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.

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.