Source: https://www.fr.com/fish-litigation/biosimilars-2018-year-in-review/
Timestamp: 2019-04-25 08:38:29+00:00

Document:
Authors: Philip Chen, Tasha Francis, Ph.D., Jenny Shmuel, Ph.D.
Eight years have passed since the enactment of the Biologics Price Competition and Innovation Act (BPCIA), and the biosimilars industry has continued to grow. In 2018, seven biosimilar drugs were approved by the U.S. Food and Drug Administration (FDA), 12 new district court patent litigations were filed, and 144 petitions for post-grant review (IPRs and PGRs) were submitted. 2018 has also brought a renewed focus by legislators and regulators on competition among biologic and biosimilar products in the U.S. market. Details regarding these developments are summarized below, and key developments to monitor in this field in 2019 are also discussed.
2018 was a record year for FDA approval of abbreviated Biologics License Applications (aBLAs), which are approved through the abbreviated regulatory pathway laid out in the BPCIA. FDA approved seven new biosimilars this year: Retacrit® (epoetin alfa-epbx), FulphilaTM (pegfilgrastim-jmdb), NivestymTM (filgrastim-aafi), HyrimozTM (adalimumab-adaz), UdenycaTM (pegfilgrastim-cbqv), Truxima® (rituximab-abbs), and Herzuma® (trastuzumab-pkrb). For comparison, FDA only approved five aBLAs in 2017. Two of the seven aBLAs approved in 2018 are particularly noteworthy: Retacrit® is the first Epogen®/Procrit® biosimilar approved for the treatment of anemia, and Truxima® is the first Rituxan® biosimilar for non-Hodgkin’s lymphoma indications. Three of the biosimilars approved in 2018 also launched in 2018: NivestymTM, FulphilaTM, and Retacrit®.
While 2018 saw an increase in the number of approved biosimilars, the number of biologics approved by FDA through traditional biologics license applications (BLAs) decreased this past year. In 2018, FDA approved 17 BLAs, down from the 22 approved in 2017. Four of the BLA applications approved in 2018 were from the French company Diagast. Oxford Immunotec, Alba Bioscience, Grifols Diagnostic Solutions, and Octapharma Pharmazeutika also each had two BLAs approved in 2018.
The following charts summarize publicly available information regarding approved and pending aBLAs, and illustrate additional trends in the biosimilar space. For example, the data in Table 1 shows that the average time from aBLA acceptance to approval has increased from 9.8 months in 2017 to 20 months in 2018, although the average was skewed by the unusually long FDA review period for Retacrit®, which lasted 40 months. Excluding Retacrit®, the average time from aBLA acceptance to approval in 2018 was 17.6 months, still almost twice the average time to approval seen in 2017. Table 2 highlights some of the currently pending aBLA applications for which information is publicly available. Note that FDA Commissioner Scott Gottlieb has recently announced that over 60 biosimilar development programs are ongoing.
FDA also issued several announcements and guidance documents relevant to the biosimilar market in 2018. For example, on June 5, 2018, FDA released draft guidance that provided recommendations regarding the timing, scope, and conduct of formal meetings between FDA and biosimilar applicants relating to the development and review of biosimilar or interchangeable biological products. Along with this notice, FDA formally withdrew the previous guidance for industry that it released on November 18, 2015. The new draft guidance provided details on the “nuts and bolts” of meetings with FDA, but did not provide greater insight into the substantive requirements for biosimilar or interchangeable approval.
Also in July 2018, FDA released final guidance on “Labeling for Biosimilar Products.” In the guidance, FDA states that while a biosimilar product’s label does not have to be identical to that of the reference product, biosimilar product labeling should incorporate relevant data and information from the reference product labeling. Such information may vary depending on the biosimilar product’s conditions of use (e.g., indications, dosing regimens), but it generally includes clinical data that helps inform safe and effective use of the product. Information from biosimilarity studies—which are typically not designed to show safety or effectiveness of the biosimilar product—should not be included on the labeling. The guidance further recommends including a statement describing the nature and meaning of biosimilarity, as well as information about the immunogenicity of the biosimilar product based on the reference product labeling.
The first and second documents provide answers to common questions from prospective biosimilar applicants and other interested parties regarding the BPCIA. The final guidance ranges from logistical questions regarding whom a sponsor should contact for various requests, to more technical questions, relating to clinical studies, pediatric assessments, and whether a proposed biosimilar product can have a formulation or delivery device that differs from the reference product. The draft questions address how a biosimilar applicant can demonstrate that its proposed injectable product has the same strength as the reference product, how biosimilar applicants can fulfill the requirements for pediatric assessments under the Pediatric Research Equity Act, and what information a biosimilar manufacturer should provide to support post-approval manufacturing changes. Other questions inquire as to the approval for routes of administration, dosage forms, strengths, or indications not previously approved for the reference product.
The third and fourth documents address the “transition” provision of the BPCIA under which an application for a biological product approved under section 505 of the Federal Food, Drug, and Cosmetic Act (FD&C Act) (21 U.S.C. § 355) as of March 23, 2020, will be deemed to be a license for the biological product under Section 351 of the Public Health Service Act (PHS Act) (42 U.S.C. § 262) on March 23, 2020 (the transition date). That is, on March 23, 2020, biologics that had been treated as small molecule drugs for historical reasons will be treated as biologic drugs going forward, and approved new drug applications (NDAs) for these biological drugs will be automatically “deemed to be” BLAs. This guidance also describes FDA’s compliance policy for the labeling of biological products that are the subject of deemed BLAs. This guidance is intended to facilitate planning for the transition date and provide further clarity regarding the Agency’s interpretation of this statutory provision.
Comments and suggestions regarding the two draft guidance documents should be submitted by February 11, 2019.
There were twelve newly-filed federal district court patent cases dealing with biosimilars in 2018, summarized in the Table 3, below. Most new cases involved 20 to 40 patents. Note that each new case does not correspond to a separate, new biosimilar. For example, three cases filed in 2018 related to Celltrion’s Herzuma® biosimilar of Genentech’s Herceptin® (trastuzumab). Similarly, three cases related to Celltrion’s Truxima® biosimilar of Genentech’s Rituxan® (rituximab). As in 2017, the most active districts for biosimilar litigation in 2018 were the District of New Jersey and the District of Delaware. The most active biosimilar litigants in 2018 were Genentech and Celltrion, named parties in eight and six complaints, respectively.
Currently pending BPCIA district court litigations, filed in 2018 and previous years, are briefly described below.
The AbbVie and Boehringer Ingelheim (“BI”) litigation concerns Cyltezo®, BI’s biosimilar to AbbVie’s Humira® (adalimumab). This is the only ongoing United States litigation related to a Humira® biosimilar.
Currently the parties are in the middle of Markman briefing, with the Markman hearing set for April 2019.
This litigation involves Erelzi®, Sandoz’s biosimilar of Immunex’s Enbrel® (etanercept). In September 2018, the parties stipulated to infringement of certain asserted claims of U.S. Patent Nos. 8,063,182 and 8,163,522. The court held a two-week bench trial on patent invalidity later that month and the parties have submitted their post-trial briefs. The parties await the Court’s final decision on validity, namely on the issues of (1) obviousness-type double patenting; (2) written description; and (3) obviousness.
This litigation involves Fulphila®, Mylan’s biosimilar of Amgen’s Neulasta® (pegfilgrastim). One ongoing dispute is whether Amgen can prove infringement by relying on evidence outside of Mylan’s aBLA. Amgen argues that Mylan’s aBLA “does not directly address the infringement questions.” In contrast, Mylan, citing Amgen Inc. v. Apotex, 712 F. App’x 985, 992 (Fed. Cir. 2017), argues that it cannot infringe “as a matter of law in view of its FDA-approved manufacturing process” set forth in its aBLA. Following the court’s claim construction order in November 2018, Mylan stated that it intends to file dispositive motions on both patents-in-suit in January 2019.
Amgen filed suit after Adello submitted an aBLA for a biosimilar of Amgen’s Neupogen® (filgrastim). In its amended complaint, Amgen alleges that Adello and Amneal entered into a license and commercialization agreement in which Amneal would market and sell Adello’s filgrastim biosimilar and Adello would develop, obtain regulatory approval, and manufacture the biosimilar product. On December 5, 2018, Amneal filed a motion to dismiss on two separate grounds. First, Amneal contended that Amgen’s amended complaint failed to state a claim upon which relief could be granted because only Adello, the aBLA applicant, could commit the artificial act of infringement under the BPCIA. Second, Amneal argued that there is no declaratory judgment jurisdiction because Amgen’s allegations of future marketing and sales—if and when FDA approves the biosimilar—do not give rise to a justiciable controversy. Alternatively, Amneal requested that the court decline to exercise declaratory judgment jurisdiction so as not to “upend the carefully crafted BPCIA statutory scheme.” Amneal’s motion to dismiss is currently pending.
This is the third suit filed by Amgen concerning Apotex’s aBLAs for Neupogen® (filgrastim) and Neulasta® (pegfilgrastim) biosimilars. In January 2018, after the Federal Circuit affirmed judgments of non-infringement from earlier cases in favor of Apotex, the U.S. Patent and Trademark Office issued U.S. Patent No. 9,586,287 (the “’287 Patent”), directed to methods of refolding proteins expressed in a nonmammalian expression system. In August 2018, Amgen filed a third complaint against Apotex, alleging infringement of the ’287 Patent. On December 10, 2018, Apotex moved to dismiss Amgen’s complaint for failure to state a claim upon which relief could be granted, alleging non-infringement on grounds of prosecution history estoppel and collateral estoppel based on prior claim construction. The motion is currently pending.
Genentech’s actions against Amgen (18-cv-00924) and Samsung Bioepis (18-cv-01363) in the District of Delaware related to the defendants’ respective Herceptin® (trastuzumab) biosimilars. Genentech has pending motions to dismiss counterclaims of unenforceability of asserted U.S. Patent No. 6,407,213 in both cases.
Amgen v. Hospira and Pfizer (18-cv-01064 D. Del.), involving a biosimilar of Neupogen® (filgrastim), which is in the middle of fact discovery.
Janssen v. HyClone Labs. (16-cv-00071 D. Utah), concerning a Janssen cell culture media patent allegedly infringed during the manufacture of a Remicade® (infliximab) biosimilar. The case was stayed pending resolution of related litigation concerning the same patent in the United States District Court for the District of Massachusetts, Janssen Biotech, Inc. v. Celltrion Healthcare Co., Ltd., No. 17-cv-11008 (D. Mass.), now on appeal.
AbbVie v. Sandoz (18-cv-12668 D.N.J.), related to Sandoz’s biosimilar of AbbVie’s Humira® (adalimumab).
Although the Federal Circuit issued only one substantive biosimilar-related decision in 2018, a number of fresh appeals raise new issues to be decided in 2019.
The two appeals, Janssen v. Celltrion and In re Janssen, were companion cases concerning U.S. Patent No. 6,284,471 (the “’471 Patent”), a patent covering Janssen’s Remicade® (infliximab). The first action was filed under the BPCIA in the District of Massachusetts and resulted in a ruling that the ’471 Patent was invalid for obviousness-type double patenting. In a separate proceeding at the USPTO, the PTAB also found all claims of the ’471 Patent invalid for obviousness-type double patenting. Janssen subsequently appealed both decisions to the Federal Circuit.
In January 2018, the Federal Circuit affirmed the PTAB’s ruling, dismissing Janssen’s arguments that obviousness-type double patenting was inapplicable because the safe-harbor provision of 35 U.S.C. § 121 protected the ’471 Patent claims. The Federal Circuit held that Janssen could not retroactively amend its continuation-in-part application and re-designate it as a divisional application subject to the safe harbor. The appeal from the district court ruling was then dismissed as moot.
Amgen asserted, inter alia, that U.S. Patent Nos. 8,940,878 (the “’878 Patent) and 6,162,427 (the “’427 Patent”) were infringed by Sandoz’s biosimilars of Neupogen® (filgrastim) and Neulasta® (pegfilgrastim). After claim construction, Amgen and Sandoz stipulated to non-infringement of the ’427 Patent. In December 2017, the Northern District of California granted summary judgment of non-infringement regarding the ’878 Patent because the asserted protein purification method required separate washing and eluting steps, but Sandoz’s process involved a single, simultaneous washing and eluting step. The court also denied Amgen’s Rule 56(d) motion to deny or continue the motion for summary judgment until Sandoz submitted its intended new purification method to FDA, since the revised method would not materially change the infringement analysis. As framed by Amgen, the questions in the consolidated appeals are: (1) whether the district court properly construed the “washing” and “eluting” elements of claim 7 of the ’878 patent, (2) whether the district court properly granted summary judgment of non-infringement of claim 7 of the ’878 patent with respect to Sandoz’s current process for manufacturing its biosimilar products, (3) whether the district court properly denied Amgen’s motion for additional discovery pursuant to Rule 56(d), and (4) whether the district court properly construed terms in the ’427 patent. The issues have been briefed and the Federal Circuit will likely hear oral argument in the first quarter of 2019.
In March 2018, the District of Delaware granted Coherus’s motion to dismiss Amgen’s complaint over Coherus’s Neulasta® (pegfilgrastim) biosimilar. The court found that Coherus’s protein purification process differed from the process claimed in Amgen’s asserted patent and Amgen was barred by prosecution history estoppel from asserting infringement under the doctrine of equivalents. Amgen thus failed to state a claim for patent infringement. Amgen’s appeal centers around two issues: (1) whether dismissal of Amgen’s complaint based on prosecution history estoppel was proper, and (2) whether dismissal of Amgen’s complaint based on disclosure-dedication doctrine was proper. The parties have fully briefed the appeal, and the Federal Circuit will likely hear oral argument in the second quarter of 2019.
In September 2017, a jury in the District of Delaware awarded Amgen $70 million in reasonable royalty damages based on Hospira’s infringement of U.S. Patent No. 5,856,298 (the “’298 Patent”) in relation to a biosimilar of Amgen’s Epogen® (epoetin alfa). The jury found that certain of Hospira’s biosimilar batches were not “solely for uses reasonably related” to obtaining biosimilar approval and thus did not qualify for safe harbor protection under 35 U.S.C. § 271(e)(1). The jury also found that Hospira did not infringe U.S. Patent No. 5,756,349 (the “’349 Patent”). In ruling on post-trial motions, Judge Andrews upheld the jury verdict. The court clarified that evidence of intent can be a relevant factor in determining whether an activity is reasonably related to obtaining FDA approval and therefore subject to the safe harbor. Judge Andrews also upheld the jury’s damages award and additionally awarded Amgen prejudgment interest of about $10 million and post-judgment interest.
Hospira appealed the district court’s judgment of infringement and validity of the ’298 Patent and the court’s award of approximately $80 million. Amgen cross-appealed. Hospira filed its opening appeal brief on December 10, 2018.
The Janssen v. Celltrion litigation concerns Celltrion’s FDA-approved infliximab biosimilar, Inflectra®. Janssen alleged that the cell culture media used by Celltrion to produce its infliximab biosimilar infringes U.S. Patent No. 7,598,083 (the “’083 Patent”) under the doctrine of equivalents. In July 2018, Judge Wolf of the District of Massachusetts granted Celltrion’s motion for summary judgment of non-infringement. The court held that the range of equivalents necessary to cover the accused product would impermissibly ensnare the prior art. In August 2018, Janssen appealed the non-infringement ruling to the Federal Circuit, and Celltrion cross-appealed. Janssen filed its opening brief on December 10, 2018, arguing the district court erred by (1) impermissibly using hindsight to find that a hypothetical claim covering Celltrion’s cell culture medium would have been obvious; (2) failing to find Celltrion’s arguments regarding ensnarement legally baseless where Celltrion failed to offer any motivation to choose and modify the prior art references; and (3) failing to draw reasonable inferences in Janssen’s favor (e.g., teaching away and evidence of copying) in its summary judgment analysis. Cross-appellant Celltrion’s brief is due on February 11, 2019.
In 2018, there were 144 petitions for post-grant review filed in the biopharma space, which accounted for 8 percent of all post-grant petitions filed. This number was down from the record-setting 251 biopharma post-grant petitions filed in 2017. The vast majority of post-grant activity in 2018 consisted of IPR petitions, but 21 PGR petitions were also filed in 2018. Of the cases that reached an institution decision in the biopharma space, approximately 63 percent were instituted, slightly less than the average institution rate of 70 percent across all technology classes. The most active petitioners in 2018 included Eli Lilly, Foundation Medicine, and Merck. The most active patent owners in this space in 2018 included Teva Pharmaceuticals, Caris MPI, and GlaxoSmithKline.
2018 also saw a marked decrease in the number of IPR petitions filed against patents covering biologic drugs. While 2017 was a record year for IPR petitions relating to biologics, with over 80 petitions filed, only a quarter of that number (20) were filed in 2018. The number of biologics-related IPR petitions filed in 2018 was more consistent with the number of biologic petitions filed in 2015 and 2016 (17 and 20, respectively). The high number of petitions filed in 2017 was largely a result of multiple petitions focused primarily on three blockbuster drugs: Herceptin® (31 petitions), Rituxan® (19 petitions), and Humira® (14 petitions). While there were multiple petitions filed on particular drug portfolios in 2018 (for example, Eli Lilly filed nine petitions challenging nine patents related to its biologic Emgality® (galcanezumab)), there were not as many biologic patent portfolios challenged, nor to the same degree as in 2017.
Another notable development related to biopharma IPRs in 2018 was the introduction of the Hatch-Waxman Integrity Act of 2018 by Senator Orrin Hatch (R-UT). The proposed legislation would modify the IPR process for pharmaceuticals—under Hatch-Waxman and the Biologics Price Competition and Innovation Act—“to restore the careful balance the Hatch-Waxman Act struck to incentivize generic drug development.” The proposed legislation would apply to both generic and biosimilar drug applicants, requiring anyone wishing to challenge a pharmaceutical patent to choose between Hatch-Waxman/BPCIA litigation and an AIA challenge (IPR/PGR). The legislation is currently under consideration.
In 2018, biosimilar developers and other private parties stepped up their attacks on reference product sponsors (RPSs) who they view as unlawfully stymieing the U.S. biosimilars market. In September 2017, Pfizer sued Johnson & Johnson (J&J) and its subsidiary Janssen in the Eastern District of Pennsylvania, alleging antitrust violations that allegedly prevented the market success of Inflectra®. Pfizer alleged that J&J and Janssen maintained their Remicade® market share through a multifaceted scheme of “exclusionary contracts that foreclose Pfizer’s access to an overwhelming share of consumers, coupled with anticompetitive bundling and coercive rebate policies designed to block both insurers from reimbursing, and hospitals and clinics from purchasing, Inflectra or other biosimilars of Remicade despite their lower pricing.” Pfizer’s case was followed by a string of direct and indirect purchaser class action complaints with comparable allegations. In June 2018, pharmacy giants Walgreen Co. and The Kroger Co. followed suit, filing a joint complaint in the same district court with similar allegations based on their alleged overpayment for direct purchases of Remicade® and as assignees of pharmaceutical wholesalers’ claims.
J&J and Janssen attempted unsuccessfully to dismiss these lawsuits. In August 2018, the court denied J&J and Janssen’s motion to dismiss the initial lawsuit filed by Pfizer, finding, inter alia, that Pfizer’s complaint sufficiently alleged antitrust injury. In December 2018, the court denied-in-part motions to dismiss the indirect and direct purchaser claims, allowing the litigation to continue. Similarly, the court denied motions to dismiss the Walgreen and Kroger claims based on direct purchases, while requesting further evidence and briefing on claims derived by assignment. The court is now positioned to provide insight into what constitutes fair competition in the biosimilars market and remedy unfair practices to the extent they exist.
On the regulatory side, FDA and the Federal Trade Commission (FTC) have also begun to scrutinize potential abuses of the citizen petition process more closely. Citizen petitions allow any interested party to ask FDA for policy changes, including requests for FDA not to approve a generic or biosimilar product until certain conditions are met. FDA Commissioner Scott Gottlieb noted that “the record shows that citizen petitions have rarely delayed specific generic drug approvals.” However, he stated that “the process requirements associated with [citizen petitions] can add to resource burdens on the generic drug review process and the FDA’s regulatory decision making” and “[t]his increased burden on the FDA can take resources away from the daily work of application review.” Commissioner Gottlieb has therefore focused on shutting down efforts to use citizen petitions as an anticompetitive tactic used to “game” the system and try to delay generic and biosimilar product entry. In October 2018, FDA issued a revised draft guidance, titled “Citizen Petitions and Petitions for Stay of Action Subject to Section 505(q) of the Federal Food, Drug, and Cosmetic Act,” describing the factors FDA will consider in determining whether a petition is submitted with the primary purpose of delaying an approval, as opposed to, for example, timely raising valid scientific or regulatory issues. In a comment letter issued on December 3, 2018, FTC indicated its readiness to work with FDA to deter abuses of the citizen petition process that delay procompetitive generic or biosimilar entry.
Since late 2017, AbbVie has entered into seven settlement agreements with multiple manufacturers of biosimilars of its blockbuster biologic, Humira® (adalimumab). The agreements all delay U.S. market entry of biosimilar competition until 2023, with each subsequent settlement having a later entry date and no acceleration based on the earlier entry of a previous licensee. At the same time, most of the settlements allow for entry into the European Union much sooner than into the U.S. market.
On September 25, 2018, the House of Representatives passed core components of the Biosimilars Competition Act of 2018, a bill designed to curb anticompetitive “pay-for-delay” agreements entered into by manufacturers of biologic and biosimilar drugs. If passed, the bill would require RPSs and biosimilar drug manufacturers to report any agreements that may keep lower-cost drugs off the market to FTC and the U.S. Department of Justice (DOJ).
In October 2018, President Trump signed into law a related piece of legislation, the Patient Right to Know Drug Prices Act. The new law amends the Medicare Prescription Drug, Improvement, and Modernization Act of 2003 to require reference biologic and biosimilar product manufacturers to report to FTC and DOJ settlement agreements relating to the “manufacture, marketing, or sale” of biosimilar products for antitrust scrutiny. The new reporting requirements would bring biosimilar settlement review procedures more in line with the FTC notification requirements already in place for branded and generic pharmaceutical manufacturers under the FTC Act.
2018 was a record year for the U.S. biosimilars market in certain respects: FDA approved seven new biosimilar drug products and a total of twelve new district court litigations were filed. However, activity has begun to slow down in other areas: the number of post-grant filings decreased from 251 in 2017 to 144 in 2018, and the number of BLAs filed is down to 17, from 22 in 2017.
Despite the overall uptick in the industry since the passing of the BPCIA, biosimilars have been relatively slow to enter the market. Currently, although there are sixteen approved biosimilar products in the United States, only seven have actually launched. Also, FDA has yet to approve the first interchangeable biosimilar. Some products that won approval over two years ago, such as Amgen’s adalimumab biosimilar, Amjevita®, and Sandoz’s etanercept biosimilar, Erelzi®, still have not been released commercially due to novel and complex legal issues that face the industry. Legislators and regulators have taken note and will be monitoring the balance between innovation and competition more closely in 2019.
In 2019, we look forward to resolution of pending antitrust issues. In addition, we anticipate guidance from the Federal Circuit in four pending BPCIA litigation appeals, and additional guidance on standing and discovery disputes in pending and future district court litigation. Continued growth of the U.S. biosimilar market is expected in 2019 based on the increased number of biosimilar aBLAs approved in 2018. Finally, interested parties should keep an eye on proposed legislation (such as the Hatch-Waxman Integrity Act) that could change the legal strategies biosimilar manufacturers pursue in entering the U.S. market.
 Approval time is calculated from the first aBLA submission date, not any resubmission date.

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