluent.

On appeal, the Federal Circuit determined that the district court had erred by excluding Sanofi and Regeneron’s post-priority-date evidence regarding written description and enablement and by improperly instructing the jury on written description.  Amgen Inc. v. Sanofi, 872 F.3d 1367, 1380-81 (Fed. Cir. 2017).  The Federal Circuit therefore vacated the judgment as to written description and enablement and remanded for a new trial on these two issues, further vacating the permanent injunction.  Id.  In January 2019, the Supreme Court denied Amgen’s petition for a writ of certiorari.

A second trial was held, and the jury entered a verdict at the conclusion of the trial on February 25, 2019.  This time, while the jury found that two asserted claims of the ’165 patent are invalid for lack of adequate written description, the jury again found that two other asserted claims of the ’165 patent and one asserted claim of the ’741 patent are not invalid for lack of enablement or written description.

Thereafter, Amgen was quick to claim victory, with its chairman and CEO stating that Amgen is “thankful that the jury weighed the evidence carefully and recognized the validity of Amgen’s patents.”[4]  Amgen’s press release also referenced decisions in foreign patent offices regarding the validity of its PCSK9 antibody patents and announced Amgen’s plan to enforce these patents against Sanofi and Regeneron in the national courts of Europe and Japan.  On the other hand, Sanofi and Regeneron issued a press release expressing disappointment and announcing that they “strongly disagree with certain aspects of [the] jury verdict” upholding three of the five asserted claims.[5]  In the press release, Sanofi and Regeneron stated their intent to utilize post-trial motion practice to seek to overturn the jury verdict and request a new trial, as well as their intent to appeal to the Federal Circuit again “if necessary.”  Although this litigation may be far from over, the recent verdict is a key development.

[1] Amgen Inc. v. Sanofi, No. 1:14-cv-01317 (D. Del.)

[2] https://www.amgen.com/media/news-releases/2019/01/amgen-reports-fourth-quarter-and-full-year-2018-financial-results/; see also Form 10-K filed with the S.E.C.

[3] https://newsroom.regeneron.com/news-releases/news-release-details/regeneron-reports-fourth-quarter-and-full-year-2018-financial; see also Form 10-K filed with the S.E.C.

[4] https://www.amgen.com/media/news-releases/2019/02/jury-upholds-amgens-patents-on-repatha-evolocumab/

[5] https://newsroom.regeneron.com/news-releases/news-release-details/regeneron-and-sanofi-strongly-disagree-verdict-upholding-three; http://www.news.sanofi.us/2019-02-25-Sanofi-and-Regeneron-strongly-disagree-with-verdict-upholding-three-of-five-Amgen-U-S-patent-claims-relating-to-PCSK9-antibodies

On March 7, 2019, the U.S. Food & Drug Administration (FDA) released updated draft guidance announcing that it will create special names for biosimilar products to distinguish them from previously approved biologic products.  Specifically, the guidance explains that:

  • The FDA no longer intends to modify the proper names of biological products that have already been licensed or approved under the Public Health Service Act without an FDA-designated suffix in their proper names.
  • The FDA does not intend to apply the naming convention to the proper names of transition biological products.
  • Going forward, for interchangeable biosimilars, the FDA intends to designate a proper name that is a combination of the core name and a distinguishing suffix that is devoid of meaning and composed of four lowercase letters.

According to the FDA’s press release, “[t]his framework will help secure pharmacovigilance so that the FDA can effectively monitor all biological products in the post market – originators and biosimilars – and promote patient safety. To aid in adverse event report tracking, originator, biosimilar and interchangeable products will have nonproprietary names that are distinct from each other.”

The FDA’s biosimilar naming guidance issued in 2017 has been criticized by brand name and biosimilars manufacturers, as well as pharmacy groups, for multiple reasons. Requiring a random four-letter suffix is argued to create financial burdens and wreak havoc on tracking and billing systems. Requiring a different non-proprietary name for a biosimilar having the same active ingredient as the reference biologic is argued to thwart competition by creating confusion and distrust among providers and patients, and potentially preventing substitution with biosimilars.  The Federal Trade Commission (FTC) issued a statement in 2015 explaining that “the FDA draft guidance on biosimilar naming may hinder competition, and [the FTC] recommends that the agency consider alternatives.”  The FTC commented that the FDA’s naming convention departed from the FDA tradition, and risked causing physicians to believe mistakenly that the suffix-labeled biosimilar have clinically meaningful differences from the branded biologic products, which would potentially result in reduced price competition in biologic drug markets.  Further, the FTC noted that the naming proposal risked creating unnecessary costs, and conflicted with efforts toward global naming harmonization.

Biosimilars manufacturers have criticized the 2017 guidance for allowing random suffixes that are not uniquely tied to biosimilar company names.  Industry also criticized the proposed retroactive application of the guidance, which has now been nixed by the March 2019 guidance.  By nixing the retroactive application of the guidance, the FDA has awarded a further win to brand biosimilar manufacturers given that all biosimilar versions of currently-approved biologic products will be designated using suffixes, while the names of all currently approved brand products will remain unchanged.  As such, critics will argue that the FDA has not ensured that there is a level playing field for biosimilars manufacturers of products that are intended to increase price competition in biologic drug markets, which account for 40 percent of U.S. pharmaceutical sales and generate annual sales of over $50 billion in the U.S.

The FDA’s stated position is that this new naming policy “will provide consistency among biologics and will help ensure health care providers and patients have confidence in the safety and effectiveness of any biological product on the market.”  To achieve these goals, the unique four-letter suffix that’s incorporated as part of a biological product’s nonproprietary name is being applied to originator products going forward, as well as to any biosimilar and interchangeable products, so they can be appropriately distinguished from one another at the pharmacy level. Because biologics are generally complex and typically impossible to replicate in the way small-compound drugs can be, and even though biosimilars have no clinically meaningful differences from the reference product, these unique suffixes are a critical component of the FDA’s ability to track adverse events to a specific biological product and manufacturer so that appropriate action can be taken when needed to protect patients.

To date, the FDA explains that proper names of all 17 approved biosimilars have been approved with the four-letter suffixes, as have the proper names of 27 originator biological products. FDA expects that a steadily increasing proportion of licensed biological products, including originator products, will have nonproprietary names that include four-letter suffixes.  Going forward, only those originator products licensed prior to the implementation of the policy will lack a suffix.  The FDA’s goal with this naming policy is primarily to ensure patient safety by helping providers and patients properly identify products where it’s important to be able to distinguish between different medicines and different versions of similar or interchangeable products.

In response to concerns from stakeholders that changing the names of older biologics to add suffixes would impose substantial costs on the health care system and has the potential to create confusion that could increase risks to patients as drug names do not often change after drugs go to market, the FDA states that it believes “that the crucial public health goals of the naming policy could still be accomplished by applying the naming convention to newly licensed biological products, while avoiding the negative consequences raised by extending the naming convention to previously licensed products.”  As such, the FDA agrees that going back to retroactively change the names of these approved products would be a costly enterprise to the health care system; if those costs were to be passed on to patients, that impact would run directly counter to the goals of access and affordability that underlie the biosimilars program. Moreover, the FDA agrees that requiring retrospective names changes would not help advance the interest of effective pharmacovigilance since these products are already generally distinguishable by their proper names. As such, the FDA has decided that it will not require the legacy names to be changed.

The FDA will receive comments on the draft guidance over the next 60 days with a view toward issuing a final version of the guidance in the future.

On February 14, 2019, the PTAB issued final written decisions in two separate IPRs filed by Sanofi-Aventis, Genzyme Corp., and Regeneron Pharmaceuticals (collectively “Sanofi”) against U.S. Patent No. 8,679,487 (“the ʼ487 patent”) assigned to Immunex Corporation (“Immunex”). Claim 1 of the ʼ487 patent is the only independent claim, and it is directed to “an isolated human antibody that competes with a reference antibody for binding to human IL-4 interleukin-4 (IL-4) receptor.” The claim also requires that the reference antibody heavy and light chains comprise particular amino acid sequences.

As we previously reported, Immunex filed suit in the Central District of California alleging that Sanofi’s Dupixent® dupilumab product infringed the ʼ487 patent. Dupilumab is a monoclonal antibody intended to inhibit signaling of interleukin-4 and interleukin-13 (IL-13) by binding to the IL-4 receptor (IL-4R). Dupilumab is indicated for the treatment of adult patients with moderate-to-severe atopic dermatitis and as an add-on maintenance treatment in patients aged 12 years old and older with moderate-to-severe asthma with an eosinophilic phenotype or oral corticosteroid dependent asthma.

In IPR2017-01884, the PTAB determined that Sanofi sustained its burden of showing claims 1-17 of the ʼ487 patent were unpatentable by a preponderance of the evidence. Central to the PTAB’s decision was its determination that the claim term “human antibody” encompassed both partially human and fully human antibodies. In reaching this conclusion, the PTAB principally relied on the disclosures of the specification, and in particular a paragraph stating that “[a] method for producing an antibody comprises immunizing…with an IL-4R polypeptide, whereby antibodies directed against the IL-4R polypeptide…Procedures have been developed for generating human antibodies in non-human antibodies. The antibodies may be partially human, or preferably completely human.” (emphasis added). According to the PTAB, this passage clearly teaches that the term “human antibody” as used in the ʼ487 patent includes both partially human and completely human antibodies.

Immunex argued that the (bolded) sentence the PTAB relied on actually modifies antibodies against IL-4R, which are referred to in the first quoted sentence, and not the human antibodies referred to in the second sentence, because the bolded sentence does not use the term “human antibodies.” However, the PTAB did not find this argument compelling in view of the specification as a whole. In particular, the PTAB pointed to instances where the specification clarified that some human antibodies are “fully human,” and explained that if a person of ordinary skill in the art (“POSA”) would have equated human with fully human, then there would have been no need for the specification to make that clarification. The PTAB also noted that the specification explained that the invention included partially human antibodies.

Immunex pointed to certain portions of the prosecution history in support for its argument that “human antibody” excludes partially human antibodies. Specifically, Immunex asserted that the term “human” was added to claim 1 to overcome an anticipation rejection, and a dependent claim reciting “human, partially human, humanized, or chimeric antibody” was canceled. According to Immunex, this combination of amendments demonstrated that “human antibodies” are distinct from “partially human, humanized, or chimeric antibodies.” However, the PTAB did not accept this reasoning because the specification does not identify partially human, humanized, or chimeric antibodies as distinct classes of antibodies, and in fact indicates that the terms overlap. Thus, the PTAB concluded that it is reasonable to interpret human and partially human as similarly overlapping terms. The PTAB also pointed out that anticipation rejection during prosecution was based on art that was directed to murine antibodies, and so it did not suggest the Applicant was limiting the claims to only fully human antibodies. According to the PTAB, the Examiner’s treatment of the claims during the remainder of prosecution is consistent with the PTAB’s understanding.

Interestingly, the district court reached a different conclusion in construing the same term. In the litigation, the district court found that human antibody was limited to fully human antibodies. The PTAB explained that it reached a different conclusion based on its use of the broadest reasonable interpretation standard, which was the claim construction standard in place when the IPR petition was filed. As a result, this IPR is a prime example illustrating the potential for inconsistency in parallel IPR and district court claim construction proceedings. The PTAB’s adoption of the Phillips standard for IPR petitions filed after November 13, 2018 (you can read more in a post on our PTAB blog here), should eliminate the potential for inconsistency based solely on the differing standards. However, it is not inconceivable that the PTAB and the district court could reach two different interpretations of a claim term even when using the same claim construction standard, and neither the PTAB nor a district court are bound by each other’s claim construction rulings.

Based on its interpretation of the term “human antibody,” the PTAB found all of the ʼ487 patent claims obvious in view of two references referred to as Hart and Schering-Plough. The Hart reference describes the use of a murine anti-hIL-4 antibody that acts as “a neutralizing antibody to IL-4Rα,” and inhibits IL-4 and IL-13 signaling. The antibody was commercially obtained. The Schereing-Plough reference explains that antibodies specific for the IL-4 receptor could be useful as therapeutic entities, and further recognizes that non-human monoclonal antibodies could be humanized and used as such therapeutic entities. Schering-Plough also describes techniques for making humanized versions of mouse anti-hIL-4R antibodies. Sanofi asserted that the Hart reference taught every limitation of claim 1 except that the antibody is murine instead of human; however, according to Sanofi, Schering-Plough supplies this limitation by teaching techniques for humanizing murine antibodies for use as human therapeutics.

Sanofi alleged that a POSA would have had reason to combine the references because it was well-known in the art that humanization of a non-human antibody would decrease its immunogenicity while maintaining its antigen binding specificity and affinity. Sanofi further alleged that a POSA would have had a reasonable expectation of success in combining the references because humanization techniques were well-developed as of the ʼ487 patent priority date.

The PTAB agreed with Sanofi’s reasoning, and found the claims unpatentable as obvious. In doing so, the PTAB addressed Immunex’s argument that Sanofi did not consider the full scope and content of the prior art by pointing out that the law requires only that the motivation to combine present a suitable option, and not necessarily the best option. Thus, the fact that other strategies for inhibiting IL-4R signaling may have existed did not alter the PTAB’s analysis. The PTAB also explained in response to Immunex’s contention that the prior art did not demonstrate a reasonable expectation of success in developing a therapeutic antibody from the Hart reference that the relevant question is whether a POSA could have arrived at the claimed invention, and not whether that antibody would be therapeutically effective. Of note, the claims here do not require therapeutic efficacy. Moreover, the PTAB explained that the law does not require absolute certainty of success, and here Sanofi’s expert testified without contradiction by Immunex that humanizing an antibody was well-within the ability of a POSA.

In contrast to its determination in IPR-01884, the PTAB found the claims not unpatentable in IPR2017-01879 in a decision that issued the same day. IPR2017-01879 was instituted on a single ground of anticipation under § 102(e) based on a reference referred to as the ʼ132 publication. The ʼ132 publication is in the priority chain of applications leading to the ʼ487 patent; however, Immunex disclaimed priority to the ʼ132 publication and earlier applications during prosecution. Immunex sought to remove the ʼ132 publication as a prior art reference to the ʼ487 patent by demonstrating that the portions of the ʼ132 publication that Sanofi relied on was the work of the ʼ487 patent inventors, and thus was not the work of another as required by the statute. The PTAB found Immunex’s evidence on this point sufficient to establish that the ʼ132 publication was not prior art. Consequently, the PTAB determined that the challenged claims were not unpatentable.

As suggested by the title of this post, the two IPRs described above are the second and third IPR challenges filed by Sanofi against the ʼ487 patent. The first challenge was in IPR2017-01129. However, the PTAB denied institution of that IPR by concluding that the cited prior art reference was not prior art.  As explained here, Immunex attempted to persuade the PTAB to exercise its discretion to deny the follow-on petitions described above, but the PTAB declined to do so.

We will continue to keep you updated on further developments.

On February 21, 2019, Sandoz Inc. (“Sandoz”) filed suit against Amgen Inc. and Amgen Manufacturing Limited (collectively “Amgen”) seeking declaratory judgment of non-infringement and invalidity of Amgen’s U.S. Patent No. 9,643,997 (“the ʼ997 patent”). The ʼ997 patent is directed to methods of purifying a protein expressed in a non-native limited solubility form in a non-mammalian expression system.

According to Sandoz, the ʼ997 patent is in the same patent family as U.S. Patent No. 8,940,878 (“the ʼ878 patent”), which Amgen asserted against Sandoz in a prior litigation. In the prior litigation, the Court found on summary judgment that Sandoz did not infringe the ʼ878 patent. In particular, the Court found that Sandoz’s accused method of protein purification did not satisfy three elements of independent claim 7 of the ʼ878 patent, which separately required three distinct steps of (i) applying a refold solution to a separation matrix, (ii) washing the separation matrix, and (iii) eluting the protein from the separation matrix. The Court also found that each of those steps required application of a distinct solution. In contrast to the claimed method, the Court found that Sandoz’s method required only a single step and a single solution.

In its Complaint, Sandoz included a comparison of independent claim 9 of the ʼ997 patent with independent claim 7 of the ʼ878 patent. Sandoz acknowledged that there are differences between the claims, but explained that the three elements central to the Court’s finding of non-infringement of the ʼ878 patent are also present in independent claim 9 of the ʼ997 patent. Consequently, Sandoz asserted that it does not infringe the ʼ997 patent for the same reasons that it was found to not infringe the ʼ878 patent.

Sandoz explained that the ʼ997 patent issued while the prior litigation was still pending, and shortly after issuance Amgen informed Sandoz of its belief that Sandoz’s method infringed the ʼ997 patent as well. Sandoz asserted that it invited Amgen to include the ʼ997 patent in the prior litigation, but Amgen did not do so. Accordingly, Sandoz filed the declaratory judgment action “to ensure any issues with respect to the ʼ997 patent….are resolved promptly, efficiently, and well in advance of the launch of Sandoz’s pegfilgrastim product.”

Sandoz’s pegfilgrastim biosimilar has not yet been approved by the FDA; however, Sandoz’s filgrastim product has been approved and marketed since September 2015. Those two Sandoz products were at issue in the prior litigation involving the ʼ878 patent. Both products address certain side effects of cancer treatment, with the primary difference being that pegfilgrastim remains in the circulatory system longer due to the inclusion of polyethylene glycol (“peg”).

We will continue to keep you updated on further developments.

  • Coherus launches UdenycaTM, a pegfilgrastim biosimilar, in the United States.
  • Pfizer launches Retacrit®, an epoetin alfa biosimilar, in the United States.
  • FDA approves the first rituximab biosimilar, although it has not yet launched in the United States.
  • European Medicines Agency approves third, fourth, and fifth pegfilgrastim biosimilars and a fifth trastuzumab biosimilar, while withdrawing approvals for an insulin glargine and an adalimumab biosimilar.

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 $71 billion in 2017[1].  In July 2018, Health and Human Services Secretary Alex Azar announced a Biosimilars Action Plan 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.  The RAND Corporation estimates that biosimilar products can save the U.S. health system approximately $54 billion over the next decade, as discussed here.

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 55 applications have been approved in Europe.  Five of the authorizations have been withdrawn post-approval (Table 1).

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, 16 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.

Currently, seven 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 at least 23 different original biologics are currently navigating biosimilar pathways or are in late stage development in the U.S. (Table 4).

In November 2018, the EMA approved three pegfilgrastim biosimilars to Amgen’s Neulasta® in Europe.  In December 2018, the EMA approved Mylan’s Ogivri, which is the fifth trastuzumab biosimilar to Roche and Genentech’s Herceptin® approved in Europe.

Two EMA biosimilar approvals were also withdrawn in late 2018 and 2019:  Merck’s insulin glargine biosimilar Lusduna was withdrawn in October 2018 and Boehringer Ingelheim’s adalimumab biosimilar Cyltezo was withdrawn in January 2019.

Biosimilar approvals by the FDA accelerated in late 2018, with approval of Sandoz’s adalimumab biosimilar Hyrimoz™, Coherus’ pegfilgrastim biosimilar Udenyca™, Celltrion’s rituximab and trastuzumab biosimilars Truxima™ and Herzuma™, and Samsung Bioepis’s trastuzumab biosimilar Ontruzant™.  Coherus launched Udenyca™ in January 2019, and the company reported that it is well-positioned in the $4 billion U.S. market for pegfilgrastim due to favorable reimbursement changes effective at launch and good adoption dynamics.

The FDA has recently provided useful guidance as reported here and available here.  Under the leadership of Dr. Scott Gottlieb, the FDA has advanced new policies aimed at promoting more competition when it comes to biosimilar products as outlined in Dr. Gottlieb’s December 11, 2018 statement on new actions advancing the agency’s biosimilars policy framework.

Table 1. European Medicines Agency List of Approved Biosimilar Drugs (updated February 5, 2019).

Table 2. U.S. Food and Drug Administration List of Approved Biosimilar Drugs (CDER list of licensed biologics updated on February 1, 2019).

Table 3. European Medicines Agency List of Biosimilars Under Evaluation for Marketing Approval (Source: EMA list of applications for new human medicines updated on January 7, 2019).

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, 2. Rituxan—Roche, 3. Enbrel—Pfizer/Amgen, 4. Herceptin—Roche, 5. Avastin—Roche, 6. Remicade—Johnson & Johnson/Merck, 7. Lantus—Sanofi, 8. Neulasta—Amgen, 9. Avonex—Biogen, 10. Lucentis—Roche/Novartis).