As we previously reported, Celltrion filed three petitions seeking inter partes review (“IPR”) of two patents related to Genentech and Biogen’s Rituxan® (rituximab).  Celltrion filed two petitions seeking review of U.S. Patent No. 7,682,612 (“the ʼ612 patent”) and one petition seeking review of U.S. Patent No. 8,206,711 (“the ʼ711 patent”).  The PTAB has now reached institution decisions on those petitions.

IPR2017-01230 and IPR2017-01227 both concern the ʼ612 patent.  Every Ground asserted in both petitions relied upon either a newsletter from the MD Anderson Cancer Center (“Newsletter”), or the transcript from an FDA public hearing that took place July 25, 1997 (“FDA Transcript”).  But, the PTAB determined that Celltrion failed to establish that either reference was sufficiently available to the public to constitute a printed publication.  Consequently, the PTAB denied institution on all grounds.

In attempting to establish the public availability of the FDA Transcript, Celltrion submitted a letter from the FDA establishing that (1) the FDA Transcript would have been received on August 8, 1997 based on a date stamp on the document, (2) the FDA would have made the document publicly available in a reading room, and (3) access to the document would have required filling out a reading room request form.  However, the PTAB noted that even taking those facts as true, “[p]etitioner has not explained how such persons may have known that this particular transcript existed and was available, upon request, in the [reading room].”  Without such an explanation, the PTAB determined that the FDA Transcript is not a prior art printed publication.

With respect to the Newsletter, the PTAB accepted Celltrion’s evidence that the Newsletter was posted on a website before the actual filing date of the ʼ612 patent, but did not accept Celltrion’s evidence that the Newsletter was sufficiently available to the public.  Celltrion submitted a declaration from a doctor involved in the clinical study discussed in the Newsletter that stated that it “was disseminated to referring physicians, and they were free to share the information with their prospective patients.”  The declaration also noted that physicians involved in the studies were “especially motivated to spread the word about the Newsletter[]” so that more patients could be enrolled in the study. But, the PTAB concluded that the declarant did not provide “any indication that he, or anyone else, in fact accessed or distributed the [Newsletter].” Nor was there any indication that the declarant “did in fact discuss the [Newsletter] relied upon in this proceeding with another physician, or direct anyone to that newsletter.” The PTAB thus concluded that there is not sufficient evidence to show that a person of ordinary skill would have been independently aware of the Newsletter.

Celltrion also attempted to establish that a print version of the Newsletter was publicly available prior to the claimed 1998 priority date and had been disseminated to several thousand physicians in the United States.  However, the PTAB found that the declarant had no firsthand knowledge of this, and based these statements on conversations with another person who had not submitted a declaration supporting the public availability of the Newsletter.  Moreover, the PTAB found that even assuming the Newsletter had been printed and published, there was not testimony showing that “the newsletter was then available to members of the interested public.”

The ʼ711 patent is involved in IPR2017-01229.  All but one of the Grounds asserted against the ʼ711 patent also relied on either the Newsletter or FDA Transcript.  Consequently, the PTAB denied institution on those Grounds for the same reasons as in the ʼ612 patent IPRs.  The remaining Ground relied on a reference published in 2005 coupled with an assertion that certain claims were entitled only to the 2009 actual filing date of the ʼ711 patent.  However, the PTAB concluded that the claims are entitled to either the 1998 provisional application filing date or the 1999 parent application filing date.  For this reason, the PTAB found the 2005 reference was not prior art to the ʼ711 patent, and denied institution on that remaining Ground.

These IPRs are the latest examples of the PTAB denying institution based on a finding that the cited prior art is not publicly available. The PTAB is clearly taking a hard look at any non-patent literature asserted in an IPR petition to ensure that it meets the “public accessibility” standard required to qualify as a prior art printed publication. Although such determinations are made on a case-by-case basis, decisions such as these can provide helpful guidance to a Petitioner seeking to establish the public availability of a cited reference.  Similarly, a Patent Owner would be well advised to take advantage of such decisions to develop potential arguments for challenging the availability of a given reference as prior art.

On August 8, 2017, Sanofi-Aventis (“Sanofi”) filed a patent infringement suit in the United States District Court for the District of New Jersey against Merck Sharp & Dohme (“Merck”) for infringement of U.S Patent Nos. 7,476,652 and 7,713,930. The suit relates to Merck’s insulin glargine vial drug product, a proposed follow-on biologic of Sanofi’s Lantus. Sanofi alleges that by submitting an NDA to the FDA seeking approval for its insulin glargine vial product, Merck committed an act of infringement under 35 U.S.C. §271(e)(2)(A). Recently, on September 14, 2017, Merck filed an Answer asserting several affirmative defenses and seeking a declaratory judgment of noninfringement and invalidity.

In relation to this lawsuit, Merck filed an NDA through the 505(b)(2) application pathway seeking FDA approval for its proposed follow-on biologic, an insulin glargine [rDNA origin] vial product. Merck also similarly filed another NDA on its other proposed follow-on biologic, an insulin glargine [rDNA origin] cartridge product. Unlike most biosimilar products, these applications are covered by the Federal Food Drug and Cosmetic Act (“FDCA”) rather than the Public Health Services Act (“PHSA”).

Currently, biosimilars (or follow-on biologics) are regulated by two different statutes and are therefore reviewed through two different approval pathways. The majority of biosimilar applications are filed as Biologics License Applications (“BLAs”) under the 351(k) pathway. The Biologics Price Competition and Innovation Act (“BPCIA”), enacted in 2010 as part of the Affordable Care Act, amended the PHSA by creating an abbreviated licensure pathway for products that are shown to be biosimilar to or interchangeable with an FDA-approved biological reference product. Section 351(k) of the PHSA requires that the application contain information showing that the biological product is biosimilar to the reference product. Section 351(i) defines “biosimilar” to mean “(a) that the biological product is highly similar to the reference product notwithstanding minor differences in clinically inactive components; and (b) there are no clinically meaningful differences between the biological product and the reference product in terms of the safety, purity, and potency of the product.” See 42 U.S.C. § 262(i).

By contrast to the 351(k) pathway, some biosimilar applications are filed under section 505(b)(2) of the FDCA. In its enactment, the BPCIA provided a transition provision where applications for biological products may be submitted under section 505(b)(2) until March 23, 2020, if the biological product is in a product class for which a biological product in said product class was approved under section 505 of the FDCA by March 23, 2010. The FDA has interpreted “product class” to mean “both products are homologous to the same gene-coded sequence (e.g., the INS gene for insulin and insulin glargine) with allowance for additional novel flanking sequences (including sequences from other genes). Products with discrete changes in gene-coded sequence or discrete changes in post-translational modifications may be in the same product class as the previously approved product even if the result may be a change in product pharmacokinetics.” See US Food and Drug Administration. Biosimilars: Questions and Answers Regarding Implementation of the Biologics Price Competition and Innovation Act of 2009 Guidance for the Industry, April 2015. For naturally derived protein products, a biological product is in the same product class if both products share a primary biological activity. See id.

There are a variety of differences between the two regulatory pathways with respect to the criteria necessary for approval. For a 351(k) application, an applicant must submit information demonstrating that the biological product: (1) is biosimilar to the reference product, (2) that it uses the same mechanism of action for the proposed condition of use, (3) conditions of use proposed have already been approved for the reference product, (4) requires the same dosage form, route of administration, and strength as the reference product, and (5) is processed, manufactured, and packaged in a location that meets the standard required to guarantee that the product is safe. Additionally, to demonstrate “biosimilarity,” the applicant must submit data taken from animal studies, analytical studies, and clinical studies.

By contrast, for a 505(b)(2) application, an applicant submits investigations of safety and effectiveness but at least one or more of the investigations relied upon were not conducted by the applicant and instead are either published literature or the FDA’s previous finding of safety or effectiveness for a listed drug. If the 505(b)(2) application relies on a listed drug, the applicant must submit adequate information to show that the proposed biological product is sufficiently similar to the listed drug. However, in a 505(b)(2) application, the biological product can differ from the reference product in its dosage form, strength, route of administration, or active ingredient (but still must have the same active moiety). An applicant must support any differences with adequate information to prove the safety and efficacy of the proposed product.

The two pathways also differ considerably with respect to patent submissions. In the 505(b)(2) pathway, like generic drug applicants, an applicant for a biological product will submit Paragraph IV patent certifications to the listed drug and final approval may be subject to a 30-month stay if an action for infringement is brought within 45 days of receipt of the Notice of Certification. In the 351(k) pathway, applicants will engage in the statutory “Patent Dance” wherein the applicant and reference product sponsor will privately discuss the potential patents at issue to arrive at a list of the patents to be litigated.

The 505(b)(2) is notably a more familiar and predictable pathway than 351(k). However, § 7002(e)(4) of the Affordable Care Act provided a provision such that as of March 23, 2020, every biological product approved under the 505(b)(2) pathway will be deemed to be a license for the biological product under 351(k). In March 2016, the FDA issued a draft guidance on its interpretation of this provision, stating that it interprets the provision to mean that as of March 23, 2020, approved section 505[1] applications for biological products will no longer exist as NDAs and will be replaced by approved BLAs[2]. The FDA also interpreted the provision to apply only to approved 505(b)(2) applications and stated that the FDA will not approve any pending or tentatively approved applications on March 23, 2020, even though the provision allows 505(b)(2) application submissions up to March 23, 2020. Thus, according to the FDA, any 505(b)(2) applications that are pending on March 23, 2020, will not be approved.

Therefore, although the 505(b)(2) pathway provides an approval pathway for biosimilars for the next two and a half years, the FDA’s interpretation suggests that applicants may want to consider other options if they don’t anticipate receiving final approval before March 23, 2020. In Merck’s case, its NDA appears to be subject to the 30-month stay pending the outcome of the litigation. Under the Hatch-Waxman Act, if a patentee files suit under 35 U.S.C. §271(e)(2)(A) for patent infringement within 45 days of receipt of the Notice of Certification, final approval of a product may only be granted “upon expiration of a 30-month period beginning date of the receipt of the notice provided under paragraph (2)(B)(i) or such shorter or longer period as the court may order because either party to the action failed to reasonably cooperate in expediting the action.” See 21 U.S.C. § 355(j)(5)(b)(iii). Presumably following the 30-month stay, the timing of a potential final approval of Merck’s second follow-on biologic should be within the March 23, 2020 date, and thus, Merck’s NDA will likely be transitioned to a BLA. Even though any 30-month stay in Merck’s case would expire a few months prior to the March 23, 2020 date, it demonstrates how the 30-month stay could cause an applicant to be in danger of not obtaining final approval in time.

In light of the FDA’s draft guidance and its interpretation of the statute, in the years remaining until the March 23, 2020, we may see a decline in the number of applicants choosing the 505(b)(2) pathway.

We will continue to keep you informed as this litigation develops and as the FDA continues to issue guidance on the subject.

[1] This includes section 505(b)(2) applications as discussed but also includes “stand-alone” NDAs filed under section 505(b)(1).

[2] Section 505 applications will be replaced by BLAs under sections 351(a) or 351(k). Section 351(a) is the traditional approval pathway for innovator biologics.

Samsung Bioepis (“Bioepis”) has joined a growing list of challengers to Genentech’s U.S. Patent No. 6,407,213 (“the ʼ213 patent”) issued to Carter, et al. by filing two new petitions for inter partes review (“IPR”).  The ʼ213 patent, entitled “Method for Making Humanized Antibodies,” is generally directed to antibodies with humanized variable domains comprising non-human complementarity determining region sequences for antigen binding and specified substitutions within the framework regions.  The company has previously stated that the ‘213 patent covers technology used in the development of Herceptin® (trastuzumab).

On September 29, 2017, Bioepis filed IPR2017-02139 and IPR2017-02140 challenging Genentech’s ʼ213 patent.  In the petitions, Bioepis is listed as the real party-in-interest.   Bioepis asserts that a skilled artisan would understand that none of the claims are directed to a specific antibody, including claim 30 of theʼ213 patent, which recites “an antibody which binds p185HER2”.  Bioepis challenges the patent on the basis that “humanization” and “reshaping” of antibodies was known in the prior art.  Bioepis filed concurrent motions for joinder of its petitions with pending petitions filed by Pfizer (reported here), contending that the petitions are practical copies of those filed by Pfizer.

As noted in the above table, previous challenges to the ʼ213 patent have come from Mylan, Celltrion, Pfizer, and Boehringer Ingleheim.  An early challenge to the ʼ213 patent from two petitions filed by Mylan was dropped (previously reported here) following a settlement agreement that was brokered between Roche and Genentech to provide Mylan with global licenses for trastuzumab.  However, the petitions filed by Celltrion (IPR2017-01373 and IPR2017-01374), Boehringer Ingelheim (IPR2017-02032 and IPR2017-02031), and Pfizer (IPR2017-01488 and IPR2017-01489) are awaiting an institutional decision by the PTAB.

We will provide updates as decisions come to light.

Last week, Pfizer, Inc. (“Pfizer”) filed two petitions for inter partes review (“IPR”) of two patents related to Genentech and Biogen’s Rituxan® (rituximab).  One petition challenges all but two claims of U.S. Patent No. 7,682,612 (“the ʼ612 patent”), and has been assigned IPR2017-02126.  The other petition seeks review of all nine claims of U.S. Patent No. 8,206,711 (“the ʼ711 patent”), and has been assigned IPR2017-02127.

The challenged claims of the ’612 patent include methods of treating chronic lymphocytic leukemia (“CLL”) by administering an anti-CD20 antibody to the patient in an amount effective to treat CLL, wherein the method does not include treatment with a radiolabeled anti-CD20 antibody (referred to as “single agent” claims).  In addition, Pfizer has challenged claims directed to methods of treating CLL by administering an anti-CD20 antibody in combination with chemotherapy (referred to as “combination” claims).  The two claims of the ʼ612 patent that are not being challenged require the anti-CD20 antibody to be a “human antibody.”

With respect to the “single agent” claims, Pfizer asserts that a joint press release from Genentech and IDEC (who subsequently merged with Biogen) issued before the priority date of the ʼ612 patent “disclosed that they were ‘planning’ clinical trials with rituximab to treat patients with ‘chronic lymphocytic leukemia’ based on ‘encouraging results’ using the drug for another cancer, low-grade non-Hodgkin’s lymphomas (‘NHL’).”  Pfizer argues it would be reasonably expected for “rituximab to treat CLL patients effectively” because it “had already been shown that rituximab can effectively treat NHL by targeting and destroying [cancerous B-] cells” that express the CD20 antigen.

Pfizer asserts the “combination” claims are also obvious because the prior art “taught that rituximab made cancerous B-cells more vulnerable to the effects of chemotherapy…”  Indeed, Pfizer argues that the prior art “expressly suggested using rituximab in ‘combination with or after standard chemotherapy.’”

The challenged claims of the ’711 patent are directed to methods of treating CLL by administering rituximab to a patient in an amount effective to treat CLL where the dosage is at 500 mg/m2.  The ʼ711 patent also contains a claim directed to administering an effective amount of rituximab to a patient at a dosage of 500 mg/m2 in combination with another chemotherapeutic agent comprising fludarabine and cyclophosphamide. Pfizer has challenged all of the ʼ711 patent claims.

For the ʼ711 patent claims, Pfizer again asserts that the Genentech/IDEC press release would have provided a reasonable expectation that rituximab could be effectively used to treat CLL patients.  Pfizer also argues the claimed dose was obvious because that dosage was within the range disclosed in prior art as effective to achieve a “rapid, and specific depletion of the B cells in all [NHL] patients.” Pfizer’s alternative reasoning is that the prior art taught that “B-cell depletion was ‘dose-dependent’ (meaning the greater the dose, the greater the depletion), and a 375 mg/m2 weekly dose was preferred for NHL patients.”  However, Pfizer contends that a person of ordinary skill would have known that a dose higher than 375 mg/m2 “would likely be necessary to treat CLL because…CLL patients have many more (on average, a 100 times more) cancerous B-cells than NHL patients.” Finally, Pfizer asserts the prior art taught that cyclophosphamide and fludarabine “effectively treated CLL patients, resulting in at least partial clinical responses in most patients.”

These two petitions are the latest that Pfizer has filed seeking review of patents related to Biogen and Genentech’s Rituxan® product.  As we previously reported here and here, Pfizer has filed four other petitions seeking review of certain patents.  Pfizer’s petition seeking review of U.S. Patent No. 7,820,161 was instituted and joined with Celltrion, Inc.’s (“Celltrion”) petition seeking review of the same patent.  The PTAB has not yet reached institution decisions in Pfizer’s other three petitions.

As we previously reported, Celltrion has also challenged the ʼ612 and ʼ711 patents.  The PTAB has not yet reached an institution decision on those petitions, but is expected to do so within the next few weeks.  Pfizer asserts that the grounds for institution advanced in its petitions “are different from the grounds asserted by petition Celltrion,” and “also includes prior art…not relied upon by the petitioner Celltrion.”

Rituximab is an anti-CD20 chimeric murine/human monoclonal antibody approved for the treatment of non-Hodgkin’s lymphoma, chronic lyphocytic leukemia, rheumatoid arthritis, granulomatosis with polyangitis, and microscopic polyangitis.

We will keep you updated on future developments.

On September 28, 2017, AbbVie and Amgen announced a global settlement of their patent dispute surrounding Amgen’s proposed biosimilar to HUMIRA.  The terms of the agreement remain confidential between the parties, but according to the announcement, AbbVie will grant Amgen a non-exclusive license for the use and sale of Amgen’s biosimilar (AMGEVITA) to HUMIRA.  Amgen will pay royalties under the terms of the agreement, and also acknowledged the validity of AbbVie’s patents related to HUMIRA.

Amgen stated that it expects to launch in Europe on October 16, 2018, and in the United States on January 31, 2023. As previously reported, the European Commission approved AMGEVITA for all available indications on March 23, 2017.  The FDA previously approved AMGEVITA in the United States on September 23, 2016.

On October 3, 2017, Pfizer, Inc. (“Pfizer”) filed a petition for inter partes review (“IPR”) against U.S. Patent No. 7,846,441 (“the ʼ441 patent”), assigned to Genentech, Inc. (“Genentech”), entitled “Treatment with anti-ErbB2 antibodies.”  The ʼ441 patent is related to Genentech’s Herceptin® (trastuzumab) product.  Last November, Pfizer announced positive results in a pivotal safety and efficacy study comparing Herceptin® to Pfizer’s potential biosimilar to Herceptin®.  Pfizer has not yet announced the filing of an application for its potential biosimilar to the FDA.

As we previously reported, two other IPR petitions have been previously filed against the ʼ441 patent.  IPR2017-00731 was filed by Hospira Inc., a Pfizer subsidiary, and institution was denied on July 27, 2017.  IPR2017-01121 was filed by Celltrion, Inc. on March 21, 2017, and an institution decision has not yet been entered.  However, Pfizer moved to join the Celltrion IPR on September 7, 2017, by filing a petition challenging the same claims on the same grounds.  That proceeding is IPR2017-02063.

In its newly-filed IPR, Pfizer asserts that the combination claimed in the ʼ441 patent was disclosed in an article in the LA Times more than one year before the priority date of the ʼ441 patent.  According to Pfizer, the article “A Lottery of Life, Death – and Hope” disclosed that “HER2-overexpressing breast cancer patients were being treated with the same combination therapy” claimed in the ʼ441 patent.  Pfizer claims that the LA Times article was newly discovered and was not identified by the examiner during prosecution.

Pfizer’s petition also includes a second ground adding a reference to a combination previously advanced in IPR2017-00731.  According to Pfizer, it reasonably believed that the limitation “in the absence of an anthracycline derivative” was sufficiently disclosed in the two references combined in its prior petition based on statements made by the patent owner and the examiner during prosecution. Thus, Pfizer asserts that it “could not have anticipated” Genentech seeking a construction of that term that would require “‘avoidance’ of anthracyclines, rather than simply their ‘absence’ in a treatment regimen.”  Pfizer claims it was “this unanticipated shift that led the Board” to deny institution. Pfizer argues the new reference supplies this limitation because it excluded patients from a clinical trial if they were previously treated with anthracycline.

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.

The newly-filed proceeding is IPR2018-00016. Pfizer is identified as the only real party-in-interest.

We will continue to keep you updated on future developments.

  • European Medicines Agency newly approves five rituximab biosimilars and an etanercept biosimilar, while recommending approval of adalimumab biosimilar
  • U.S. Food & Drug Administration approves second 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 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 $44 billion over the next decade.

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 34 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 five 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 nine different original biologics are currently navigating the FDA’s biosimilar pathway or are in late stage development (Table 4).

On August 29, 2017, Boehringer Ingelheim announced (here) that the FDA approved its CyltezoTM biosimilar to AbbVie’s Humira®.  Boehringer Ingelheim indicated that its adalimumab biosimilar is a pre-filled syringe for the treatment of multiple chronic inflammatory diseases.  The CyltezoTM approval marks the second adalimumab biosimilar to clear the FDA’s regulatory review following Amgen’s Amjevita® approved in September 2016, although no adalimumab biosimilars are commercially available yet in the United States.

Despite the recent FDA approval of CyltezoTM, the European market extended its large lead in biosimilar drug approvals during the summer of 2017.  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 September 6, 2017).

Table 2. U.S. Food and Drug Administration List of Approved Biosimilar Drugs (CDER list of licensed biologics updated on September 1, 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 September 5, 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.

 

 

 

Biologic drugs are quickly reshaping the pharmaceutical landscape as they dominate the drug market in annual sales revenue.  Abbvie’s Humira® (adalimumab) rocketed to the best-selling drug in the world with sales generating over $16 billion USD in 2016. The top biologic drugs are all driving revenues well beyond the $1 billion sales revenue demarcation that traditionally defines a blockbuster drug.  The staggering revenue generated by the latest generation of drugs has launched major efforts by companies over the last 10 years to quickly develop biosimilar versions of these drugs to carve out their own market share.

Recent market analysis indicates that there could be a tidal shift in the biologic drug market in the years to come. Evaluate Pharma’s 2017 World Preview reports that the entry of biosimilars into the global markets is expected to erode the total sales of biologic drugs by as much as 54% through 2022.  According to the report, biologic sales may stand to lose up to $194 billion USD as patents on the top biologic drugs set to expire.  In particular, patents covering infliximab, bevacizumab, trastuzumab, and rituximab will be expiring in the next couple of years.  The table below lists the top grossing biologic drugs in 2016 compared to the projected sales in 2022.  Despite the market changes, biologics are expected to contribute 52% of the top 100 product sales by 2022.

Netscribes – a global marketing intelligence and content management firm – recently released its own analysis of the world-wide biosimilar market.  Netscribes reports the biosimilar global market value is expected to reach $36 billion USD by the year 2022.

The biggest impact on global biologic sales will likely come from the European block.  Europe has already vastly outpaced the rest of the world in biosimilar approvals.  In fact, the EU has given marketing authorization to 28 biosimilar drugs, compared to a mere five biosimilar drugs receiving approval in the U.S.  Given the substantial lead in the biosimilar field, Europe stands to dominate the global biosimilar landscape for years to come.

The European Commission recently released a report analyzing data from the year 2016 over six established therapy areas with biosimilar competition, including epoietin, G-CSF, hGH, anti-TNF, fertility/gonadotropin drugs, and recombinant human insulins.  The report provided several interesting details into the effects from biosimilar market entry.

  • Biosimilar entry consistently reduced drug pricing over the whole product class, not just for the challenged reference product
  • The first biosimilar entering the market grabs the largest market share
  • The correlation between biosimilar market share and market price reduction is weak
  • Biosimilar entry significantly increased product consumption
  • Lowering the price of certain biologics (anti-TNF and hGH) reduced market penetration of the biosimilar competitor

The analysis by the European Commission provides a useful glimpse into the changes that are soon expected to take shape more broadly across the globe.  Biosimilars will significantly impact the sales revenue across many therapeutic areas, even if the initial market penetration is weak.  However, the overall impact on the major pharmaceutical companies manufacturing the originator products is less clear as the report indicates certain variables could potentially mitigate lost revenue.  In particular, price reduction of the originator product appears to slow market penetration of the biosimilar.  In addition, entry of the biosimilar appears to increase product consumption overall.

Biosimilar drugs will undoubtedly reshape the global pharmaceutical market as they grab market share in the years to come.  The speed with which this happens will depend on how the biosimilar manufacturers choose to use their capital to position themselves in the global market.  Given the enormous revenue generated by biologic drugs, even shaving a few years off market exclusivity by attacking pharmaceutical patents could render a major win for the generic company, particularly as the report from the European Commission shows that early entry into the market has major advantages.

Recently, AbbVie, Inc. and AbbVie Biotechnology, LTD (collectively “AbbVie” or “Plaintiffs”) filed a Complaint in the United States District Court for the District of Delaware against Boehringer Ingelheim International GMBH, Boehringer Ingelheim Pharmaceuticals, Inc., and Boehringer Ingelheim Fremont, Inc. (collectively “Boehringer Ingelheim” or “Defendant”) related to Boehringer Ingelheim’s adalimumab product, a proposed biosimilar to AbbVie’s Humira®.  The Complaint, filed on August 2, 2017, alleges that Boehringer Ingelheim’s filing of a biologics license application (“BLA”) for adalimumab under the abbreviated section (k) pathway of the BPCIA constitutes an artificial action of statutory patent infringement pursuant to 35 U.S.C. §271(e)(2)(C).

Boehringer Ingelheim announced in January of this year that the FDA had accepted for review its abbreviated biologics license application for BI 695501, a proposed adalimumab biosimilar.  The FDA’s BSUFA date (target goal) for Boehringer’s adalimumab application is estimated to be in September 2017.  Adalimumab is a TNF (tumor necrosis factor) inhibitor that binds to TNF-alpha (TNF-α), preventing it from activating TNF receptors, which cause the inflammatory reactions associated with autoimmune diseases. Humira® is indicated for the treatment of rheumatoid arthritis, juvenile idiopathic arthritis, psoriatic arthritis, ankylosing spondylitis, Crohn’s disease, psoriasis, and ulcerative colitis.

AbbVie alleges in the Complaint that “Boehringer seeks to copy AbbVie’s work and ignore AbbVie’s patents.” According to the Complaint, AbbVie has identified 74 patents related to Humira, which “AbbVie has identified as infringed” by Defendants.  However, the current complaint asserts infringement of only eight patents, including: U.S. Patent No. 8,926,975; U.S. Patent No. 9,018,361; U.S. Patent No. 9,090,867; U.S. Patent No. 9,096,666; U.S. Patent No. 9,255,143; U.S. Patent No. 9,266,949; U.S. Patent No. 9,272,041; and U.S. Patent No. 9,546,212.

According to AbbVie, after the parties exchanged patent lists in accordance with the BPCIA’s patent dance, “Boehringer selected the number of patents … each side could litigate in this first wave.” See Complaint.  Boehringer selected five patents per side, and “the eight patents-in-suit constitute the compilation of the two lists” after accounting for the fact that two patents appeared on both side’s subsequent list.  Id.  AbbVie further notes that it “will have the opportunity to assert the remainder of the patents” later in the case “if and when Boehringer provides its 180-day Notice of Commercial Marketing, and as circumstances otherwise warrant.”  Id.

The new Boehringer Ingelheim litigation is Civ. No. 17-cv-00165, and the case has not yet been assigned to a specific judge.  According to the court’s docket system, Defendants currently have until August 23, 2017, to file an Answer or otherwise respond to the Complaint.

This is not the only litigation involving adalimumab.  AbbVie previously filed an infringement suit against Amgen in Delaware related to its proposed biosimilar adalimumab therapeutic.  Other manufacturers have also filed IPRs on patents related to Humira® (adalimumab), as reported here and here.

Amgen and Allergan recently announced that they submitted a Biologics License Application (“BLA”) for ABP 980, a proposed biosimilar to Genentech’s Herceptin® (trastuzumab), to the Food and Drug Administration (“FDA”).  According to the press release, Amgen and Allegan have “formed a collaboration to develop and commercialize, on a worldwide basis, four oncology antibody biosimilar medicines.”

Celltrion and Teva also announced last week that the FDA has accepted their BLA for CT-P6, a proposed trastuzumab biosimilar, for review.  According to the announcement, the companies expect regulatory action on the CT-P6 application during the first half of 2018.

Trastuzumab is a monoclonal antibody that interferes with the human epidermal growth factor receptor (HER2)/neu. Herceptin® 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.

Several other companies, including at least Pfizer (Hospira), Mylan, and Biocon are also developing biosimilars of trastuzumab, as discussed in this prior post.  A complete list of IPRs related to trastuzumab and other proposed biosimilars can be found in RFEM’s IPR Dashboard.