On December 14, 2017, the Federal Circuit issued an opinion in Amgen v. Sandoz,[i] holding that the Biologics Price Competition and Innovation Act of 2009 (“BPCIA,” the “Act”) preempts state law, and thus state laws cannot be used to enforce participation in the BPCIA’s patent dispute resolution procedures and disclosure process. In light of the Supreme Court’s holding earlier this year that such participation is not enforceable by an injunction under federal law and that biosimilar applicants need not wait for approval from the U.S. Food and Drug Administration (“FDA”) before providing the statutorily required notice of commercial marketing, this case is a major win for biosimilar applicants and manufacturers alike.

The instant case surrounds a dispute stemming from Sandoz’s filing of an abbreviated biologics license application (“aBLA”) in May 2014, seeking FDA approval for a biosimilar of Amgen’s filgrastim, marketed under the brand name Neupogen®. Following the FDA’s acceptance of Sandoz’s application for review, Sandoz notified Amgen that the application had been filed and accepted for review, but informed Amgen that it had opted not to provide the biosimilar application or its product’s manufacturing information according to § 262(l)(2)(A). Instead, Sandoz noted that Amgen was entitled to sue Sandoz under § 262(l)(9)(C) to force such a disclosure through 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, in October 2014, Amgen sued Sandoz in the Northern District of California, asserting claims of (1) unfair competition under California law, based on violations of the BPCIA for failing to disclose the information required under § 262(l)(2)(A); (2) conversion for allegedly wrongful use of Amgen’s approved license on Neupogen®; and (3) infringement of Amgen’s U.S. Patent 6,162,427, which claims a method of using filgrastim. Sandoz counterclaimed, in part, for a declaratory judgment that the BPCIA permitted its actions, and asserted as an affirmative defense preemption of the state law claims by the BPCIA. Following a final judgment dismissing Amgen’s state law claims, a subsequent appeal to the Federal Circuit, a writ of certiorari to the Supreme Court, and then a remand back to the Federal Circuit, the main question that remained before the court last Thursday was whether the BPCIA preempts any additional remedy available under state law for a biosimilar applicant’s failure to comply with § 262(l)(2)(A).

The Federal Circuit explained that the Supremacy Clause preempts state law by means of express preemption, field preemption, or conflict preemption, finding the latter two applicable in this case. With regard to field preemption, the court found that BPCIA’s complex and comprehensive scheme of federal regulation of biosimilars and of resolving patent disputes between licensed biologics and manufacturers of biologics indicated that the federal government has fully occupied the field, leaving no room for supplementation by the states. With regard to conflict preemption, the Federal Circuit found that Amgen sought to impose on Sandoz the penalties of injunctive relief and damages, for which the BPCIA does not provide. Thus, the permission of state law penalties would conflict with the regulatory framework envisioned by Congress. The court also noted that casting the BPCIA’s “detailed regulatory regime in the shadow of 50 States’ tort regimes” and unfair competition standards could “dramatically increase the burdens on biosimilar applicants beyond those contemplated by Congress in enacting the BPCIA.”[ii] Concluding that Amgen’s state law claims conflict with the BPCIA and intrude upon a field (biosimilar patent litigation) that Congress reserved for the federal government, the Federal Circuit accordingly ruled that Amgen could not proceed with its state law claims.

This case ultimately makes clear that biosimilar applicants may choose to opt out of the patent resolution regime and information exchange described in the BPCIA without facing any legal liability aside from those provisions expressly set forth in the Act itself. Consequently, by deciding not to engage in this information exchange, biosimilar applicants can avoid a compelled disclosure of proprietary information that may be commercially sensitive for the applicant. In addition, brand name drug manufacturers will be forced to essentially “operate in the dark,” by asserting the entire patent portfolio for the drug against the biosimilar applicant, as opposed to the much more targeted and prepared attack that would result from a full disclosure of the biosimilar application and manufacturing process under the BPCIA.[iii]

 

[i] Amgen Inc. and Amgen Manufacturing Ltd. v. Sandoz Inc., Case No. 2015-1499 (Fed. Cir. Dec. 14, 2017), available at http://www.cafc.uscourts.gov/sites/default/files/opinions-orders/15-1499.Opinion.12-13-2017.1.PDF (last accessed Dec. 18, 2017).

[ii] Id. at page 22.

[iii] Kelly Davio, “Federal Circuit Sides with Biosimilar Developer Sandoz in Landmark Decision,” The Center for Biosimilars, December 14, 2017, available at http://www.centerforbiosimilars.com/news/federal-circuit-sides-with-biosimilar-developer-sandoz-in-landmark-decision (last accessed Dec. 18, 2017).

In October, a Federal Circuit panel vacated a permanent injunction against Sanofi and Regeneron’s Praluent® and remanded the proceeding to the district court for a new trial on the defendants’ written description and enablement defenses.[i] The panel had held that the district court erred by (i) excluding the defendants’ evidence of written description and enablement, and (ii) improperly instructing the jury on written description.

On Wednesday, November 6, 2017, Amgen filed a petition for rehearing en banc by the entire Federal Circuit for consideration of the written description and enablement issues.[ii] Amgen asserted two grounds for rehearing in its petition.

First, Amgen argued the panel decision abrogated the “newly-characterized antigen” test, which, over the past 15 years, the Federal Circuit has recognized in multiple decisions as the test for compliance with the written description requirement. According to Amgen’s petition, the “newly characterized antigen” test states that “written description for ‘an antibody to [a] novel protein’ is satisfied ‘without describing the antibody when (1) the applicant fully discloses the novel protein and (2) generating the claimed antibody is so routine that possessing the protein places the applicant in possession of an antibody.’ ”[iii] Amgen asserts the panel erred in dismissing the Federal Circuit’s prior cases as “dictum” because the “cases apply the test as the ratio decidendi[,] … the opposite of dictum.”[iv] This issue is exceptionally important, Amgen argues, as the “PTO has issued myriad patents under the newly-characterized-antigen test.”[v] Innovators will not invest in developing therapeutic agents “absent confidence they can take [the Federal Circuit’s] precedents at their word, especially in an industry where the few successful medicines must also fund the many research dead ends.”[vi] The panel decision overturning the ratio decidendi of three cases as “dictum,” Amgen asserts, gravely undermines that confidence.[vii]

Second, Amgen argues that the panel erred by holding that later-created embodiments are relevant to whether a patentee meets the written description requirement by disclosing representative species, upending “four decades of precedent holding post-priority-date embodiments irrelevant to patent validity.”[viii] Amgen contends that the Federal Circuit has held for decades that advances in the art after the priority date, such as new embodiments, are irrelevant to validity.[ix] According to Amgen, the panel agreed “that evidence of later-discovered embodiments is generally irrelevant,” but “nonetheless held that post-priority-date embodiments are relevant to whether a ‘patent fails to disclose a representative number of species.’ ”[x] Amgen contends the ruling will lead to dire consequences for both antibody innovation and PTO examinations because patent prosecutors will need to disclose embodiments developed after the priority date continually as they are discovered in order to avoid claims of inequitable conduct.[xi] As a result, inventors will have little reason “to invest billions of dollars to address unknown and difficult targets … if easier, subsequent developments—enabled by the patentee’s own disclosures—can be the basis for invalidating the patent that made them possible[.]”[xii] Amgen asserts this decision by the panel creates a “zone of uncertainty” since validity has hinged on the priority date for decades.[xiii]

Stay tuned to BiosimilarsIP for future updates in the case.

 

[i] Amgen Inc. v. Sanofi, 872 F.3d 1367 (Fed. Cir. 2017).

[ii] Amgen’s Petition for Rehearing En Banc, Amgen Inc. v. Sanofi, 872 F.3d 1367 (Fed. Cir. 2017) (No. 17-1480).

[iii] Id. at 13 (citing Centocor Ortho Biotech, Inc. v. Abbott Labs., 636 F.3d 1341, 1351-52 (Fed. Cir. 2011)).

[iv] Id. at 9.

[v] Id. at 17.

[vi] Id. at 18.

[vii] Id.

[viii] Id. at 10.

[ix] Id. at 19-20 (citing In re Hogan, 559 F.2d 595, 605 (C.C.P.A. 1977); U.S. Steel Corp. v. Phillips Petroleum Co., 865 F.2d 1247, 1251-52 (Fed. Cir. 1989); In re Koller, 613 F.2d 819, 823-24 (C.C.P.A. 1980)).

[x] Id. at 21 (citing Amgen, 872 F.3d at 1374–75).

[xi] Id. at 10-11.

[xii] Id. at 24.

[xiii] Id. at 25, 27

The FDA has only approved eight biosimilar products to date. The second most recently approved biosimilar is Mvasi (bevacizumab-awwb), which is manufactured by Amgen and was approved as a biosimilar to Genentech’s Avastin (bevacizumab) on September 14, 2017.[1]

On October 6, 2017—about three weeks after the FDA approved Mvasi—Amgen provided Genentech with a notice of commercial marketing and filed a declaratory suit in the U.S. District Court for the Central District of California of non-infringement and invalidity of Avastin-related patents. Genentech, on the other hand, filed a suit involving the Avastin patents in the U.S. District Court for the District of Delaware on that same day (or “[s]hortly after midnight, on October 7, 2017” according to a filing by Amgen in the case) and then another such suit on October 18, 2017. Currently pending in both Delaware cases are motions by Amgen to transfer to the Central District of California and to dismiss Genentech’s complaints for failure to state a claim. Meanwhile, in the Central District of California, Genentech has filed a motion to dismiss for lack of jurisdiction, which is still pending an order.

Mvasi is significant because it is the first biosimilar approved in the United States for the treatment of cancer. The second U.S. biosimilar approved for the treatment of cancer is the most recently approved biosimilar: Ogivri (trastuzumab-dkst). Co-developed by Mylan and Biocon, Ogivri is a biosimilar to Genentech’s Herceptin (trastuzumab). Ogivri is the first U.S. biosimilar approved for treatment of breast cancer or stomach cancer. The FDA announced approval of Ogivri on December 1, 2017.[2]

Unlike with Mvasi, no litigation is likely to follow this approval of Ogivri because Mylan, Genentech, and Genentech’s parent (Roche) previously agreed to a global settlement and license agreement related to the Herceptin patents. This arrangement was announced in March 2017 and is mostly confidential, though it did involve Mylan withdrawing inter partes review challenges against two of Genentech’s patents. Also, Mylan’s announcement of the settlement and license agreement[3] stated that the “global license will provide a clear pathway for Mylan to commercialize its trastuzumab product” and that “[i]n addition to eliminating any legal uncertainty over the launch of Mylan’s trastuzumab, the settlement eliminates further patent litigation expenses associated with Genentech and Roche.”

Biosimilar manufacturers have many decisions to make regarding how to proceed under the Biologics Price Competition and Innovation Act (BPCIA) and the “patent dance” it prescribes. As demonstrated by Mvasi though, one option is to avoid the costs, risks, and uncertainties of litigation by negotiating license agreements. Of course, circumstances surrounding such agreements can always change, which Mylan recognized when it qualified the above statements about its own settlement and license agreement as “forward-looking statements” that “inherently involve risks and uncertainties.”

 

[1] https://www.fda.gov/newsevents/newsroom/pressannouncements/ucm576112.htm

[2] https://www.fda.gov/NewsEvents/Newsroom/PressAnnouncements/ucm587378.htm

[3] http://newsroom.mylan.com/2017-03-13-Mylan-Announces-Global-Settlement-and-License-Agreements-with-Genentech-and-Roche-on-Herceptin-R

As we previously reported, Pfizer filed three IPR petitions against Biogen-owned patents claiming methods of treatment with rituximab in April 2017. The three proceedings are: IPR2017-01166, regarding U.S. Patent No. 8,329,172 (“the ’172 patent”); IPR2017-01167, regarding U.S. Patent No. 8,557,244 (“the ’244 patent”); and IPR2017-01168, regarding U.S. Patent No. 8,821,873 (“the ’873 patent”). Institution decisions for all three IPRs have come down within the past three weeks, with institution being denied for the ’172 and ’244 patents, and trial being instituted for the ’873 patent.

In brief review, the three patents cover methods of treating certain types of lymphoma with an anti-CD20 antibody, and all three patents contain at least one claim where that antibody is specifically rituximab. The ’172 patent claims a method for treating low grade B-cell non-Hodgkin’s lymphoma comprising chemotherapy followed by maintenance therapy involving administering four weekly administrations of rituximab at 375 mg/m2 every six months over a period of two years. The ’244 patent claims a method for treating diffuse large cell lymphoma in patients over 60 by administering anti-CD20 antibody (or rituximab specifically) and a specific chemotherapy regimen, CHOP (which is cyclophosphamide, hydroxydaunorubicin/doxorubicin, oncovin/vincristine, and prednisone/prednisolone). The treatment claimed in the ʼ244 patent is specific to a patient who is greater than 60 years old, has bulky disease, and has a tumor greater than 10 cm in diameter. The ’873 patent claims treatment of diffuse large cell lymphoma with a similar CHOP regimen, with the additional requirement that the antibody is administered in combination with a stem cell transplantation regimen.

In IPR2017-01168, trial was instituted as to all challenged claims of the ’873 patent on November 6, 2017. In considering Pfizer’s argument, the Board was persuaded by the combination of the primary reference, which was asserted to teach all elements of the claim except for rituximab, with additional references teaching a combination of a CHOP regimen and rituximab to treat patients with diffuse large cell lymphoma as an improvement to CHOP therapy alone.  Further references in the combination support the overall motivation to combine by noting that older patients have issues with the CHOP regimen, and that the combination of CHOP and rituximab could help that population.  In brief, the PTAB adopted all of Pfizer’s arguments relating to the obviousness of the claims. Notably, Biogen elected not to file a preliminary response. Although there are a number of reasons that a Patent Owner may not choose to file a preliminary response, it is interesting to note that the Rituxan® label does not disclose stem cell transplantation as an indicated treatment for diffuse large cell lymphoma as claimed in the ʼ873 patent.

Next, in IPR2017-01167, the PTAB denied institution as to all challenged claims of the ’244 patent on November 6, 2017. In its preliminary response, Biogen largely attacked the asserted art as not actually disclosing the treatment of patients over 60 with diffuse large cell lymphoma and who have bulky disease, as claimed. For example, Biogen attacked a “Shipp” reference, which was part of both combinations asserted by Pfizer, by noting that Shipp did contain certain claimed elements, such as the treatment of patients 60 or older, but that it did not disclose the histology of lymphoma presented in those patients, such as diffuse large cell or other lymphomas. Biogen also attacked a “Link” reference along similar lines. Biogen further attacked at length the motivation to combine the asserted references, as well as attacking the combination for not having a reasonable expectation of success. The Board ultimately agreed with Biogen, including that the Shipp reference did not adequately describe the patient population and whether the older patients had diffuse large cell lymphoma.  This was the second IPR petition denied institution regarding the ’244 patent, as a Celltrion IPR, the filing of which we previously reported, was denied on October 2, 2017. That denial was similar in many ways, including determining that the Link reference did not disclose the claimed patient population.

Finally, in IPR2017-01166, the PTAB denied institution of all challenged claims of the ’172 patent on November 13, 2017. This was the third petition denied institution for this patent, with this denial joining earlier efforts by Boehringer Ingelheim on December 15, 2014, and another by Celltrion, filed March 15, 2017.

Institution on Boehringer Ingelheim’s petition was denied on October 5, 2015. Denial was based in part on the Board finding that certain references were not actually printed publications as required for IPR proceedings. These references were two clinical study protocols from an oncology research organization. The protocols were argued to have been potentially available to physicians at institutions affiliated with the organization based on general practices and a declaration from a doctor who had worked with similar organizations. However, the Board found that no direct evidence had been presented from anyone with firsthand knowledge of these documents or the actual originating organization as to whether they were distributed or otherwise available. Celltrion’s petition, the filing of which we previously reported, again relied on one of the clinical study protocols at issue in Boehringer Ingelheim’s petition—this time accompanied by the declaration of a doctor who had worked with the research organization and who actually took part in the clinical study as a sub-investigator. However, despite Celltrion’s efforts to show the protocol as a printed publication, the Board denied institution on October 6, 2017, determining that Celltrion had not demonstrated that the protocol or related forms were actually “disseminated or otherwise made available” to interested artisans. The Board noted that times of receipt of the documents or any possible distribution were not disclosed in the doctor’s declaration, that the fact that the documents were not confidential was insufficient to show availability, and that the remaining testimony was largely hypothetical and lacking any evidence to suggest that any of these speculative events actually occurred.

The Board additionally determined that a label for Rituxan® relied upon as prior art by Celltrion was not established as a printed publication. The label had similarly been used by Boehringer Ingelheim, although in that case Biogen had not challenged, and the Board did not discuss, it’s availability as a printed publication. The Board determined Celltrion did not introduce evidence as to its availability, including what date it was alleged to be publically accessible or any evidence that the specific label relied upon was disturbed with the drug itself or otherwise made available to the interested artisan.

As such, when Pfizer filed its IPR petition on April 21, 2017, it may have been aware of Boehringer Ingelheim’s issues regarding proving public accessibility of the study protocols but unaware of the arguments facing the Rituxan® label. Instead of attempting to prove the printed publication status of the study protocol as Celltrion did, Pfizer asserted a new primary reference which had been published, distributed, and shelved in libraries. However, Pfizer also relied upon the Rituxan® label. Perhaps wary due to the outcome of the Boehringer Ingelheim IPR, even though the label had not previously been challenged, Pfizer attempted to cover its bases and assert the availability of the label by showing its origin as a label approved in 1997 on the FDA’s website, by showing the availability of a Rituxan® label on Genentech’s website as of January 1998 according to the Internet Archive, by demonstration of the citation to a Rituxan® label in other publications in 1998, by showing that a label with the same information was contained in a Physician’s Desk Reference® available in December 1998, and by showing that much of the information relied upon in the label was contained in a published paper.

Biogen challenged the status as a printed publication of the specific label relied upon by Pfizer in its preliminary response. Noting that the document presented by Pfizer contained handwriting, Biogen argued that even if the document contained information consistent with the Rituxan® label which may have been distributed, that Pfizer had not demonstrated that the actual document relied upon had ever been distributed.  The Board agreed with Biogen, stating that arguments that the same information was available before the priority date did not support the actual version of the label relied upon (“handwriting and all”) as having been made available to interested artisans.

A relatively rare dissenting opinion was also filed with the Board’s decision, noting that additional evidence establishing the label as a printed publication might be found through trial. The dissent discussed the standard for institution of IPRs as a question of deciding whether the petition supported a reasonable likelihood of proving by a preponderance of the evidence that the petitioner would prevail on a challenged claim by the conclusion of the trial and the close of evidence. Whether Pfizer would be able to establish the status of the label as a printed publication by the close of evidence was thus seen as only a factor in deciding that question. The majority opinion, however, treated whether the label was a printed publication as a threshold issue, and held that as the petition did not sufficiently demonstrate the availability of the document, that institution relying on that document would be improper.

As such, IPR2017-01166 and the other IPRs addressing the ’172 patent are yet further examples, as we recently reported, of the growing body of institution decisions involving the Board’s scrutiny of non-patent literature asserted in IPR grounds. These IPRs highlight not only the importance to petitioners of providing adequate support for the printed publication status of any non-patent references, but also of choosing the best version of a reference for which prior art dates and actual distribution can most clearly be established.

Several of the Federal Circuit’s initial decisions involving the Biologics Price Competition and Innovation Act (the “BPCIA”) focused on unpacking the contours of the statute.  The Federal Circuit’s recently issued opinion in Amgen Inc. v. Apotex Inc., No. 2017-1010, Slip Op. Nov. 13, 2017, by contrast, involves standard principles of appellate review.

We previously described the district court litigation, and the factual background, in detail.  Briefly then, this litigation involves Apotex’s efforts to bring to market biosimilar versions of filgrastim and pegfilgrastim.  The bench trial focused on a single patent, U.S. Patent No. 8,952,138.  Claim 1 of the ’138 Patent, the only independent claim, is as follows:

  1. A method of refolding a protein expressed in a non-mammalian expression system and present in a volume at a concentration of 2.0 g/L or greater comprising:

(a) contacting the protein with a refold buffer comprising a redox component comprising a final thiol-pair ratio having a range of 0.001 to 100 and a redox buffer strength of 2 mM or greater and one or more of:

(i) a denaturant;

(ii) an aggregation suppressor; and

(iii) a protein stabilizer;

to form a refold mixture;

(b) incubating the refold mixture; and

(c) isolating the protein from the refold mixture.

’138 Patent, Claim 1.  Importantly for present purposes, the district court construed the term “refold mixture” to have “high protein concentration[] . . . at or above about 1 g/L.”  Slip Op. at 5.  This construction was not challenged on appeal.

As noted in our initial post, the parties here (unlike some other BPCIA cases) engaged in the “patent dance.”  During that process, Apotex stated that it did not infringe the ’138 Patent because its “concentration of [filgrastim or filgrastim critical intermediate] in the refold buffer” was limited to 0.9–1.4 g/L (i.e., the “inclusion body concentration” listed on the applications).”  Slip Op. at 5-6.  Of course, under the Court’s construction of “refold mixture,” this would be infringing.  But Apotex changed its position at trial.  Specifically, an Apotex fact witness testified “that the maximum concentration of protein in its refold mixture would actually be 0.708 g/L.”  Slip Op. at 6.  The witness testified that Apotex’s letters were incorrect, as the “inclusion bodies” were not pure protein but instead were two-thirds water.  Apotex supported this testimony with “batch records.”  The district court ultimately credited this testimony and concluded that Apotex did not infringe the ’138 Patent.  Amgen challenged this conclusion on appeal.

First, Amgen argued that the district court incorrectly dismissed Apotex’s pre-litigation letters.  Indeed, the district court stated that the letters “are not probative on the issue of protein concentration.”  Slip Op. at 8.  The Federal Circuit stated that while this would be incorrect as an absolute statement, it read the district court as concluding that the letters did not outweigh Apotex’s evidence of non-infringement.  The Federal Circuit found that the district court did not err in crediting Apotex’s evidence and reaching this conclusion.

Second, Amgen offered a claim construction argument of sorts, contending that the “protein concentration” in the patent was interchangeable with the “inclusion body.”  In this way, Amgen sought to equate the inclusion bodies with protein, resulting in infringement.  The Federal Circuit disagreed, finding that the patent’s specification “pervasively disprove[d]” of this theory.

Third and finally, Amgen argued that under Sunovion Pharm., Inc. v. Teva Pharm. USA, Inc., 731 F.3d 1271 (Fed. Cir. 2013), the district court was required to “assess infringement based on the full range of processes that would be consistent with Apotex’s applications.”  Slip Op. at 12.  The Federal Circuit agreed with the legal principle, but found that the district court’s decision was without error in concluding that Apotex’s applications did not authorize infringing processes.  Again, the district court found credible Apotex’s fact testimony, as well as Apotex’s batch records.

While the Federal Circuit’s opinion is in large part an application of straight-forward legal principles, it provides important lessons for future litigation.  First, although a party should always be careful in its written representations (pre-litigation or otherwise), this opinion is useful in demonstrating that a party should not fear that it is unequivocally bound by a factual statement that it later determines to be inaccurate.  Second, this opinion demonstrates the importance of witness credibility—both the district court and the Federal Circuit relied heavily on the testimony of a single company witness.  Finally, the Federal Circuit’s opinion is indicative of the uphill battle of an appeal, particularly where the arguments rest on findings of fact rather than conclusions of law.

  • European Medicines Agency newly approves two adalimumab biosimilars
  • U.S. Food & Drug Administration approves first 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 nine branded biologic drugs were estimated to total $63 billion in 2016[1].  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 35 out of 40 applications have been approved in Europe.  Three of the authorizations have been withdrawn post-approval by the marketing authorization holders (Table 1).

The U.S. did not implement a regulatory framework for biosimilar evaluation until after enactment of the Biologics Price Competition and Innovation (BPCI) Act 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, only six other biosimilar drugs have gained U.S. approval to date (Table 2).  As illustrated in the following graph, the EU’s significant head start led to the existent imbalance in the number of biosimilar drugs available in the respective markets.

Currently, thirteen biosimilar applications are under review by the EMA for marketing authorization (Table 3).  As an increasing number of U.S. patents expire on blockbuster biologic drugs, the number of abbreviated biologics license applications are also increasing.  Biosimilars for at least eleven different original biologics are currently navigating the FDA’s biosimilar pathway or are in late stage development (Table 4).

On September 14, 2017, Amgen and Allergan announced that the FDA approved MvasiTM, a bevacizumab biosimilar to Genentech’s Avastin®.  Amgen and Allergan stated that their bevacizumab biosimilar is also undergoing review by the EMA following a Marketing Authorization Application submitted in December 2016.  The companies indicated that they are collaborating on the development and commercialization of four oncology biosimilars.

Given biosimilar applicant experience in navigating the EMA process and the EMA’s high authorization rate, the FDA will need to continue to provide useful guidance and streamline the approval process in order to reduce the imbalance.

Table 1. European Medicines Agency List of Approved Biosimilar Drugs (updated November 16, 2017).

Table 2. U.S. Food and Drug Administration List of Approved Biosimilar Drugs (CDER list of licensed biologics updated on September 14, 2017).

Table 3. European Medicines Agency List of Biosimilars Under Evaluation for Marketing Approval (Source: EMA list of applications for new human medicines updated on October 30, 2017).

Table 4. Biologics with recent or nearing primary patent expiry in the U.S. that have biosimilars in the regulatory pipeline.

 

[1] Mullard, Asher. “Bracing for the biosimilar wave.” Nature Reviews Drug Discovery 16.3 (2017): 152-154.

On November 6, 2017, Sandoz, Inc. filed its eighth inter partes review (“IPR”) against AbbVie Biotechnology Ltd. (“AbbVie”), challenging yet another patent from the Humira® patent portfolio. Humira®, used for the treatment of autoimmune diseases such as rheumatoid arthritis and Crohn’s disease, continues to be the number one selling drug in the world.[i] With over $16 billion in sales for 2016, pharmaceutical competitors have been targeting the drug, hoping to gain a piece of the market pie by developing biosimilar equivalents.[ii] However, with a shield of over 100 patents covering different aspects of the drug, from formulations and dosages to methods of production, challengers face a long road ahead in dethroning the Humira® giant.[iii]

Sandoz’s most recent IPR filing fits nicely into a pattern of Humira® patent challenges by the corporation, who, since July, has initiated post-grant review proceedings at the PTAB for one to two AbbVie patents each month. A list of the IPRs and the challenged patents is set forth in Table 1 below. Thus far, none of the Sandoz IPRs have progressed much beyond the filing of the petition, although that will change within the week. With the patent owner preliminary responses for both IPR2017-01823 and IPR201-01824 due on November 14, 2017, we will finally gain some insight into how AbbVie plans to defend Humira® against Sandoz and be able to better assess whether Sandoz stands to be a true threat to the drug’s market share.

Table 1. IPRs filed by Sandoz, Inc. against Humira® patents

Sandoz is currently developing and seeking approval for their Humira® biosimilar (adalimumab). Their application to the European Medicines Agency (“EMA”) for regulatory review of the biosimilar was accepted back in May, and is currently still pending.[iv] In September, following conclusion of the Phase III ADACCESS (NCT02016105) study, Sandoz confirmed that the biosimilar adalimumab matches the safety and efficacy profile of reference medicine Humira®.[v]

Other Major Players

Aside from Sandoz, several other pharmaceutical companies vying for a place in the adalimumab market have also challenged the Humira® patents at the PTAB, with varying degrees of success.

Coherus BioSciences, Inc. (“Coherus”) filed ten IPRs against AbbVie from November 2015 through March 2017.[vi] Of those, two were dismissed and five were denied institution. In the remaining three, the Board determined the patents to be unpatentable, although AbbVie has since appealed those decisions to the Federal Circuit. Coherus is also currently developing its own Humira® biosimilar, which has produced positive results in a recent bioequivalents study.[vii]

German pharmaceutical company Boehringer Ingelheim (“Boehringer”) was also successful in challenging the patentability of two of the Humira® patents through two IPRs filed at the end of 2015.[viii] In late July, AbbVie appealed both Board decisions to the Federal Circuit. Boehringer additionally faces a patent infringement suit brought by AbbVie, currently pending in the Eastern District of Delaware. However, Boehringer is ahead of other adalimumab competitors, receiving FDA approval of its Humira® biosimilar “Cyltezo” on August 25, 2017.

Amgen, Inc. (“Amgen”) also has FDA approval for its biosimilar “Amjevita,” granted on September 23, 2016. While Amgen filed two IPRs against the Humira® patent in 2015, the challenges were unsuccessful.[ix] Amgen also recently settled with AbbVie on September 28, 2017, in a patent infringement case initiated by AbbVie in the Eastern District of Delaware.

Samsung Bioepis (Bioepis), a joint venture between Samsung BioLogics and Biogen, is another key player in the market, having received approval for its Humira® biosimilar “Imraldi” in Europe on August 24, 2017. Although Bioepis has not yet challenged any of AbbVie’s U.S. patents, “Imraldi” will surely start to chip away at AbbVie’s record-high sales of Humira®, especially on a global scale, as soon as it is launched.

 

[i] https://www.humira.com/, last accessed on November 7, 2017.

[ii] https://www.pharmacompass.com/radio-compass-blog/top-drugs-by-sales-in-2016-who-sold-the-blockbuster-drugs, last accessed on November 7 2017.

[iii] Id.

[iv] https://www.novartis.com/news/media-releases/sandoz-proposed-biosimilars-adalimumab-and-infliximab-accepted-regulatory-review, last accessed on November 7, 2017.

[v] https://www.sandoz.com/news/media-releases/sandoz-proposed-biosimilar-adalimumab-matches-reference-biologic-terms-efficacy, last accessed on November 7, 2017.

[vi] IPR2016-00172 (filed Nov. 9, 2015); IPR2016-00189 (filed Dec. 7, 2015); IPR2016-00188 (filed Dec. 7, 2015); IPR2016-01018 (filed May 9, 2016); IPR2017-00827 (filed Jan. 31, 2017); IPR2017-00826 (filed Jan. 31, 2017); IPR2017-00822(filed Jan. 31, 2017); IPR2017-00823 (filed Jan. 31, 2017); IPR2017-01008 (filed Mar. 2, 2017); IPR2017-01009 (filed Mar. 2, 2017).

[vii] https://www.coherus.com/our-products/, last accessed on November 7, 2017.

[viii] IPR2016-00408 (filed Dec. 29, 2015); IPR2016-00409 (filed Dec. 29, 2015).

[ix] IPR2015-01514 (filed June 26, 2015); IPR2015-01517 (filed June 26, 2015).

According to a new report by RAND Corporation, biosimilars could save $54 billion in healthcare spending on biologics over the next ten years.[i] The report’s key findings include:

  • The estimated cost savings potential of biosimilars is $54 billion over the next decade, or about 3% of total estimated biologic spending during the same period, with a lower and upper range of $24 to $150 billion.
  • The potential for cost savings will vary across biologic classes based on sales, the degree of competition, and the timing of biosimilar entry into the market.
  • Evolving payment arrangements, regulatory policies and guidance, patient and prescriber acceptance of biosimilars, and other factors will influence the magnitude of potential savings.
  • Stakeholders will accrue savings in the short term, but patients and taxpayers will benefit in the long term.

As stated in the report, only 1-2% of the U.S. population is treated with a specialty drug – a category that includes biologics and other complex drugs – each year.[ii] However, biologics accounted for 38% of the total U.S. prescription drug spending in 2015 and for 70% of drug spending growth from 2010 to 2015. The Biologics Price Competition and Innovation Act (BPCIA), which authorized the FDA to create a new regulatory approval pathway for biosimilars, was designed to introduce competition among biologic manufacturers, and in turn, lead to savings in healthcare spending on biologics.

The developing U.S. biosimilar market could reduce spending on biologics, and the RAND report pointed out important evolving features of the U.S. biosimilar market: uncertainty surrounding intellectual property, interchangeability, and payment rates.[iii]  RAND calculated their estimate of savings by reviewing the sales history of more than 100 biologic drugs, examining other studies that have explored the issue, and examining the experience that Zarxio (filgrastim-sndz), Sandoz’s biosimilar of Amgen’s cancer treatment drug Neupogen (filgrastim), has had on the market.

The BPCIA requires Medicare payment for biosimilars to include a fixed percentage based on the more expensive reference biologic to prevent providers from facing disincentives to prescribe the cheaper biosimilars. As required, Medicare implemented a new payment policy for biosimilars that pays a blended average sales price for all biosimilars that share a common reference biologic, plus a fixed percentage of the more expensive biologic. The report notes that this payment approach could shift over time and that it is not yet known whether private insurers are more aggressively incentivizing biosimilars through payment.[iv]

The report also noted that the potential for cost savings will vary across biologic classes based on sales, the degree of competition, and the timing of biosimilar entry.[v] Anti-tumor necrosis factor (anti-TNF) products, monoclonal antibody antineoplastics, and immunostimulants excluding interferons alone account for 87% of the estimated savings from biosimilars. The actual amount of cost savings depends on several key challenges and sources of uncertainty that the researchers identified in the report: patent litigation’s effect on the timing of future biosimilar launches; payment arrangements for biologics and biosimilars; price competition; switching from one drug (e.g., reference biologic) to a similar drug (e.g., a biosimilar) for a nonclinical reason such that it may impact the safety of the patient, or have other consequences; next-generation biologics that compete with biosimilars and older reference biologics; and future designations of interchangeability.[vi]

The report finally notes that policymakers are presented with two choices regarding the uncertainty in the U.S. biosimilars market:[vii] they can let the market continue to develop under the current policies, or they can intervene and help steer the U.S. biosimilar market more quickly to a more sustainable, competitive state. Although the report did not address whether any policy action is currently needed, the researchers believe the answer will become clearer over the next few years as the biosimilar market continues to develop.[viii]

****

[i] Mulcahy, Andrew W., Jakub P. Hlavka and Spencer R. Case, Biosimilar Cost Savings in the United States: Initial Experience and Future Potential, RAND Corporation (2017), https://www.rand.org/pubs/perspectives/PE264.html.

[ii] Id. at 2.

[iii] Id. at 4.

[iv] Id. at 5.

[v] Id. at 10

[vi] Id. at 13-15.

[vii] Id. at 15

[viii] Id. at 16.

Sandoz announced that its biosimilar application for Neulasta® (pegfilgrastim) has been accepted for regulatory review by the European Medicines Agency (“EMA”).  According to Sandoz, “[t]he comprehensive data package, submitted as part of the Marketing Authorization Application, includes analytical, preclinical and clinical data and strongly demonstrates that the biosimilar pegfilgrastim matches the reference medicine in terms of safety, efficacy and quality.”

Sandoz previously withdrew its application for pegfilgrastim from the EMA.  In its withdrawal letter, Sandoz indicated that it “will not be able to provide the additional information required by the CHMP [Committee for Medicinal Products for Human Use] within the regulatory timeframe for this procedure.”  However, Sandoz also stated that it “intends to resubmit the application as soon as the outstanding information is available.”

The EMA had two main concerns with Sandoz’s prior application.  First, was that “study results were not able to show that the concentrations of pegfilgrastim in blood were the same after taking Zioxtenzo [Sandoz’s proposed biosimilar] and Neulasta.”  Second, the EMA objected to “the lack of a certificate of Good Manufacturing Practice (GMP) for the medicine’s manufacturing site.”   The EMA further noted that at the time of the withdrawal Sandoz had not demonstrated that its proposed biosimilar was highly similar to Neulasta® and an inspection of the manufacturing facility had not yet occurred.

We will continue to keep you updated on further developments.

As previously reported, earlier this year Celltrion, Inc. (“Celltrion”) filed petitions seeking inter partes review (“IPR”) of certain Genentech patents covering Herceptin® (trastuzumab).  In particular, Celltrion challenged the patentability of certain claims of U.S. Patent Nos. 7,846,441 (“the ʼ441 patent”); 7,892,549 (“the ʼ549 patent”); 6,626,196 (“the ʼ196 patent”); 7,371,379 (“the ʼ379 patent”).  Earlier this month, the PTAB issued decisions instituting trial on all four patents.

The ʼ441 patent is the subject of IPR2017-01121.  The claims of the ʼ441 patent are directed to a method of treating cancers linked to the overexpression of the human ErbB2 protein by administering an anti-ErbB2 antibody and a taxoid chemotherapeutic agent in the absence of an anthracycline derivative.  The claims further require that the combination be administered “in an amount effective to extend the time to disease progression in said human patient, without increase in overall severe adverse events.”

In the institution decision, the PTAB interpreted only the term “extend the time to disease progression in said human patient, without increase in overall severe adverse events.”  Relying heavily on “unequivocal” statements made during prosecution, the PTAB determined that the term requires a comparison of the claimed combination therapy to no treatment.  Interestingly, the PTAB’s construction differs from the construction advanced by Celltrion – a construction that Genentech did not challenge.  Celltrion had proposed that the term be construed to require a comparison of the combination of Taxol® and Herceptin® to Taxol® alone.

Applying its adopted construction, the PTAB found that the record contained sufficient evidence that “compared to no treatment, anti-ErbB2 antibodies alone would extend the time to disease progression in patients with breast cancer.”   The PTAB also agreed with Petitioner’s view that “the combination therapy satisfies the limitation of clinical efficacy, because each of trastuzumab and paclitaxel extends time to disease progression relative to no treatment, and an ordinary artisan ‘would not have expected the combination to change this.’”  With respect to the “without increase in overall severe adverse events” portion of the claim, the PTAB again reiterated that the proper comparison is to no treatment, and accepted the testimony of Petitioner’s expert that “a patient with untreated HER2-positive cancer will experience more overall severe adverse events due to the underlying disease itself, compared to severe adverse events experienced due to treatment.”  Finally, the PTAB concluded that it would have been obvious to avoid anthracyclines because they were known to cause irreversible cardiotoxicity, and “many patients would have been previously treated with, and become resistant to, first-line anthracycline chemotherapeutics.”

The PTAB addressed Genentech’s argument that the prior art taught away from combining a taxoid with an anti-ErbB2 antibody, but concluded that “we are not persuaded that prior art as a whole teaches away from combining paclitaxel and an anti-ErbB2 antibody in treating HER2-positive cancers.”  In reaching this conclusion, the PTAB referenced Petitioner-cited references that show “paclitaxel is effective in treating HER2-positive cancers, demonstrates ‘strong synergy’ of paclitaxel and an anti-ErbB2 antibody…and suggests clinical trials of the combination therapy.”  The PTAB also acknowledged evidence of secondary considerations that was submitted by Genentech, but noted that Petitioner had not been given an opportunity to respond to that evidence.  Accordingly, the PTAB concluded that it would not weigh that evidence until the record has been fully developed during trial.

The ʼ549 patent is the subject of IPR2017-01122.  The ʼ549 patent is a continuation of the application that issued as the ʼ441 patent discussed above. The claims of the ʼ549 patent are directed to a method of treating cancers characterized by the overexpression of ErbB2 by administering a combination of an anti-ErbB2 antibody, a taxoid chemotherapeutic agent, and another growth inhibitory agent.  The claims further require that administration be “in an amount effective to extend the time to disease progression in the human patient.”

Much like in IPR2017-01121, and again relying on “applicant’s unequivocal statement” during prosecution, the PTAB interpreted the “…extend the time to disease progression…” term to require a comparison to no treatment.  The PTAB also interpreted the term “effective amount” in independent claim 5 to encompass “an amount effective to extend the time to disease in the human patient.”  The PTAB declined to construe any other proposed terms, although it did adopt the construction of “administering a combination” that was previously advanced by Genentech in the earlier IPR2017-00737, which was filed by Hospira.  Trial was not instituted on the Hospira ʼ549 patent IPR.

Based on these constructions, the PTAB applied the same reasoning regarding clinical efficacy of the claimed combination, and the avoidance of anthracyclines (in claim 16) as in the ʼ441 patent IPR.  Consequently, the PTAB determined that Celltrion had established the required reasonable likelihood that it would prevail in showing the challenged claims are unpatentable.

The ʼ196 patent is the subject of IPR2017-1139, and the ʼ379 patent is the subject of IPR2017-1140.  The ʼ196 patent and the ʼ379 patent originate from the same patent family, which is a different family from the ʼ441 or ʼ549 patents discussed above.

The ʼ196 patent is directed to methods for treating cancer characterized by overexpression of ErbB2 receptors by administering an initial dose of an anti-ErbB2 antibody followed by administration of subsequent doses spaced at least two weeks apart that are equal to or less than the initial dose.  The ʼ379 patent is directed to similar methods, but also requires the administration of an effective amount of a chemotherapeutic agent to the patient.  Notably, the ʼ196 patent and the ʼ379 patent are the subjects of IPR2017-00804 and IPR2017-00805, respectively.  Those IPRs were both filed by Hospira, and the PTAB has instituted trial on both patents.

The institution decisions for the ʼ196 patent and the ʼ379 patent are virtually identical.  In both cases, the PTAB declined to construe any claim terms despite both Celltrion and Genentech proposing constructions for various terms.  Turning to the asserted grounds, the PTAB recognized that the “prior art only explicitly described weekly dosing intervals,” but accepted Celltrion’s contention – supported by expert testimony – that “the skilled artisan would have been motivated to use a three week dosing interval in order to align both the antibody and chemotherapy infusion treatments on the same schedule.”  With respect to the initial dose, the PTAB accepted Celltrion’s calculations that an ordinary skilled artisan “would have administered an 8 mg/kg loading dose…followed by 6 mg/kg maintenance doses…each administered three weeks apart.”  The PTAB found this dosing schedule would have been clinically effective because it would have maintained a target serum concentration above the concentration taught by the prior art to be required for efficacy.

Genentech challenged Celltrion’s reliance on a reference on the basis that it had already been before the Examiner during prosecution.  Under 35 U.S.C. § 325(d), the PTAB can “reject the petition or request because, the same or substantially the same prior art or arguments previously were presented to the Office.”  However, here the PTAB declined to deny institution because it concluded that Celltrion had presented the disputed reference in a “new light” by using an expert declaration to explain its significance.  In particular, the PTAB found “there is no basis to suggest that the Examiner considered the calculations set forth by [Celltrion’s expert] showing that a tri-weekly dosing regimen would have resulted in an acceptable trough serum concentration…”

The PTAB also rejected various other arguments made by Genentech in its Preliminary Patent Owner Response.  For example, Genentech asserted that a skilled artisan would not use the chemotherapy dosing strategy of maintaining dose intensity to adjust antibody dose, and further asserted that the increasing dose amount and lengthening the dosing interval was known to cause higher peak and lower trough concentrations as opposed to smaller doses administered more frequently.  Genentech also asserted that Celltrion had failed to establish a reasonable expectation of success with respect to efficacy due to the non-linear pharmacokinetics of the antibody.  But, in each instance, the PTAB pointed out that Genentech had not submitted expert testimony with its response, and so the PTAB would “decline to give [Celltrion’s] arguments, which are based on expert testimony, less weight in comparison to [Genentech’s] attorney arguments.”

Herceptin® is a monoclonal antibody that interferes with human epidermal growth factor receptor (HER2)/neu.  The produce is indicated for the treatment of patients with metastatic breast cancer whose tumors overexpress the HER2 protein and who have received one or more chemotherapy regimens for their metastatic disease.

We will continue to keep you updated on future developments.