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).

The PTAB recently denied institution of two IPRs filed by CSL Behring LLC, CSL Behring GMBH, and CSL Behring Recombinant Facility AG (collectively “CSL”) targeting U.S. Patent No. 9,623,091 (“the ʼ091 patent”) owned by Bioverativ Therapetutics, Inc. (“Bioverativ”).   More specifically, on January 6, 2019, the PTAB denied institution of IPR2018-01313 (“the ʼ313 IPR”), and on January 16, 2019, denied institution of IPR2018-01345 (“the ʼ345 IPR”).

The challenged claims of the ʼ091 patent are directed to a method of treating hemophilia B in a human subject comprising administering multiple doses of 50-100 IU/kg of a chimeric factor IX polypeptide comprising factor IX and an FcRn binding partner at a dosing interval of about 10 to 14 days between doses. The administration maintains the plasma factor IX activity about 1 IU/dL between dosing intervals, and treats the human subject by reducing the frequency of spontaneous bleeding.

Hemophilia B is an X-linked genetic disorder that impairs blood clotting due to a deficiency of factor IX. As a result of this deficiency, a person with hemophilia B is subject to recurrent and extended bleeding episodes. Hemophilia B is treated by infusing the missing factor IX protein into a patient’s bloodstream. The infusion may be given on a designated schedule (referred to as prophylactic therapy) to help prevent bleeding episodes, or on an as needed basis.  However, prophylactic therapy of conventional recombinant factor IX requires multiple infusions a week due to the short half-life of factor IX. Consequently, efforts were made in an attempt to extend the half-life of factor IX, and the results of those efforts include the FDA approved products Aprolix® and Idelvion ®.

Aprolix is a recombinant factor IX fusion protein that comprises factor IX fused to the Fc portion of an IgG1 protein.  The FDA approved the Aprolix Biologics License Application (“BLA”) in March 2014.  Aprolix is indicated for both on-demand and prophylactic administration, and is marketed by Bioverativ.

Idelvion is a recombinant factor IX fusion protein that comprises factor IX fused to albumin.  Albumin is a naturally occurring protein with a long half-life. The FDA approved the Idelvion BLA in March 2016.  Idelvion is also indicated for on-demand and prophylactic administration, and is marketed by CSL.

In the ʼ313 IPR, CSL asserted two grounds of unpatentability. The first ground challenged claims 1-17, 20, 22, 24, and 28 as obvious in view of two references, one of which was the Peters 2010 reference.  Peters is an inventor of the ʼ091 patent, although the Peters 2010 reference lists a number of other co-authors. During prosecution, the Examiner cited the Peters 2010 reference in an obviousness rejection, but Bioverativ removed Peters 2010 as prior art by submitting a declaration from Peters asserting that Peters 2010 was not the work of another, and so did not qualify as § 103(a) prior art. In its Petition, CSL asserted that the Peters declaration was insufficient to remove the Peters 2010 reference as prior art because the statement that Peters alone was responsible for the work in the Peters 2010 reference amounted to an uncorroborated assertion. CSL supported its contention by pointing to a paragraph in the Peters 2010 reference that indicates other co-authors designed research reported in Peters 2010. The PTAB did not find this argument persuasive and explained that CSL did not provide any evidence that the level of direction and control by Peters was insufficient to remove the Peters 2010 reference as prior art.

CSL next argued that the ʼ091 patent was not entitled to the benefit of a provisional application. Without the benefit of the provisional application, the Peters 2010 reference would qualify as § 102(b) prior art that could not be removed by the Peters declaration. CSL’s contention was that the provisional application does not provide written description or enablement support for the claimed invention because the claimed genus of a chimeric factor IX:Fc binding partner includes a vast number of structural variants, but the provisional application only describes one such variant. According to CSL, a single variant cannot describe or enable a representative number of species within the claimed genus. Bioverativ responded by arguing the provisional application describes more than a single variant because it specifically incorporates by reference the disclosure of a number of functional variant factor IX and Fc sequences. The PTAB concluded that because CSL and its expert apparently did not consider the material incorporated by reference in the provisional application, CSL did not meet its burden of showing the ʼ091 patent is not entitled to the benefit of its provisional application filing date.

CSL’s first ground relied on the Peters 2010 reference to teach the claimed polypeptide. Because the Peters 2010 was not available as a prior art reference, the PTAB concluded that CSL could not meet its burden of showing the ʼ091 patent claims were unpatentable under the first proposed ground.

The second ground asserted in the ʼ313 IPR challenged claims 1-16, 18, 19, 21, and 23-27 in view of four references. CSL claimed that two of the cited references disclose chimeric factor IX (Metzner and ʼ755 Publication) polypeptides that have activity and extended half-life in animal testing, whereas the other two references (Shapiro and Carlsson) teach factor IX prophylaxis regimens. According to CSL, Shapiro teaches that administration of once weekly doses of 50-100 IU/kg of chimeric factor IX reduces frequency of spontaneous bleeding, and Carlsson teaches effective prophylactic treatment generally maintains factor IX activity above 1 IU/dL   Similarly, CSL asserted that Metzner and the ʼ755 Publication teach that chimeric factor IX have comparable efficacy and a 2- to 5- fold half-life extension when compared to recombinant factor IX. CSL also contended that arriving at the claimed 10-14 day interval is only routine optimization.

Bioverativ countered that Shaprio and Carlsson do not establish that the once weekly doses in Shaprio maintain a factor IX activity above the claimed range. According to Bioverativ, Shapiro did not “overturn the prevailing consensus” that factor IX must be administered two to three times a week for prophylaxis. Bioverativ also asserted that Metzner and the ʼ755 Publication merely provide animal data that demonstrates chimeric factor IX proteins have some degree of extended half-life in some animal models, but not others. Consequently, Bioverative insisted that a person of ordinary skill in the art (“POSA”) would not have been able to predict the degree of half-life extension in a human patient based on the data in those publications. Bioverativ also asserted that the claimed 10-14 dosing interval is substantially longer than what had been previously disclosed in the art, and does not reflect routine optimization.

The PTAB agreed with Bioverativ and found that CSL failed to establish that once weekly doses in Shapiro maintained the required level of factor IX.  The PTAB also concluded that CSL had failed to address inconsistences in the animal half-life data reported in Metzner and the ʼ755 Publication and the application of that data to dosing in humans. Consequently, the PTAB declined to institute review on this ground as well.

In the ʼ345 IPR, CSL asserted a single ground of obviousness that combined Shapiro and Carlsson with two additional references, i.e., Peters 2007 and the ʼ956 patent. The Peters 2007 and ʼ956 patent are relied on for the disclosure of a recombinant fusion protein comprising factor IX and the Fc region of IgG. Shapiro and Carlsson were again relied on for the teachings of factor IX prophylactic regimen.

CSL’s obviousness theory was similar to the theory set forth in the second ground of the ʼ313 IPR.  According to CSL, a POSA would have found it obvious to administer the claimed dosage of a factor IX:Fc fusion protein every 10-14 days with a reasonable expectation that such administration would result in maintaining a plasma factor IX activity above 1 IU/dL and reducing the frequency of spontaneous bleeding. CSL once again asserted that a POSA would know from Shaprio and Carlsson that administration of 50-100 IU/kg of a factor IX:Fc fusion protein once weekly would result in maintaining the required factor IX activity. CSL again considered arriving at the claimed 10-14 day interval to be nothing more than routine optimization. CSL supported its assertion by pointing to the disclosure in the Peters 2007 reference that factor IX:Fc fusion proteins have an increased half-life.

Bioverativ responded by again pointing out that Shapiro does not disclose weekly doses of factor IX:Fc fusion protein can maintain plasma factor IX activity at levels above I IU/dL. Bioverativ again noted it was understood that dosing of two to three times per week was required to maintain the required factor IX activity level, and this is reflected in several references cited by Petitioner. Bioverativ also pointed out that Peters 2007 only discloses effective clotting activity in animals for 6 days, does not indicate the amounts of fusion protein dosed, and merely speculates that the results of its studies are consistent with once weekly human dosing.

The PTAB again agreed with Bioverativ that the claimed combination of references would not have rendered the ʼ091 patent claims obvious. The PTAB found that the Shaprio and Carlsson references did not disclose that the claimed factor IX activity level could be obtained via Shaprio’s once weekly dosage. On this point, the PTAB referenced the contrary teachings in CSL’s cited art that two to three weekly doses were required to obtain the claimed level. The PTAB also noted that CSL did not explain how the six day duration of the clotting effect in Peters 2007 is consistent with maintaining the required plasma level of factor IX for the claimed 10-14 day interval. Accordingly, the PTAB also denied institution of the ʼ345 IPR.

Bioverativ also asserted a claim for patent infringement against CSL in the District of Delaware.  In the Complaint, Bioverativ asserted CSL’s Idelvion product infringes the ʼ091 patent along with two other patents. The District Court action is currently pending with a jury trial set to begin on March 30, 2020.

We will continue to keep you updated on further developments.

The Biologics Price Competition and Innovation Act (“BPCIA”) requires applications to market a biological product be submitted for review by the FDA under § 351 of the Public Health Service Act (“PHS Act”). However, it carved out a limited exception for biological products that are in a product class that had already been approved under § 505 of the Food, Drug, and Cosmetic Act (“FD&C Act”) prior to enactment of the BPCIA. For biological products in that limited category, the applicant was given the option to seek approval under §505 of the FD&C Act provided that the application was submitted prior to enactment of the BPCIA, or was submitted not later than 10 years after enactment of the BPCIA. Thus, the BPCIA created a 10-year transition period wherein certain biological products could be approved under § 505 instead of § 351.

March 23, 2020, marks the end of that 10-year transition period. According to the BPCIA, on that date, all NDAs for biological products that were approved under §505 of the FD&C Act will be “deemed to be a license for the biological product” under § 351 of the PHS Act. The FDA has now published guidance on how it will interpret the “deemed to be a license” transition provision of the BPCIA.

In brief, the FDA interprets the “deemed to be a license” provision to only apply to NDAs that have been approved as of the transition date. The FDA explains that the statutory language does not provide a path for approved NDAs to be transitioned to a BLA, either before or after the specified transition date. Consequently, the FDA will not approve any application for a biological product submitted under § 505 that is pending or tentatively approved on March 23, 2020, and will instead issue a complete response letter to any such application. For this reason, the FDA suggests that applicants who are contemplating submitting a § 505 application for a product that will be transitioned consider instead submitting the application under § 351.

The FDA also explains that all biological products subject to the transition provision will be removed from the Orange Book on the transition date. Those products will then be listed in the Purple Book. Moreover, any unexpired exclusivity (except for orphan drug or pediatric exclusivity) for an approved NDA that is transitioned to a BLA will no longer be in effect. Orphan drug and pediatric exclusivity will remain in force because the § 351 also provides for those types of exclusivity.

On the question of exclusivity, the FDA makes it clear that transitioned NDAs will not be granted the exclusivity that applications originally approved under § 351 enjoy. More specifically, transitioned NDAs will not be granted a 12-year period wherein the FDA may not approve a § 351(k) application, or a 4-year period wherein an applicant may not submit a § 351(k) application to the FDA. The FDA’s reasoning is that those exclusivity periods begin on the date that the § 351(a) application was first licensed, and a transitioned § 505 application was not first licensed under § 351(a). As articulated by Commissioner Gottlieb in remarks accompanying the release of the guidance documents, the FDA’s reasoning is also guided by a desire to encourage competition, which would be blunted by granting an additional 12 years of exclusivity to these products, some of which were first approved over 30 years ago.

So, what products will be impacted by this transition provision? The FDA has published a preliminary list of products that are anticipated to be affected by the transition provision. Perhaps the most notable are the various insulin products, although there are a number of other significant products listed.

The FDA has also published a Question and Answer document on the “Deemed to be a License” Provision. In this document, the FDA explains that transitioned applications will be deemed § 351(a) BLA. These transitioned NDAs will also be subject to the requirements under the PHS Act, including those requirements that differ from the FD&C Act. However, the FDA also indicates its belief that there will be minimal disruption due to those differences. The FDA specifically identifies differences in labeling and CMC requirements that transitioned BLAs will need to address. However, the FDA specifically addresses those differences and provides its guidance in the Q & A document.

Last month, the FDA released four new guidance documents providing insight on the FDA’s interpretation of provisions of the Biologics Price Competition and Innovation Act (“BPCIA”), as it amends the Public Health Service Act (“PHS Act”) and the Patient Protection and Affordable Care Act (“ACA”), among other statutes. Two of the documents relate to the “Deemed to be a License” provision in section 7002(e) of the BPCIA, and are covered in a separate post. The remaining two documents, which will be discussed here, address recommended practices for biosimilar development and meeting the application requirements for biosimilar and interchangeable products.[1]

The Questions and Answers on Biosimilar Development and the BPCI Act (Revision 1) guidance document is intended to enhance transparency of the FDA’s interpretation of the BPCIA by providing responses to common questions from prospective applicants and interested parties. The content is largely pulled from two of the FDA’s prior draft guidance documents issued in April 2015 and May 2015, respectively, with some updates and revisions.

In particular, the Q&A addresses questions regarding the permissible differences between a proposed biosimilar product and a reference product, as related to formulation and delivery device and the number of routes of administration, presentations (e.g., strengths or delivery devices), and conditions of use. One noteworthy change from the earlier drafts that spans several of the questions is the reference to a new January 2017 guidance document entitled “Considerations in Demonstrating Interchangeability With a Reference Product.” While the 2015 drafts included brief explanations about the FDA’s review process for interchangeable products as relevant to each question, the revised responses now direct applicants to the comprehensive 30-page guidance, which provides detailed suggestions for the development of and applications for a proposed interchangeable product specifically.

Other relevant differences between the drafts include: a change in the recommended length of time to retain reserve samples of the products used in comparative clinical studies intended to support a 351(k) application (now for at least 5 years following the date on which the 351(k) application is licensed, or, if such application is not licensed, at least 5 years following the date of completion of the studies); removal of the recommendations related specifically to retaining samples from multi-site studies and products intended for multi-dose administration; and an expanded definition of “publicly-available information” in relation to FDA’s previous determination that the reference product is safe, pure, and potent to include in a 351(k) application (the definition now includes “FDA-approved labeling for the reference product,” in addition to the types of information found in the “action package” for a Biologics License Application (“BLA”)). Lastly, while some Q&As were withdrawn and moved to the companion draft guidance document (addressed below), one  question relating to the permissibility of extrapolated clinical data was withdrawn entirely, and instead refers applicants with questions about the standards for clinical data to another guidance from April 2015, entitled “Scientific Considerations in Demonstrating Biosimilarity to a Reference Product.”

The companion document to Questions and Answers on Biosimilar Development and the BPCI Act (Revision 1) is New and Revised Draft Q&As on Biosimilar Development and the BPCI Act (Revision 2), which includes additional Q&As that address the requirements for pediatric assessments or investigations under the Pediatric Research Equity Act (“PREA”), the suggested support for post-approval manufacturing changes for a licensed biosimilar product, and the definition of “protein” in section 351(i)(1) of the PHS Act. Notably, the document also clarifies that a 351(k) application is not the appropriate vehicle to seek approval for routes of administration, dosage forms, strengths, or conditions of use that differ from those of the reference product, implying that sponsors must instead utilize the regular, unabbreviated pathway for licensure in those instances.

A new topic that the FDA addresses in this second guidance is the issue of when a reference product holder refuses to sell a product to a prospective applicant that is seeking to conduct studies to support approval of a biosimilar product, based on a belief that supplying the product for that purpose would violate the risk evaluation and mitigation strategy (REMS) with elements to assure safe use (ETASU) for the reference product. Noting that such incidents have occurred, the FDA proposes a solution where the prospective applicant may submit study protocols to the FDA and request a letter from the FDA stating that the proposed studies contain safety protections that would comply with the REMS. If the FDA finds that the safety protections are comparable to those in the REMS, the FDA would then notify the reference product holder with a separate letter indicating that the Agency would not consider the supply of the reference product to the prospective applicant for the required testing to be a violation of the REMS. The FDA hopes that this solution will help facilitate a prospective applicant’s access to the reference product for purposes of supporting the license application.

[1] The FDA clarifies that a “biosimilar” or “biosimilar product” refers to a product that the FDA has determined to be biosimilar to the reference product under sections 351(i)(2) and 351(k)(2) of the PHS Act, and that an “interchangeable biosimilar” or “interchangeable product” refers to a biosimilar product that the FDA has determined to be interchangeable with the reference product under sections 351(i)(3) and 351(k)(4) of the PHS Act.

The FDA recently proposed an amendment to its regulations defining the term “biological product.”  The proposed amendment incorporates changes made by the Biologics Price Competition and Innovation Act (BPCIA) into the FDA’s regulations, and provides the FDA’s interpretation of the statutory terms “protein” and “chemically synthesized polypeptide.”  The proposed definitions of the statutory terms are not too surprising because they are the same definitions that the FDA has provided in previously issued guidance documents.

The FDA’s proposed definition of “protein” is “any alpha amino acid polymer with a specific, defined sequence that is greater than 40 amino acids in size.”  The proposed definition of “chemically synthesized polypeptide” is “any alpha amino acid polymer that is made entirely by chemical synthesis and is greater than 40 amino acids but less than 100 amino acids in size.”  The proposed definitions for both terms include the proviso that if two or more chains of an amino acid polymer are associated with one another as they are in nature the size of the amino acid polymer will be based on the total number in the chain and is not limited by the number in a contiguous sequence.  The FDA also explains in the rulemaking document that if a product comprises amino acid chains that are associated in a manner not found in nature, then the FDA will conduct a fact-specific, case-by-case analysis to determine whether the size of the amino acid polymer should be determined by adding the total number of amino acids together, or if it should be based on the amino acid chain lengths in isolation.

The purpose of the proposed amendment is to clarify the statutory authority under which protein products are regulated.  In particular, the proposed amendment will help determine whether a product comprised of amino acids will be regulated under section 351 of the Public Health Service Act (PHSA), or section 505 of the Food, Drug, and Cosmetic Act (FD&C Act).  For example, under the proposed rule, an amino acid polymer with a specific, defined sequence less than 40 amino acids in size will be considered a peptide, and will be regulated under the FD&C Act instead of the PHSA.  In contrast, non-chemically synthesized proteins greater than 40 amino acids in length will be regulated by the PHSA.

The FDA also explains that the phrase “made entirely by chemical synthesis” in its proposed definition of “chemically synthesized polypeptide” means that the amino acids in the chain were added by a process that does not involve cell-based or cell-free recombinant DNA directed synthesis or recombinant RNA directed synthesis.  If that condition is met, and the product does not otherwise fall under the definition of biological product, such as by being a vaccine, then the chemically synthesized polypeptide product will be regulated under the FD&C Act.

The clarification provided by the proposed rule is important as the end of the BPCIA transition period draws near.  More specifically, on March 23, 2020, NDAs for certain biological products will be transitioned to BLAs as mandated by the BPCIA.  For this reason, it is not surprising that the FDA also released guidance on how it will interpret certain statutory provisions relating to that transition on the same day as it published its proposed rule.  The transition guidance documents will be discussed in a separate post.

Electronic or written comments on the FDA’s proposed amendment may be submitted until February 25, 2019.