On November 5, 2018, twenty-nine organizations representing various groups including insurance companies, patient and consumer advocacy groups, unions, and retirees, submitted a letter to U.S. Trade Representative Robert Lighthizer to raise serious concerns that the recently renegotiated version of the North American Free Trade Agreement (NAFTA) – now proposed to be called the U.S.-Mexico-Canada Free Trade Agreement (USMCA) – will exacerbate the problem of high prescription drug prices in the United States.

Intellectual Property Rights provisions are set forth in Chapter 20 of the USMCA.   Article 20.F.14 provides that, “[w]ith regard to protecting new biologics, a Party shall, with respect to the first marketing approval in a Party of a new pharmaceutical product that is or contains a biologic, provide effective market protection through the implementation of Article 20.F.13.1 (Protection of Undisclosed Test or Other Data) and Article 20.F.13.3 (Protection of Undisclosed Test or Other Data), mutatis mutandis [once the necessary changes have been made], for a period of at least ten years from the date of first marketing approval of the product in that Party.”

The groups argue that the provisions proposed in the USMCA will keep drug prices high in the United States, will prevent Congress from being able to take action to lower drug prices, and that several provisions within the agreement are inconsistent with U.S. law.  Despite the groups’ focus on U.S. laws and prices, one specific gripe is with the USMCA’s requirement that Canada and Mexico extend their biologic data exclusivity provisions.  However, in the United States, the Biologics Price Competition and Innovation Act (“BPCIA”) already provides for 12 years of data exclusivity for new biologics, exceeding the minimum 10 years under the USMCA.  In Mexico and Canada, however, new biologics receive just five and eight years of data exclusivity, respectively.  Thus, the USMCA does not purport to extend biologics monopolies in the United States at all.  Rather, the groups argue that the USMCA will tie Congress’ hands in case Congress decides in the future to reduce the biologics data exclusivity from 12 years to less than the 10 years required by the USMCA.

Further, the groups argue that “[w]hile the proposed USMCA text includes numerous monopoly protections and deterrents to competition — extended biologics exclusivity, broad exclusivities for drugs, patent term extensions and patent term adjustments, to name a few — the agreement lacks critical features of U.S. law that encourage generic and biosimilar competition.”

The groups urge that the imbalance be addressed through: a more robust regulatory review provision (“Bolar”); an appropriate incentive to encourage market entry by generic and biosimilar applicants; requirements for transparency around patents and exclusivities; and, a “best mode” requirement.

Further, the groups urge that Congress ensure that the USMCA is consistent with the terms used in U.S. law, particularly the Drug Price Competition and Patent Term Restoration Act (known as the Hatch-Waxman Act) and the BPCIA.  The groups seek changes to the USMCA to “foster a free, fair, and balanced trade agreement with Mexico and Canada that ensures an adequate balance between access to affordable medicines and support for pharmaceutical innovation.”

These groups join the Canadian Generic Pharmaceutical Association (CGPA), who released a statement that the “pharmaceutical provisions in USMCA will delay access to competition from biosimilar biologic drugs in Canada, extending the period of market exclusivity for these products to 10 years from the current period of 8 years. Biologic medicines represent the fastest growing cost segment of health-care spending, and these delays will be costly to patients, businesses that sponsor employee drug plans, private payers and our industry.”

The USMCA is still subject to a majority vote in both the Senate and House of Representatives, and Senate Majority Leader Mitch McConnell, R-Ky., stated on October 16, 2018, that the Senate was not going to be able to vote on the USMCA until 2019.

The August 2018 Update to the PTAB Trial Practice Guide added guidance regarding the Patent Trial and Appeal Board’s (“the Board”) discretion under 35 U.S.C. § 325(d) to deny institution of an AIA trial when the same or substantially the same prior art or arguments were previously presented to the United States Patent and Trademark Office.  This statutory provision allows the Board to balance the petitioner’s desire to be heard against the interest of the patent owner in avoiding duplicative challenges to its patent.  The Board recently exercised its § 325(d) discretion in denying institution of IPR2018-00919 (Paper 13).

IPR2018-00919 was initiated by petitioner Merial, Inc., an animal health company headquartered in Duluth, Georgia.  As of 2017, Merial is a wholly owned subsidiary of Boehringer Ingelheim GmbH.  Merial filed its petition on April 13, 2018, challenging patent owner Intervet International B.V.’s U.S. Patent No. 8,008,001 (“the ’001 patent”).

The ’001 patent, issued on August 30, 2011, relates to a method for protecting piglets against porcine circovirus type 2 (“PCV-2”), which is linked to multiple diseases, poor growth rate, failure to thrive, and wasting.  According to the patent, conventional vaccines based on inactivated whole PCV-2 virus were inadequate because PCV-2 does not replicate to high titers in cell culture.  Moreover, the presence of maternally derived antibodies (“MDAs”) was known to interfere with vaccination, and although alternative vaccines based on recombinant antigens derived from PCV-2 were known, testing for those vaccines was conducted on specific pathogen-free pigs that did not have MDAs.  Intervet argued that the ’001 patent solved these problems by providing a method for protecting piglets against PCV-2 even in the presence of MDAs—specifically, the ’001 patent claims a method of protecting MDA positive piglets against PCV-2  infection by administering a vaccine comprising at least 20 micrograms/dose of recombinant open reading frame-2 (“ORF-2”) protein of PCV-2.

Merial relied on references Jestin, Blanchard, and Meng, either alone or in combination, as rendering obvious claims 1-6 of the ’001 patent, and Merial further relied on references Pinelli-Saavedra and Rijke for the additional limitations of claims 7 and 8.  Intervet filed a Patent Owner Preliminary Response, arguing first that Merial’s petition should be denied under § 325(d) because Merial “failed to raise a single argument that ha[d] not been considered and overcome during prosecution,” and arguing second that the petition should otherwise be denied on the merits.

Following Intervet’s Preliminary Response, Merial requested authorization from the Board to file a Reply to address Intervet’s arguments regarding § 325(d).  The Board denied Merial’s request, however, finding that no good cause existed because Intervet’s arguments regarding § 325(d) were reasonably foreseeable and yet Merial chose not to address the issue in the petition.

The Board exercised its discretion under § 325(d) to deny institution without ever reaching the merits of Merial’s obviousness arguments.  In accordance with the Trial Practice Guide August 2018 Update, the Board evaluated whether to exercise its discretion under § 325(d) by weighing the non-exclusive factors set forth in Becton, Dickinson & Co. v. B. Braun Melsungen AG, IPR2017-01586, slip op. at 17-18 (Paper 8) (PTAB Dec. 15, 2017) (informative):

i) The similarities and material differences between the asserted art and the prior art involved during examination;

ii) The cumulative nature of the asserted art and the prior art evaluated during examination;

iii) The extent to which the asserted art was evaluated during examination, including whether the prior art was the basis for rejection;

iv) The extent of the overlap between the arguments made during examination and the manner in which Petitioner relies on the prior art or Patent Owner distinguishes the prior art;

v) Whether Petitioner has pointed out sufficiently how the Examiner erred in its evaluation of the asserted prior art;

vi) The extent to which additional evidence and facts presented in the petition warrant reconsideration of the prior art or arguments.

The Board found that many of the same prior art references asserted by Merial were considered by the Examiner during prosecution of the ’001 patent, as Merial’s base references (Jestin, Blanchard, and Meng) are three of only ten references cited on the face of the patent.  Also, claims were rejected based on Jestin during prosecution of the ’001 patent, and claims were rejected based on Blanchard during prosecution of a parent application to the ’001 patent.  Moreover, the Board determined that Meng was cumulative because Merial did not explain how Meng differed from Jestin or Blanchard but rather relied on similar disclosures from Meng, Jestin, and Blanchard.

The Board then found that during prosecution the Examiner substantively evaluated Jestin, Blanchard, and a cumulative reference Van Woensel and used these references as the bases for rejections that the Applicants overcame.  Additionally, the Board found “no substantive difference between the Examiner’s findings during prosecution and [Merial’s] arguments.”  For example, just as the Examiner had argued that piglets utilized in Jestin’s studies inherently carried MDAs, Merial also argued that the limitation requiring MDA positive piglets is inherent in the disclosures of Jestin, Blanchard, or Meng.  The Board agreed with Intervet that “the Petition does not present new arguments.”

Importantly, Merial did not discuss § 325(d) in its Petition. Merial also did not discuss the prosecution history of the ’001 patent and thus failed to point out whether or how the Examiner erred in evaluating the prior art.  Merial did offer expert testimony that was not considered during prosecution.  However, given the substantial overlap of prior art and arguments between the Merial’s petition and the prosecution of the ’001 patent, this expert testimony was not a sufficient reason for the Board to reconsider those assertions.

Ultimately, the Board found that the Becton Dickinson factors weighed in favor of denying institution.  Decisions such as this are good news for patent owners, who wish to avoid the cost of challenges based on recurring prior art and arguments.  This decision also provides lessons to would-be petitioners who wish to assert at least some prior art or argument that was previously presented to the Patent Office.  For example, to avoid a discretionary denial of institution under § 325(d), consider asserting at least some new and non-cumulative art and pointing out how the Examiner erred in evaluating any previously presented prior art.  Also, be advised to address the issue in the petition rather than betting on a Reply to the Patent Owner Preliminary Response.

  • European Medicines Agency approves first two pegfilgrastim biosimilars and another adalimumab biosimilar
  • Pfizer launches NivestymTM, a filgrastim biosimilar, in the United States
  • Only five of twelve approved biosimilars have launched in the United States

As pharmaceutical drug costs attract increasing media attention and political scrutiny, a growing number of biosimilar drugs are set to enter the U.S. and European markets in the coming years.  Global sales for the top ten branded biologic drugs totaled approximately $71 billion in 2017[1].  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 48 out of 53 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 Act (BPCIA) of 2009.  Given that the first U.S. biosimilar drug was approved almost a decade after the first in Europe, the number of authorized biosimilar drugs in Europe far exceeds the number of biosimilars approved in the United States.  Sandoz’s filgrastim biosimilar Zarxio® received the first U.S. approval in 2015, whereas nine filgrastim biosimilars have been approved in Europe dating back to multiple authorizations in 2008.  Zarxio® (in the U.S.) and Zarzio® (in Europe) are biosimilar to the reference product Neupogen® marketed by Amgen and originally licensed in 1991.   Subsequent to Zarxio®’s approval, only eleven other biosimilar drugs have gained U.S. approval to date (Table 2).  As illustrated in the following graph, while the EU’s significant head start led to an imbalance in the number of biosimilar drugs available in the respective markets, the EU’s relatively higher rate of approvals in recent years has widened its lead over the United States.

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

On September 19, 2018, the EMA approved Hulio®, another biosimilar to Abbvie’s Humira® in Europe.  On October 17, 2018, upon expiration of a European patent covering Abbvie’s Humira®, several biosimilar adalimumab products that had been previously authorized by the EMA launched in Europe including Novartis’ Hyrimoz, Amgen’s Amgevita, Biogen’s Imraldi, and Mylan and Fujifilm’s Hulio.

On September 25, 2018, the EMA approved Coherus’ UdenycaTM and Accord Healthcare’s Pelgraz®, the first pegfilgrastim biosimilars to Amgen’s Neulasta® in Europe.

On October 11, 2018, Celltrion and Teva announced that the FDA Oncologic Drugs Advisory Committee voted unanimously to recommend approval of CT-P10, a proposed monoclonal antibody (mAb) biosimilar to Roche’s Rituxan® (rituximab).

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 October 19, 2018).

Table 2. U.S. Food and Drug Administration List of Approved Biosimilar Drugs (CDER list of licensed biologics updated on October 22, 2018).

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 28, 2018).

Table 4. Biologics having already expired or nearing primary patent expiry in the U.S. that have biosimilars in the regulatory pipeline.

 

[1] Based on sales reported by respective manufacturers (1. Humira—Abbvie, 2. Rituxan—Roche, 3. Enbrel—Pfizer/Amgen, 4. Herceptin—Roche, 5. Avastin—Roche, 6. Remicade—Johnson & Johnson/Merck, 7. Lantus—Sanofi, 8. Neulasta—Amgen, 9. Avonex—Biogen, 10. Lucentis—Roche/Novartis).

Recently, Pfizer was denied institution of two follow-on inter partes review (IPR) petitions, IPR Nos. 2018-00330 and 2018-00331 (“the 2018 petitions”), filed on December 18, 2017, asserting invalidity of Genentech patents, U.S. 6,339,142 (“the ’142 patent”) and U.S. 9,249,218 (“the ’218 patent”).  The Patent Trial and Appeal Board (“the Board”) denied instituting the IPRs using its discretion under 35 U.S.C. § 314(a) in light of the factors applied in Nvidia[1] and General Plastics[2].  The decision reached by the Board illustrates the need to explain the rationale for follow-on petitions clearly and in light of the General Plastics doctrine.

Genentech’s patents are directed to anti-HER2 antibody compositions and generally disclose purification procedures using ion exchange chromatography to resolve the antibodies from one or more contaminants or “variants.”  Genentech’s patents claim a composition comprising a mixture of anti-HER2 antibody and one or more acidic variants thereof, wherein the amount of the acidic variant(s) is less than about 25%, and wherein the anti-HER2 antibody is humMAb4D5-8.  The claims of the ’218 patent further require that the acidic variant(s) are predominately deamidated variants, wherein one or more asparagine residues of the anti-HER2 antibody have been deamidated, and wherein the deamidated variants have asparagine 30 in CDR1 of either or both variable light regions converted to aspartate.

The 2018 petitions came on the heels of two earlier IPRs, IPR Nos. 2017-02019 and 2017-02020 (“the 2017 petitions”), filed on August 29, 2017, by Pfizer against the’142 patent and the ’218 patent using Andya, Waterside, and Harris as prior art references[3], which were similarly asserted in both the 2017 and 2018 petitions[4].  In particular, Pfizer asserted in its 2017-02020 petition against the ’218 patent that Andya anticipates the claims because Andya discloses an anti-HER2 composition comprising full length humanized huMAb4D5-8 and acidic variants thereof.  Pfizer pointed to disclosures in Andya, stating that the anti-HER2 antibody was observed to degrade by deamidation of asparagine 30.  Notably, Pfizer also asserted that Andya inherently discloses deamidated variants with asparagine 30 of CDR1 of a variable light chain converted to aspartate because Andya teaches that asparagine 30 in the light chain is deamidated and asparagine necessarily converts to aspartate when humMAb4D5-8 deamidates.

In support of its arguments, Pfizer also submitted expert declarations that would ultimately be an issue in the Board’s decision of whether or not to institute the 2018 petitions.  In particular, Pfizer submitted the declaration of Dr. Buick in support of their assertion of inherent anticipation by showing that Dr. Buick could prepare humMAb4D5-8 compositions using the disclosures provided in the asserted prior art references and arrive at a composition that meets all the limitations of the challenged claims.

The Board decided to institute Pfizer’s 2017 petitions, concluding that Pfizer had shown a reasonable likelihood that it would prevail in showing unpatentability of the disputed claims over Andya and Harris.  However, the Board decided to exercise its discretion by declining to proceed on the grounds involving Waterside, which was comprised of slides depicting the work of Harris and which were presented at a conference approximately one year after publication of Harris.

Prior to institution of the 2017 petitions and four days after the patent owner’s preliminary response in those proceedings, Pfizer filed the 2018 petitions asserting that the disputed claims are invalid over Andya, Waterside, and Harris.  Of note in the 2018 petitions, Pfizer included an expert declaration by Dr. Buick showing additional experiments using a different cell line than the cell line used in the 2017 petitions and a second declaration supporting the Waterside reference as a printed publication within the meaning of section 102.  Pfizer filed an unsuccessful motion for joinder of the follow-on petitions.

In response to the 2018 petitions, Genentech argued that Pfizer offered new evidence and arguments in the 2018 petitions using the same prior art references to attack the same claims and failed to provide any rationale for why the follow-on petitions should be instituted in light of the General Plastics doctrine.  We previously outlined the General Plastics factors here.

The Board agreed with Genentech and denied institution of the 2018 petitions citing the factors applied in General Plastics.  Factors 2 and 3 weighed heavily on the Board’s decision not to institute.  In particular, Pfizer relied upon a new declaration from Dr. Buick describing a second set of experiments aimed at producing humMAb4D5-8 with the claimed amount of variants in HEK cells.  Genentech argued that the first petition could have provided those experiments in the first petition, and moreover Pfizer should have provided those experiments in the first petition because the time stamp shows that Dr. Buick completed the experiments prior to the filing of the first petition.

Genentech also asserted that Pfizer used their patent owner’s preliminary responses in the 2017 petitions, filed four days before Pfizer filed the 2018 petitions, as a road map to refine the 2018 petitions[5]. In that regard, Genentech contended that the 2018 petitions merely address what they contend are major deficiencies in Pfizer’s assertions that they highlighted in their responses to the 2017 petitions.  For example, Genentech argued that Dr. Buick’s experiments failed to demonstrate the prior art was enabling because he used CHO cells instead of the HEK cells employed in the prior art references, and new experiments by Dr. Buick in the 2018 petitions now included experiments using HEK cells.  Genentech also argues that Pfizer attempted to address what it contended are deficiencies in their declaration supporting Waterside as a valid printed publication available to the public as prior art.

In regard to factors 4 and 5, Genentech argued that Pfizer’s new petitions used the same prior art references and failed to provide any explanation for why the new evidence was not previously presented.  Genentech argued that Pfizer’s only justification for the follow-on petitions was that the 2018 petitions are substantively identical to the original petitions as stated in their motion for joinder.  Along that same vein, Genentech argued that factor 6 also disfavors institution because the 2018 petitions are amongst 15 others filed by Pfizer against Genentech’s anti-HER2 patents, which they contended put a strain on the Board’s finite resources.  Finally, Genentech also contended that Pfizer’s staggered petitions challenge the statutory requirement that the Board resolve a petitioner’s challenge to a patent claim’s validity within one year of institution.

Here, the Board found Genentech’s arguments persuasive and denied institution in light of the General Plastics factors outlined by Genentech in their response. The Board also indicated that institution would be denied under § 325(d) because both petitions rely on similar disclosures from the same prior art to make substantially the same arguments for both anticipation and obviousness.

Thus, the Board’s decision not to institute in view of the General Plastics doctrine in these cases was generally motivated by a lack of sufficient explanation for why the arguments provided in the follow-on petitions could not be presented earlier.

In contrast to the Board’s decision in the 2018 petitions, the Board will institute follow-on petitions where the reasons for the later filed petitions are clearly explained in light of the General Plastics factors. As we previously reported in Sanofi-Aventis U.S. LLC v. Immunex Corporation, IPR Nos. 2017-01879 and IPR2017-01884, the petitioners persuasively showed that the arguments presented in their follow-on petitions could not have been included in their original petitions because the disputed patent did not specify how to determine whether an antibody “competes with a reference antibody,” as required by the claims.  In that case, it was only after filing their petition that the patent owner endorsed two competition assays in the course of a foreign proceeding that allowed them to complete experiments included in the follow-on petitions.  The Board found the petitioners’ reasoning persuasive, reasoning that the petitioners did not appear to strategically stage prior art and arguments in multiple petitions.

Accordingly, general guidance following from this line of cases should compel petitioners filing follow-on petitions to clearly explain the rationale for why the arguments and evidence could not be earlier presented.  Particularly in instances where the same references are used, petitioners must convince the Board that they are not strategically staging their arguments, or using the original petition as a place holder while they build their arguments for later petitions.  Alternatively, patent owners can view the decision as a roadmap for arguing against institution of follow-on petitions.

 

[1] NVIDIA Corp. v. Samsung Elec. Co., Case IPR2016-00134 (PTAB May 4, 2016).

[2] General Plastic Indus. Co., Ltd. v. Canon Kabushiki Kaisha, Case IPR2016-01357 (PTAB Sept. 6, 2017).

[3] WO 97/04801 to Andya et al. (“Andya”); Reed J. Harris, Chromatographic Techniques for the Characterization of Human MAbs (Slides presented at the Waterside Monoclonal Conference held at the Omni Waterside Hotel in Harborside-Norfolk, Virginia on Apr. 22–25, 1996) (“Waterside”); Reed J. Harris, Processing of C-terminal Lysine and Arginine Residues of Proteins Isolated from Mammalian Cell Culture, 705 J. CHROMATOGRAPHY A 129 (1995) (“Harris”).

[4] IPR2017-02020 and IPR2018-00330 challenged claims 1 and 5-7 based on Andya, Harris, and Waterside and IPR2017-02019 and IPR2018-00331 challenged claims 1-3 based on Andya and Waterside.

[5] See General Plastic, IPR2016-01357, slip op. at 17 (“The absence of any restrictions on follow-on petitions would allow petitioners the opportunity to strategically stage their prior art and arguments in multiple petitions, using our decisions as a roadmap, until a ground is found that results in the grant of review.”).

Earlier this month, Amgen initiated suit against Apotex in the Middle District of Florida, alleging infringement of U.S. Patent No. 9,856,287 (“the ’287 patent”). This is the third complaint that Amgen has brought against Apotex under the Biologics Price Competition and Innovation Act (the “BPCIA”), based on Apotex’s abbreviated biologic license applications (“aBLAs”) for biosimilars of Amgen’s cancer drugs Neupogen® (filgrastim) and Neulasta® (pegfilgrastim).[1]

As described in detail in our previous posts here and here, Amgen previously sued Apotex in the Southern District of California in August 2015 for infringing two patents, U.S. Patent Nos. 8,952,138 (“the ’138 patent”) and 5,824,784 (“the ’784 patent”), in connection with its biosimilar of Neulasta®, and then again in October 2015 for infringing the ’138 patent and U.S. Patent No. 6,162,427 (“the ’427 patent”), in connection with its biosimilar of Neupogen®. The two cases were consolidated in November 2015. Following the district court’s dismissal of all claims and counterclaims related to the ’427 and ’784 patents on June 14, 2016, the only remaining issue was with regard to the infringement of the ’138 patent, which was drawn to a method of refolding a protein. The district court ultimately found that Apotex did not infringe the ’138 patent, and on November 13, 2017, the Federal Circuit affirmed.

The ’287 patent issued earlier this year on January 2, 2018, and is also directed to methods of protein refolding in non-mammalian expression systems. Representative claim 16 of the ’287 patent recites:

  1. A method of refolding proteins expressed in a non-mammalian expression system, the method comprising:
    preparing a solution comprising:
    the proteins;
    at least one ingredient selected from the group consisting of a denaturant, an aggregation suppressor and a protein stabilizer;
    an amount of oxidant; and
    an amount of reductant,
    wherein the amounts of the oxidant and the reductant are related through a thiol-pair ratio and a thiol-pair buffer strength,
    wherein the thiol-pair ratio is in the range of 0.001-100, and
    wherein the thiol-pair buffer strength maintains the solubility of the solution; and
    incubating the solution so that at least about 25% of the proteins are properly refolded.

Since the ’287 patent issued after Amgen provided Apotex with lists of patents which may be infringed for both aBLAs pursuant to 42 U.S.C. § 262(l)(3)(A), Amgen supplemented its lists pursuant to § 262(l)(7) to include the ’287 patent on January 31, 2018. The complaint alleges that on March 2, 2018, Apotex provided Amgen with its statements under 42 U.S.C. (l)(3)(B), explaining why the ’287 patent is invalid, unenforceable, and/or is not infringed based on its pegfilgrastim aBLA and the filgrastim aBLA. Amgen seeks to push off the launch of both of Apotex’s biosimilar products for another two decades, until the expiration of the ’287 patent.

[1] Apotex’s aBLA for filgrastim was accepted by the FDA for review on February 13, 2015; the aBLA for pegfilgrastim was accepted in December 2014.

In a 104-page ruling, U.S. District Judge Mark L. Wolf granted summary judgment in favor of Celltrion and Hospira, finding that a doctrine of equivalents claim made by Janssen Biotech (“Janssen”) with respect to a Remicide®-related patent would ensnare the prior art.

Janssen makes Remicade®, a biologic drug whose active ingredient is the monoclonal antibody infliximab. Id. at 2.  Celltrion and Hospira produce a biosimilar of infliximab sold under the tradenames Inflectra® and Remsima®. Id.  Janssen filed suit in the United States District Court for the District of Massachusetts alleging that Celltrion and Hospira infringe U.S. Patent No. 7,598,083 (“the ’083 patent”) under the doctrine of equivalents through the process used for making the Inflectra® and Remsima® biosimilar products. Id.

Janssen originally alleged that Celltrion and Hospira infringed a patent covering the infliximab antibody; however, the Court invalidated the patent in 2016 for obviousness-type double patenting. Id. (citing Janssen Biotech, Inc. v. Celltrion Healthcare Co., Ltd., 211 F. Supp. 3d 364, 366 (D. Mass. 2016)).  The focus in the case then shifted to the ’083 patent, which “claims a soluble composition [] suitable for producing a final volume of cell culture media and lists 61 ingredients for the media and a concentration range for each.” Id. (internal quotation marks omitted).  The court noted that the ’083 patent does not mention infliximab and that Janssen does not use an embodiment of the claimed invention to produce Remicade®. Id. at 3.  However, Janssen alleged that Celltrion indirectly infringed the ’083 patent by employing a third party to make the cell culture media used to produce its infliximab products and that Hospira was liable for Celltrion’s actions as a joint venturer. Id. at 4.

Celltrion and Hospira “moved for summary judgment of non-infringement on the grounds that Janssen’s asserted scope of equivalents would ensnare the prior art.” Id. at 5.  “The ensnarement defense prevents the patentee from obtaining under the doctrine of equivalents coverage that could not be lawfully obtained from the PTO by literal claims.” Id.  “In other words, the patentee cannot assert a right to a monopoly over equivalents that is so broad that such claims, if included in the patent application, would not have been patentable over prior art.” Id. at 7-8.  When determining whether a doctrine of equivalents theory would ensnare the prior art, the court conducts a “hypothetical claim” analysis, where a hypothetical claim is constructed that literally covers the accused device (i.e., the claimed limitations of the patent are expanded to encompass the features of the accused product). Id. at 8.  The court then determines whether the hypothetical claim is patentable over the prior art. Id.

After conducting a lengthy obviousness analysis, the court found that “no reasonable factfinder could conclude that Janssen [had] satisfied its burden of proving that the hypothetical claims would have been patentable over the [prior art] media,” and held that Celltrion and Hospira were “entitled to summary judgment of non-infringement of the ’083 Patent because Janssen [had] not produced sufficient evidence to prove that the scope of equivalents would not ensnare the prior art.” Id. at 103.

This decision brings an end to a long-running dispute over patents covering and related to infliximab between Celltrion, Hospira, and Janssen.

On August 10, 2018, AbbVie, Inc. and AbbVie Biotechnology Ltd. (collectively “AbbVie”) sued Sandoz Inc., Sandoz GMBH, and Sandoz International GMBH (collectively “Sandoz”) in the district of New Jersey alleging infringement of two patents related to Humira®:  U.S. Patent 9,187,559 (“the ʼ559 patent”) and U.S. Patent No. 9,750,808 (“the ʼ808 patent”).

According to the complaint, the parties began exchanging information as required by the BPCIA in January of this year.  AbbVie alleges that although Sandoz made its application available to AbbVie, it did not provide other relevant information that describes the manufacturing process.  On March 18, 2018, AbbVie provided Sandoz with the list of patents for which it believed a claim for patent infringement could be asserted, and it twice supplemented that list.  On May 16, 2018, Sandoz contested its infringement and the validity of those patents, and provided additional information regarding its manufacturing process.  However, AbbVie asserts that the additional information is still not sufficient to confirm that Sandoz does not infringe the claims of each of the patents identified by AbbVie.

According to the complaint, on July 15, 2018, AbbVie responded to Sandoz’s non-infringement/invalidity contentions with a “detailed” statement alleging infringement of 84 patents.  AbbVie further alleges that during the negotiations, Sandoz informed AbbVie that it wished to litigate only a single patent.  Under the applicable provisions of the BPCIA, this means that the maximum number of patents that could be a part of this lawsuit is two.  However, AbbVie repeatedly asserts throughout its complain that when Sandoz provides its Notice of Commercial Marketing, AbbVie will have an additional opportunity to assert the remaining 82 patents.

The ʼ559 patent is entitled “Multiple-Variable Dose Regimen for Treating Idiopathic Inflammatory Bowel Disease,” and issued on November 17, 2015.  The ʼ559 patent issued with two independent claims, and 30 total claims.   AbbVie’s complaint alleges infringement of all 30 claims either literally or under the doctrine of equivalents.  The independent claims are directed to a method for treating idiopathic inflammatory bowel disease in a human comprising subcutaneously administering 160 mg of adalimumab within a day followed by a second dose of 80 mg adalimumab within a day, wherein the second dose is administered two weeks following the first dose.

The ʼ808 patent is entitled “Formulation of Human Antibodies for Treating TNF-α Associated Disorders,” and issued on September 5, 2017.   The ʼ808 patent issued with one independent claim, and 30 total claims.   AbbVie’s complaint alleges infringement of claims 1-10, 14-17, and 24-27 either literally or under the doctrine of equivalents.  Independent claim 1 is directed to a stable liquid aqueous pharmaceutical formulation comprising a human anti-TNF-α IgG1 antibody at a concentration of 45 to 105 mg/mL, and a buffer system wherein the formulation is isotonic, suitable for single-use subcutaneous injection, and has a pH of 4 to 8.   The claim also specifies that the antibody is D2E7, which was the initial name for adalimumab during development.

AbbVie’s complaint points out that Sandoz has previously challenged the validity of the ʼ559 patent in an IPR, but in that case the PTAB declined to institute review.  We reported that decision here.  The validity of the ʼ808 patent has not yet been challenged in an IPR.

We will continue to keep you apprised of future developments.

  • FDA approves first Neulasta® (pegfilgrastim) and Procrit® (epoetin alfa) biosimilars and second Neupogen® (filgrastim biosimilar)
  • European Medicines Agency approves third and fourth trastuzumab, fourth infliximab, and fifth, sixth and seventh adalimumab biosimilars
  • Only four of twelve approved biosimilars have launched in the United States

As pharmaceutical drug costs attract increasing media attention and political scrutiny, a growing number of biosimilar drugs are set to enter the U.S. and European markets in the coming years.  Global sales for the top ten branded biologic drugs totaled approximately $71 billion in 2017[1].  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 45 out of 50 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 Act (BPCIA) of 2009.  Given that the first U.S. biosimilar drug was approved almost a decade after the first in Europe, the number of authorized biosimilar drugs in Europe far exceeds the number of biosimilars approved in the United States.  Sandoz’s filgrastim biosimilar Zarxio® received the first U.S. approval in 2015, whereas nine filgrastim biosimilars have been approved in Europe dating back to multiple authorizations in 2008.  Zarxio® (in the U.S.) and Zarzio® (in Europe) are biosimilar to the reference product Neupogen® marketed by Amgen and originally licensed in 1991.   Subsequent to Zarxio®’s approval, only eleven 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, fifteen biosimilar applications are under review by the EMA for marketing authorization (Table 3).  As an increasing number of patents expire on blockbuster biologic drugs, the number of abbreviated biologics license applications is also increasing.  Biosimilars for at least twelve different original biologics are currently navigating the United States Food & Drug Administration’s (FDA’s) biosimilar pathway or are in late stage development (Table 4).  Interestingly, Neulasta® (pegfilgrastim) biosimilars have failed to gain approval in Europe thus far and the FDA finally approved the first pegfilgrastim biosimilar in June 2018.  There are currently eight applications for pegfilgrastim pending in Europe.

On May 15, 2018, Pfizer announced that the FDA approved Retacrit®, the first biosimilar to Epogen® and Procrit® (epoetin alfa), for all indications of the reference product as reported here. RETACRIT is now the first and only biosimilar erythropoiesis-stimulating agent (ESA) to be approved in the U.S.  No launch date was announced.

On May 16, 2018, the EMA approved KanjintiTM, the third trastuzumab biosimilar to Roche’s Herceptin® in Europe.  The EMA previously approved Celltrion’s HerzumaTM in February 2018 and Samsung Bioepis’ Ontruzant TM in November 2017.  On June 1, 2018, Amgen reported that the FDA had issued a complete response letter rejecting Kanjinti and that it “would work closely with the FDA to bring this important medicine to patients in the U.S.”

On June 4, 2018, Mylan announced that the FDA approved FulphilaTM, the first biosimilar pegfilgrastim available in the U.S. for reducing the risk of infection following myelosuppressive chemotherapy in patients with nonmyeloid cancers as reported here.  FulphilaTM is the second FDA-approved biosimilar through the Mylan-Biocon collaboration.  Mylan stated that it anticipated launching FulphilaTM “in the coming weeks.”    In late July 2018, Mylan reportedly launched Fulphila in the United States marketplace.

On July 20, 2018, Pfizer announced that the FDA approved NivestymTM, the second biosimilar filgrastim available in the U.S.  No launch information was provided.

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 August 2, 2018).

Table 2. U.S. Food and Drug Administration List of Approved Biosimilar Drugs (CDER list of licensed biologics updated on July 24, 2018).

Table 3. European Medicines Agency List of Biosimilars Under Evaluation for Marketing Approval (Source: EMA list of applications for new human medicines updated on July 13, 2018).

Table 4. Biologics having already expired or nearing primary patent expiry in the U.S. that have biosimilars in the regulatory pipeline.

[1] Based on sales reported by respective manufacturers (1. Humira—Abbvie, 2. Rituxan—Roche, 3. Enbrel—Pfizer/Amgen, 4. Herceptin—Roche, 5. Avastin—Roche, 6. Remicade—Johnson & Johnson/Merck, 7. Lantus—Sanofi, 8. Neulasta—Amgen, 9. Avonex—Biogen, 10. Lucentis—Roche/Novartis).

The PTAB recently instituted a second IPR of US Patent 9,296,821 (“the ’821 patent”), which covers certain uses of Rituxan® (rituximab), a monoclonal antibody marketed by Genentech and Biogen Pharmaceuticals.  The ‘821 patent claims methods of treating low grade or follicular non-Hodgkin’s lymphoma (NHL) by administering rituximab during a chemotherapeutic regimen of cyclophosphamide, vincristine, and prednisone (CVP therapy), wherein the method provides a beneficial synergistic effect.  The recently-instituted IPR was filed by Pfizer (IPR2018-00186).

This decision presents an interesting example of how the Patent Trial and Appeal Board (“the Board” or “the PTAB”) may apply the Supreme Court’s decision in SAS Inst., Inc. v. Iancu, 138 S. Ct. 1348, 1360-61 (2018) to “follow-on petitions” in which a new petitioner challenges the same patent at issue in a prior petition or IPR by a third-party.  The Board held that “when considering whether to exercise our discretion to deny institution under 35 U.S.C. § 325(d), we must consider not simply whether to deny institution regarding certain claims or certain challenges, but whether to do so regarding the petition, as a whole.”  Institution Decision (IPR2018-00186, Paper 15) at 19.  Here, Pfizer’s new argument as to a single claim persuaded the Board not to exercise its discretion to deny the Petition under § 325(d).

Last October, the PTAB instituted IPR of claims 1-3 and 5-6 of the ’821 patent based on a petition by Celltrion.  (IPR2017-01095, Paper 12.)  Following the Supreme Court’s decision in SAS, the Celltrion IPR was expanded to include all claims (i.e., claims 1-6) and all grounds raised in the petition.  (IPR2017-01095, Paper 39.)  That proceeding is pending, and oral argument is scheduled for August 21, 2018.

In the Celltrion institution decision, the PTAB preliminarily determined that claims 1-3 of the ’821 patent were entitled to a priority date of August 11, 1999, but gave claims 4-6 a priority date of June 15, 2012, the filing date of the application that issued the ’821 patent.  In the recently-instituted Pfizer IPR (IPR2018-00186), the Board maintained this preliminary priority determination.

The priority date determination for claims 4-6 turns on whether the specification of the ’821 patent adequately describes “administering 375 mg/m2 of rituximab once every 3 weeks for 8 doses.”  The Patent Owner, Biogen, argued that the specification discloses the claimed dosing regimen by teaching rituximab (375 mg/m2) in combination with “standard CVP therapy,” and that one skilled in the art would understand “standard CVP therapy” to be six to eight cycles of CVP spaced three weeks apart.  Institution Decision (IPR2018-00186, Paper 15) at 13.  The Board found, however, that the specification’s disclosure of “standard CVP therapy” was in the context of a study in which Rituximab® would be dosed weekly as maintenance therapy following CVP therapy.  Id.  At this stage in the proceeding, the Board found this inadequate to describe dosing once every 3 weeks for 8 doses, and accorded claims 4-6 a June 15, 2012 priority date.  Id.

Pfizer also argued that the claim phrase “beneficial synergistic effect” is non-limiting as to claim 4, because it “essentially duplicates the dosage amounts recited in the claims’ and is nothing more than ‘an expression of intended result.’”  Institution Decision at 6 (quoting Bristol-Myers Squibb Co. v. Ben Venue Labs., Inc., 246 F.3d 1368, 1375 (Fed. Cir. 2001)).  The Board preliminarily agreed with Pfizer that, because claim 4 recites a specific dosing regimen for rituximab along with “standard CVP therapy,” the “beneficial synergistic effect” recited in the claim is “an intended result of administering the combination in the recited manner” and is not a claim limitation.  Id. at 7.

Due to its preliminary decision that the priority date for claims 4-6 was June 15, 2012, the Board considered relatively recent references as prior art to those claims.  Id. at 14.  In particular, Marcus, published in 2005, describes a clinical trial comparing CVP and rituximab every 21 days for a maximum of 8 cycles to CVP alone.  The Board found, on the current record, that Marcus describes every limitation of claims 4-6.  Institution Decision at 15-16.  The Board relied, in part, on its preliminary determination that the requirement for a “beneficial synergistic effect” is not a claim limitation.  Id. at 16.  Alternatively, the Board found a reasonable likelihood that Pfizer could show every limitation, including the beneficial synergistic effect, was rendered obvious by a combination of references.

The Board then addressed Biogen’s arguments that Pfizer’s petition should be denied under § 325(d) or §314(a) based on overlap with the Celltrion IPR.  The Board agreed with Biogen that Pfizer’s obviousness challenges to claims 1-3 present “the same or substantially the same prior art and arguments presented in the Celltrion petition.”  Institution Decision at 18.  While the Board found “similarities” between Pfizer’s other challenges and those presented by Celltrion, it did not consider them “substantially the same.”  In particular, the Board noted Pfizer’s challenges to claim 4, including its new argument that the term “beneficial synergistic effect” is non-limiting.  The Board found these differences sufficiently distinguished Pfizer’s petition as a whole from Celltrion’s.  Id. at 18-19.

The Board also declined to “expand” the General Plastics Industrial Co. v. Canon Kabushiki Kaisha, Case IPR2016-01357, Paper 19 (PTAB Sept. 6, 2017) decision to this case, noting Pfizer itself had not previously filed a petition on the ’821 patent.

In this case, the Board found that where a new Petitioner raises a substantially new argument as to at least one patent claim, the entire petition, including all challenged claims on all grounds, may be granted, despite a third party’s IPR having been instituted on the same patent on overlapping grounds.