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.

U.S. Patent No. 8,329,172 (“the ’172 patent”), a Biogen-owned patent covering a treatment regime for low-grade B-cell non-Hodgkin’s lymphoma, has been a relatively frequent subject of our posts. We first wrote about it in March of 2017, reporting on the filing of Celltrion’s IPR petition against the patent, then again that May, reporting on Pfizer’s first attempt to have the PTAB invalidate the patent. Most recently, in November, we reported that the PTAB denied institution of Pfizer’s petition, joining denials of the Celltrion petition as well as an earlier effort by Boehringer Ingelheim. On July 9, 2018, the PTAB ordered institution of a second IPR petition filed by Pfizer, the first IPR to be instituted on the ’172 patent after multiple attempts.

In the article reporting on the denied Pfizer petition, we discussed how a challenge to the asserted prior art as actually being available as a printed publication led to the denial of institution of Pfizer’s petition. There, the Board found that a version of the label for Rituxan® relied upon in the ground of the petition was not adequately supported in the petition as having been made available to interested artisans. The issue came down to Pfizer not demonstrating that the actual document had ever been distributed, rather than whether the contents of the document had been made available.

In December 2017, Pfizer filed another IPR challenging the validity of the ’172 patent, IPR2018-00285. The petition in this IPR directly discussed the procedural failure of the previous petition, and Pfizer clearly attempted to avoid the same issue as thoroughly as possible. First, Pfizer substituted the challenged Rituxan® label for a journal article containing the same information and which was clearly published and accessible well before the critical date of the patent.  Next, Pfizer presented a second ground challenging the ’172 patent, where three different versions of the Rituxan® label were used with each argued to be an adequate printed publication. Finally, Pfizer essentially copied the substance of its prior IPR to avoid fairness issues with responding to the arguments made in the Patent Owner’s Preliminary Response in the previous IPR, and it argued that the new petition should not be rejected as a “follow-on” petition because the earlier IPR had never been addressed on the merits.

Biogen’s Preliminary Response addressed the merits of the petition, but also argued that institution should be denied under 35 U.S.C. § 325(d) because substantially the same prior art and arguments had been presented to the PTAB in the three prior petitions. Biogen also presented an argument that the petition should not be instituted under the seven factors presented in the precedential General Plastic PTAB decision.

On July 9, 2018, the PTAB entered its decision granting institution, finding that the petition had shown a reasonable likelihood of success for either of the grounds set forth in the petition. The same panel of administrative patent judges decided both this and the previous Pfizer petition, with the author of the previous dissent now writing the opinion and the previous majority opinion author now writing her own dissent.

The PTAB’s decision regarding § 325(d) noted that although the statute grants discretion to decline institution based on the presentation of the same or substantially the same art, the statute does not require the result and the Board’s discretion may take into account the facts of each case. The Board here found that the petition presented new arguments relative to the earlier Boeheringer and Celltrion petitions, and the previous Pfizer petition involved a split in the panel as to the public accessibility of the Rituxan® label that was not at issue in this IPR.

The panel also was not persuaded that the seven General Plastic factors required them to exercise their discretion to deny the petition, as the panel had not reached the issue of actually applying the asserted art to the claim and the use of the prior decision regarding the question of printed publication status was limited and not in a manner that would have the panel deny the petition.

The dissenting opinion focused primarily on the General Plastic factors and that Pfizer’s reliance on the previous opinion as a roadmap in drafting its petition should have warranted denial of institution under 35 U.S.C. § 314(a). Specifically, the dissent was critical of Pfizer’s characterization of its changes to its petition as being only a “procedural” issue, as the dissent states the question of whether asserted art is a printed publication requires substantive consideration and goes to the heart of the PTAB’s patentability analysis. The dissent spelled out its specific concerns as being that Pfizer 1) previously filed a petition directed to the same claim, 2) knew of the newly asserted references at the time of the original petition, 3) had access to the prior Preliminary Response and institution decision, and 4) did not provide adequate explanation for its previous failure to demonstrate that the Rituxan® label qualified as a printed publication, and for these reasons, denial of institution was warranted.

Although Pfizer obtained a positive result here with the first IPR instituted against the ’172 patent, the dissent continues to demonstrate the importance for petitioners of clearly demonstrating such threshold statutory requirements as showing all your art to be a patent or printed publication. The PTAB may not always be so kind as to grant “a second bite at the apple,” as this petition was characterized by the dissent.

On July 2, 2018, Genentech filed suit against Eli Lilly and Company (“Lilly”) in the Southern District of California alleging Lilly’s Taltz® infringes newly issued U.S. Patent 10,011,654 (“the ʼ654 patent”).  According to the complaint, the ʼ654 patent issued at 12:00 am Eastern time on July 3, 2018, and the complaint was filed immediately thereafter.

Taltz® was first approved in the United States in 2016 and is currently approved for the treatment of adults with active psoriatic arthritis or moderate to severe plaque psoriasis who are candidates for systemic therapy or phototherapy.   Lilly also recently announced that Taltz® met the primary and key secondary endpoints in a Phase 3 study evaluating the safety and efficacy of Taltz® for the treatment of Ankylosing Spondylitis.

The active ingredient in Taltz® is ixekizumab, a humanized monoclonal antibody specific for interleukin 17A.  Ixekizumab functions by blocking the activity of interleukin 17A, a pro-inflammatory cytokine.   The newly issued ʼ654 patent is titled “Antibodies Directed to IL-17A/IL-17F Heterodimers.”  Claim 1 recites “[a]n isolated humanized monoclonal antibody that binds to an IL-17A/IL-17F heterodimer comprising the polypeptide of SEQ ID NO: 3 and the polypeptide of SEQ ID NO: 4 with or without their associated signal peptides.”  Genentech alleges that ixekizumab binds to the heterodimer specified in the claim, and thus infringes that claim.

In its prayer for relief, Genentech requests that instead of being granted a permanent injunction, it be awarded “a running or ongoing royalty adequate to compensate Genentech for ongoing infringement.” Genentech further alleges that prior to filing the lawsuit, it notified Lilly that the ʼ654 patent would soon issue and offered Lilly a license at a royalty rate to be determined by arbitration, but Lilly declined.  Taltz® reportedly generated U.S. revenue of $486 million in 2017.

We will continue to keep you apprised of further developments.

As we previously reported here and here, Celltrion filed suit against Genentech seeking declaratory judgment that a host of patents covering Rituxan® and Herceptin® were non-infringed, invalid, and/or unenforceable.  Genentech responded by moving to dismiss, arguing that Celltrion’s claims were statutorily barred by the BPCIA.  As we reported here, the Court agreed with Genentech and dismissed Celltrion’s suits.

On July 11, 2018, Genentech filed new lawsuits for patent infringement in the District of New Jersey (Rituxan® patents) and the District of Delaware (Herceptin® patents).  Genentech previously filed suits in those districts immediately after Celltrion filed its declaratory judgment actions, and those actions are still pending before the respective Courts.  The infringement allegations in the newly filed Complaints are essentially identical to those previously filed.

Genentech asserts that it filed these new actions as a result of Celltrion taking the position that it has now complied with the requirements of the BPCIA’s patent dance.  More specifically, Genentech alleges that following dismissal of Celltrion’s declaratory judgment action, Celltrion attempted to “resurrect the patent dance” and sent Genentech the list of patents it believed should be subject to infringement litigation on June 5, 2018.  Genentech further alleges that shortly after, on June 11, 2018, Celltrion sent Genentech the list of patents that it believed should be included in the first-phase of patent infringement litigation.  Genentech asserts that although it objected to Celltrion’s attempts to reengage in the patent dance, it provided its own list of patents to be included in the first-phase of infringement litigation out of an abundance of caution.

Genentech makes clear in its complaints that it believes Celltrion’s exchange of lists in June 2018 has no legal effect because the deadline for Celltrion to comply with the BPCIA’s requirements passed in January.  Nonetheless, Genentech filed this suit to preclude any argument from Celltrion that Genentech forfeited its right to bring suit and so limited any potential relief to a reasonable royalty, which is the only relief permitted by the BPCIA when the reference product sponsor does not bring suit within 30 days of the parties’ exchange of patents to be included in the first-phase of litigation.  Genentech further asserts that it will file a motion to consolidate the newly filed suits with those filed in January if Celltrion does not stipulate to consolidation.

We will keep you apprised of further developments.

On June 14, 2018, Senator Orrin Hatch of Utah, the co-author of the Hatch-Waxman Act, filed an amendment to the Hatch-Waxman Act in an effort to further incentivize generic drug development. The language of the amendment, known as the Hatch-Waxman Integrity Act of 2018, states that its purpose is “to prevent the inter partes review process for challenging patents from diminishing competition in the pharmaceutical industry and with respect to drug innovation.” Senator Hatch has indicated that while he strongly supports the inter partes review (“IPR”) process, he feels that it is producing unintended consequences in the pharmaceutical industry by allowing two separate pathways for attacking a brand patent, and that it has upset the brand-generic balance put in place by the Hatch-Waxman Act. In a statement made at a Senate Judiciary Committee hearing, Senator Hatch stated that the amendment would preserve the ANDA/biosimilar process as the standard pathway for companies to challenge brand patents, and that “it would prevent companies from using IPR to put added litigation pressure on innovators above and beyond what Hatch-Waxman already provides. And it would prevent a company that rightfully loses a Hatch-Waxman suit from getting a second bite at the apple.”[1]

Changes Proposed by the Hatch-Waxman Integrity Act

The act provides amendments to Section 505 of the Federal Food, Drug, and Cosmetic Act for generic and brand drug makers and to Section 351(k) of the Public Health Service Act for biosimilar drug makers. For biosimilar applications, the proposed amendment would require an applicant to submit an application including “with respect to any patent that is, or that could be, included on a list of patents under subsection 18 (l)(3)(A)(i), … a certification that neither the applicant nor any party in privity with the applicant has filed, or will file, a petition to institute inter partes review or post grant review of that patent under chapter 31 or 32, respectively, of title 35, United States Code.’’[2]  Similar amendments were proposed for ANDA applicants.

The Hatch-Waxman Integrity Act essentially would require an ANDA or biosimilar applicant to choose between engaging in the ANDA/biosimilar approval pathway or challenging a patent in an IPR or PGR proceeding.  As noted by Senator Hatch, engaging in the ANDA/biosimilar process, a company may “rely on the brand company’s safety and efficacy studies for FDA approval,” whereas a party who files an IPR proceeding would have to develop its own safety and efficacy data.[3]

Potential Impacts for Biosimilar Applicants

Currently, under the Biologics Price Competition and Innovation Act (“BPCIA”), a biosimilar applicant is not required to disclose any patents when submitting its application. Thus, at the outset, the amendment would require more work and costs to be expended by a biosimilar applicant in preparing an application. Furthermore, it may be difficult for a biosimilar applicant to identify all the patents applicable for the proposed certification. There is no FDA listing of the patent exclusivities for biologics similar to the Orange Book. Thus, a biosimilar applicant may not be able to identify the necessary patents, or may be forced to identify the entire patent portfolio related to the biologic whether it would actually apply to its product or not.

Conclusions

In addition to the specific impacts it may have for biosimilar applicants, the Hatch-Waxman Integrity Act may cause significant impacts to ANDA and biosimilar applicants generally. For ANDA/biosimilar applicants, what was originally seen as a quick and cost-effective alternative to engaging in lengthy patent litigation may no longer be a feasible or favorable option. IPR and PGR proceedings are quicker and cheaper than filing a patent litigation lawsuit. However, the added costs and time ANDA/biosimilar applicants would need to spend to develop new safety and efficacy studies would likely far outweigh any potential savings to be had by challenging patents through the IPR process. Therefore, despite recently being upheld to be constitutional, IPR and PGR proceedings may be effectively eliminated in the pharmaceutical industry if the Hatch-Waxman Integrity Act is enacted.

 

[1] “Hatch Amendment to Incentive Generic Drug Development”, Senator Hatch Press Release, (June 14, 2018) https://www.hatch.senate.gov/public/index.cfm/2018/6/hatch-amendment-to-incentivize-generic-drug-development

[2] S. 974, 115th Cong. (2018).

[3] See supra note 1.

Earlier this month, the U.S. FDA announced approval of Mylan’s Fulphila biosimilar to Neulasta® (pegfilgrastim).  Neulasta® was developed by Amgen and first approved in the U.S. and Europe in 2002.  Following the approval announced on June 4, 2018, Fulphila, which was co-developed with Biocon, becomes the first biosimilar to pegfilgrastim approved in the U.S.

The FDA approved Fulphila to treat cancer patients with non-myeloid cancers receiving myelosuppressive chemotherapy that have clinically significant incidence of febrile neutropenia.  As we reported previously, Neulasta® (pegfilgrastim) biosimilars have failed to gain approval in Europe and in the United States despite numerous attempts.  The FDA previously rejected several pegfilgrastim applications, including the first Biologics License Application filed by Mylan/Biocon, and there are currently eight applications for pegfilgrastim pending in Europe.

Nevertheless, the FDA explained in their announcement that the review of evidence showed “extensive structural and functional characterization, animal study data, human pharmacokinetic and pharmacodynamic data, clinical immunogenicity data, and other clinical safety and effectiveness data that demonstrates Fulphila is biosimilar to Neulasta.”  The announcement marks another major win for Mylan and Biocon following the December 2017 approval of their co-developed Ogivri biosimilar to Herceptin® (traztuzumab).

The patents covering Neulasta® expired in October 2015 in the U.S. and August 2017 in Europe.  Mylan and Biocon also submitted an application for their pegfilgrastim candidate biosimilar product (MYL-1401H) to the European Medicines Agency (EMA).  However, Europe has yet to approve a pegfilgrastim biosimilar.

The FDA Commissioner, Scott Gottlieb, stressed that the U.S. agency will continue to prioritize review of biosimilar products.  As a result, the U.S. may start to gain some ground on the European markets, which have seen biosimilar approvals rapidly increase over the last three years. Click here to learn more about how the U.S. compares to Europe in biosimilars approvals and products in the pipeline.

The Patent Trial and Appeal Board (“PTAB”) recently denied Sandoz’s petition for inter partes review (“IPR”) of claims 1-30 of AbbVie’s patent, U.S. Patent No. 9,187,559 (“the ’559 patent”). The ’559 patent is directed towards a multiple-variable dose regimen for treating idiopathic inflammatory bowel disease. The patent discloses administering a high dose of a TNFα inhibitor in an induction phase and following up with a second administration of the inhibitor during a maintenance or treatment phase. Claim 1 specifically recites administering a first dose of 160 mg of adalimumab and two weeks after administration of the first dose, administering a second dose of 80mg of adalimumab. In its petition, Sandoz asserted that the ’559 patent claims were unpatentable under 35 U.S.C. §103(A) over the combination of a 2003 Humira Package Insert, WO 02/100330 A2 (“WO ’330”), Goodman & Gilman’s The Pharmaceutical Basis of Therapeutics, a 2002 Remicade Package Insert, and Hanauer’s Evolving Treatment Strategies for Inflammatory Bowel Disease. The PTAB denied institution, concluding that Sandoz failed to demonstrate that the 160mg/80mg dosing regimen of the ’559 patent claims would have been obvious. See Sandoz Inc. v. AbbVie Biotechnology LTD., IPR2018-00156 (PTAB June 5, 2018) (Paper 11).

Sandoz argued that the asserted prior art references disclosed all of the elements of the claims except the 160mg/80mg induction dosing regimen. Id. at 17. However, Sandoz argued that the dosing regimen would have been obvious because WO ’330 disclosed using higher doses of adalimumab, such as 80 mg every other week, to treat TNFα related disorders. Id. at 18. Sandoz argued that a person of ordinary skill in the art (“POSITA”) would have expected an 80 mg every other week dosing regimen to serve as good baseline for determining an induction or loading dose. Id. at 18. Sandoz also argued that a POSITA would have modified the 80mg every other week induction dose to arrive at the claimed 160mg/80mg dosing scheme based on several teachings in the prior art. Id. at 18. For example, Sandoz argued that the prior art taught that an “80 mg dose administered 2 weeks after the 160 mg dose would maintain heightened blood levels for 4 weeks, at which time the 40 mg every other week maintenance dosing would begin.” Id. at 18-19 (citing Petition at 22-23).

The PTAB held that Sandoz failed to show, without the use of hindsight, that a POSITA would have been motivated to use 160 mg as an induction dose or to select an intermediate dose to serve as a base for determining an induction dose. The PTAB agreed with Sandoz that the prior art disclosed that an induction/loading dose “is twice the size of the maintenance dose, if the maintenance dosing interval corresponds to the biological half-life of the drug.” Id. at 19. However, the PTAB concluded that “[a]pplying the general rules for determining an appropriate loading dose…results in an adalimumab loading dose of 80mg (i.e. a doubling of the 40 mg dose that Petitioner identifies as the maintenance dose), not a dose of 160 mg as recited in the claims.” Id. at 20. The PTAB stated that the prior art does not show how a POSITA would thus have arrived at the recited dosing regimen.

The PTAB also rejected Sandoz’s argument that the prior art discloses using a baseline dose to select an induction dose for a dosing regimen. The PTAB stated that instead, an induction dose is determined based on the maintenance dose. Thus, the PTAB denied institution of Sandoz’s petition, finding that the claims of the ’559 patent were not obvious over the cited prior art.

This is not the first time the PTAB has denied Sandoz’s petitions for IPR of AbbVie’s patents relating to the treatment of diseases using adalimumab. As discussed in a previous blog post, the PTAB recently denied Sandoz’s petition for IPR of AbbVie’s patent, U.S. Patent No. 9,512,216, directed towards a method of treating moderate to severe chronic plaque psoriasis using adalimumab.

On March 8, 2018, Amgen Inc. (“Amgen”) filed suit against Adello Biologics, LLC (“Adello”) in the District of New Jersey, alleging infringement of seventeen patents:  U.S. Patent Nos. 6,180,391; 7,083,948; 7,118,884; 7,384,765; 7,427,659; 7,662,930; 7,735,525; 7,781,395; 8,191,566; 8,273,707; 8,940,878; 8,952,138; 9,418,416; 9,632,095; 9,643,997; 9,704,239; and 9,856,287.  The case is assigned to Judge Claire C. Cecchi and Magistrate Judge Mark Falk, and is Civil Action No. 18-cv-3347.

According to the complaint, in a letter dated September 11, 2017, Adello “purported to provide notice, pursuant to 42 U.S.C. § 262(l)(8)(A), of its intent to commercially market a proposed biosimilar to NEUPOGEN® ” and “informed Amgen that Adello took advantage of the abbreviated subsection (k) pathway in submitting its aBLA.”  Complaint ¶12.

However, the complaint also asserts that Adello’s September 11, 2017 letter explained that Adello did not intend to participate in the patent dance, stating that “Adello ‘is not required to and does not intend to provide Amgen with [the Adello aBLA] or manufacturing information contemplated by 42 U.S.C. § 262(l)(2)(A).’”  Id. ¶13.  As a result of not having this information, Amgen has stated in each count of infringement that it is “thus unable to provide a more detailed infringement analysis for the Adello Filgrastim Product or the process(es) of its manufacture at this time without discovery, including the Adello aBLA and other information that describes the process or processes used to manufacture the Adello Filgrastim Product.”  Complaint ¶¶95, 106, 117, 128, 139, 150, 161, 172, 183, 194, 205, 216, 227, 238, 249, 260, and 271.  The Complaint alleges infringement under 35 U.S.C. § 271(e)(2)(C)(ii) based on Adello’s aBLA submission to FDA, Id. ¶18, and alleges that “[u]nless enjoined by this Court, upon information and belief, Adello will infringe one or more claims of each of the Asserted Patents under 35 U.S.C. §§ 271(a) and 271(g) by making, using, offering to sell or selling within the United States, or importing into the United States the Adello Filgrastim Product which Adello makes by a process covered by the Asserted Patents, before the expiration of Asserted Patents.”  Id. at ¶20.

Adello recently answered the complaint on May 17, 2018, denying infringement and asserting counterclaims of non-infringement and invalidity for all seventeen patents.  Relying on the Supreme Court’s Sandoz, Inc. v. Amgen, Inc. decision (137 S. Ct. 1664, 1674-75 (2017)), Adello admitted “that it was not required to, and did not, provide Amgen with a copy of its aBLA or manufacturing information prior to Amgen filing this lawsuit.”  Answer ¶13.  In its counterclaims, Adello points out that two of the patents-in-suit, U.S. Patent Nos. 8,940,878 and 8,952,138, were the subject of prior district court litigations where the biosimilar applicants, Sandoz and Apotex, respectively, were found not to infringe.  Counterclaim ¶¶15-16.  Adello also alleges in its counterclaims that “[n]one of the Patents-in-Suit specifically claim G-CSF or methods of treatment using G-CSF. Nor are any of the Patents-in-Suit identified on the label for NEUPOGEN® as covering that product. Upon information and belief, Amgen does not practice any of the Patents-in-Suit in its manufacture of NEUPOGEN®.”  Id. ¶19.

A scheduling conference is set for June 19, 2018.