The PTAB recently denied institution of two IPRs filed by CSL Behring LLC, CSL Behring GMBH, and CSL Behring Recombinant Facility AG (collectively “CSL”) targeting U.S. Patent No. 9,623,091 (“the ʼ091 patent”) owned by Bioverativ Therapetutics, Inc. (“Bioverativ”).   More specifically, on January 6, 2019, the PTAB denied institution of IPR2018-01313 (“the ʼ313 IPR”), and on January 16, 2019, denied institution of IPR2018-01345 (“the ʼ345 IPR”).

The challenged claims of the ʼ091 patent are directed to a method of treating hemophilia B in a human subject comprising administering multiple doses of 50-100 IU/kg of a chimeric factor IX polypeptide comprising factor IX and an FcRn binding partner at a dosing interval of about 10 to 14 days between doses. The administration maintains the plasma factor IX activity about 1 IU/dL between dosing intervals, and treats the human subject by reducing the frequency of spontaneous bleeding.

Hemophilia B is an X-linked genetic disorder that impairs blood clotting due to a deficiency of factor IX. As a result of this deficiency, a person with hemophilia B is subject to recurrent and extended bleeding episodes. Hemophilia B is treated by infusing the missing factor IX protein into a patient’s bloodstream. The infusion may be given on a designated schedule (referred to as prophylactic therapy) to help prevent bleeding episodes, or on an as needed basis.  However, prophylactic therapy of conventional recombinant factor IX requires multiple infusions a week due to the short half-life of factor IX. Consequently, efforts were made in an attempt to extend the half-life of factor IX, and the results of those efforts include the FDA approved products Aprolix® and Idelvion ®.

Aprolix is a recombinant factor IX fusion protein that comprises factor IX fused to the Fc portion of an IgG1 protein.  The FDA approved the Aprolix Biologics License Application (“BLA”) in March 2014.  Aprolix is indicated for both on-demand and prophylactic administration, and is marketed by Bioverativ.

Idelvion is a recombinant factor IX fusion protein that comprises factor IX fused to albumin.  Albumin is a naturally occurring protein with a long half-life. The FDA approved the Idelvion BLA in March 2016.  Idelvion is also indicated for on-demand and prophylactic administration, and is marketed by CSL.

In the ʼ313 IPR, CSL asserted two grounds of unpatentability. The first ground challenged claims 1-17, 20, 22, 24, and 28 as obvious in view of two references, one of which was the Peters 2010 reference.  Peters is an inventor of the ʼ091 patent, although the Peters 2010 reference lists a number of other co-authors. During prosecution, the Examiner cited the Peters 2010 reference in an obviousness rejection, but Bioverativ removed Peters 2010 as prior art by submitting a declaration from Peters asserting that Peters 2010 was not the work of another, and so did not qualify as § 103(a) prior art. In its Petition, CSL asserted that the Peters declaration was insufficient to remove the Peters 2010 reference as prior art because the statement that Peters alone was responsible for the work in the Peters 2010 reference amounted to an uncorroborated assertion. CSL supported its contention by pointing to a paragraph in the Peters 2010 reference that indicates other co-authors designed research reported in Peters 2010. The PTAB did not find this argument persuasive and explained that CSL did not provide any evidence that the level of direction and control by Peters was insufficient to remove the Peters 2010 reference as prior art.

CSL next argued that the ʼ091 patent was not entitled to the benefit of a provisional application. Without the benefit of the provisional application, the Peters 2010 reference would qualify as § 102(b) prior art that could not be removed by the Peters declaration. CSL’s contention was that the provisional application does not provide written description or enablement support for the claimed invention because the claimed genus of a chimeric factor IX:Fc binding partner includes a vast number of structural variants, but the provisional application only describes one such variant. According to CSL, a single variant cannot describe or enable a representative number of species within the claimed genus. Bioverativ responded by arguing the provisional application describes more than a single variant because it specifically incorporates by reference the disclosure of a number of functional variant factor IX and Fc sequences. The PTAB concluded that because CSL and its expert apparently did not consider the material incorporated by reference in the provisional application, CSL did not meet its burden of showing the ʼ091 patent is not entitled to the benefit of its provisional application filing date.

CSL’s first ground relied on the Peters 2010 reference to teach the claimed polypeptide. Because the Peters 2010 was not available as a prior art reference, the PTAB concluded that CSL could not meet its burden of showing the ʼ091 patent claims were unpatentable under the first proposed ground.

The second ground asserted in the ʼ313 IPR challenged claims 1-16, 18, 19, 21, and 23-27 in view of four references. CSL claimed that two of the cited references disclose chimeric factor IX (Metzner and ʼ755 Publication) polypeptides that have activity and extended half-life in animal testing, whereas the other two references (Shapiro and Carlsson) teach factor IX prophylaxis regimens. According to CSL, Shapiro teaches that administration of once weekly doses of 50-100 IU/kg of chimeric factor IX reduces frequency of spontaneous bleeding, and Carlsson teaches effective prophylactic treatment generally maintains factor IX activity above 1 IU/dL   Similarly, CSL asserted that Metzner and the ʼ755 Publication teach that chimeric factor IX have comparable efficacy and a 2- to 5- fold half-life extension when compared to recombinant factor IX. CSL also contended that arriving at the claimed 10-14 day interval is only routine optimization.

Bioverativ countered that Shaprio and Carlsson do not establish that the once weekly doses in Shaprio maintain a factor IX activity above the claimed range. According to Bioverativ, Shapiro did not “overturn the prevailing consensus” that factor IX must be administered two to three times a week for prophylaxis. Bioverativ also asserted that Metzner and the ʼ755 Publication merely provide animal data that demonstrates chimeric factor IX proteins have some degree of extended half-life in some animal models, but not others. Consequently, Bioverative insisted that a person of ordinary skill in the art (“POSA”) would not have been able to predict the degree of half-life extension in a human patient based on the data in those publications. Bioverativ also asserted that the claimed 10-14 dosing interval is substantially longer than what had been previously disclosed in the art, and does not reflect routine optimization.

The PTAB agreed with Bioverativ and found that CSL failed to establish that once weekly doses in Shapiro maintained the required level of factor IX.  The PTAB also concluded that CSL had failed to address inconsistences in the animal half-life data reported in Metzner and the ʼ755 Publication and the application of that data to dosing in humans. Consequently, the PTAB declined to institute review on this ground as well.

In the ʼ345 IPR, CSL asserted a single ground of obviousness that combined Shapiro and Carlsson with two additional references, i.e., Peters 2007 and the ʼ956 patent. The Peters 2007 and ʼ956 patent are relied on for the disclosure of a recombinant fusion protein comprising factor IX and the Fc region of IgG. Shapiro and Carlsson were again relied on for the teachings of factor IX prophylactic regimen.

CSL’s obviousness theory was similar to the theory set forth in the second ground of the ʼ313 IPR.  According to CSL, a POSA would have found it obvious to administer the claimed dosage of a factor IX:Fc fusion protein every 10-14 days with a reasonable expectation that such administration would result in maintaining a plasma factor IX activity above 1 IU/dL and reducing the frequency of spontaneous bleeding. CSL once again asserted that a POSA would know from Shaprio and Carlsson that administration of 50-100 IU/kg of a factor IX:Fc fusion protein once weekly would result in maintaining the required factor IX activity. CSL again considered arriving at the claimed 10-14 day interval to be nothing more than routine optimization. CSL supported its assertion by pointing to the disclosure in the Peters 2007 reference that factor IX:Fc fusion proteins have an increased half-life.

Bioverativ responded by again pointing out that Shapiro does not disclose weekly doses of factor IX:Fc fusion protein can maintain plasma factor IX activity at levels above I IU/dL. Bioverativ again noted it was understood that dosing of two to three times per week was required to maintain the required factor IX activity level, and this is reflected in several references cited by Petitioner. Bioverativ also pointed out that Peters 2007 only discloses effective clotting activity in animals for 6 days, does not indicate the amounts of fusion protein dosed, and merely speculates that the results of its studies are consistent with once weekly human dosing.

The PTAB again agreed with Bioverativ that the claimed combination of references would not have rendered the ʼ091 patent claims obvious. The PTAB found that the Shaprio and Carlsson references did not disclose that the claimed factor IX activity level could be obtained via Shaprio’s once weekly dosage. On this point, the PTAB referenced the contrary teachings in CSL’s cited art that two to three weekly doses were required to obtain the claimed level. The PTAB also noted that CSL did not explain how the six day duration of the clotting effect in Peters 2007 is consistent with maintaining the required plasma level of factor IX for the claimed 10-14 day interval. Accordingly, the PTAB also denied institution of the ʼ345 IPR.

Bioverativ also asserted a claim for patent infringement against CSL in the District of Delaware.  In the Complaint, Bioverativ asserted CSL’s Idelvion product infringes the ʼ091 patent along with two other patents. The District Court action is currently pending with a jury trial set to begin on March 30, 2020.

We will continue to keep you updated on further developments.

The Biologics Price Competition and Innovation Act (“BPCIA”) requires applications to market a biological product be submitted for review by the FDA under § 351 of the Public Health Service Act (“PHS Act”). However, it carved out a limited exception for biological products that are in a product class that had already been approved under § 505 of the Food, Drug, and Cosmetic Act (“FD&C Act”) prior to enactment of the BPCIA. For biological products in that limited category, the applicant was given the option to seek approval under §505 of the FD&C Act provided that the application was submitted prior to enactment of the BPCIA, or was submitted not later than 10 years after enactment of the BPCIA. Thus, the BPCIA created a 10-year transition period wherein certain biological products could be approved under § 505 instead of § 351.

March 23, 2020, marks the end of that 10-year transition period. According to the BPCIA, on that date, all NDAs for biological products that were approved under §505 of the FD&C Act will be “deemed to be a license for the biological product” under § 351 of the PHS Act. The FDA has now published guidance on how it will interpret the “deemed to be a license” transition provision of the BPCIA.

In brief, the FDA interprets the “deemed to be a license” provision to only apply to NDAs that have been approved as of the transition date. The FDA explains that the statutory language does not provide a path for approved NDAs to be transitioned to a BLA, either before or after the specified transition date. Consequently, the FDA will not approve any application for a biological product submitted under § 505 that is pending or tentatively approved on March 23, 2020, and will instead issue a complete response letter to any such application. For this reason, the FDA suggests that applicants who are contemplating submitting a § 505 application for a product that will be transitioned consider instead submitting the application under § 351.

The FDA also explains that all biological products subject to the transition provision will be removed from the Orange Book on the transition date. Those products will then be listed in the Purple Book. Moreover, any unexpired exclusivity (except for orphan drug or pediatric exclusivity) for an approved NDA that is transitioned to a BLA will no longer be in effect. Orphan drug and pediatric exclusivity will remain in force because the § 351 also provides for those types of exclusivity.

On the question of exclusivity, the FDA makes it clear that transitioned NDAs will not be granted the exclusivity that applications originally approved under § 351 enjoy. More specifically, transitioned NDAs will not be granted a 12-year period wherein the FDA may not approve a § 351(k) application, or a 4-year period wherein an applicant may not submit a § 351(k) application to the FDA. The FDA’s reasoning is that those exclusivity periods begin on the date that the § 351(a) application was first licensed, and a transitioned § 505 application was not first licensed under § 351(a). As articulated by Commissioner Gottlieb in remarks accompanying the release of the guidance documents, the FDA’s reasoning is also guided by a desire to encourage competition, which would be blunted by granting an additional 12 years of exclusivity to these products, some of which were first approved over 30 years ago.

So, what products will be impacted by this transition provision? The FDA has published a preliminary list of products that are anticipated to be affected by the transition provision. Perhaps the most notable are the various insulin products, although there are a number of other significant products listed.

The FDA has also published a Question and Answer document on the “Deemed to be a License” Provision. In this document, the FDA explains that transitioned applications will be deemed § 351(a) BLA. These transitioned NDAs will also be subject to the requirements under the PHS Act, including those requirements that differ from the FD&C Act. However, the FDA also indicates its belief that there will be minimal disruption due to those differences. The FDA specifically identifies differences in labeling and CMC requirements that transitioned BLAs will need to address. However, the FDA specifically addresses those differences and provides its guidance in the Q & A document.

Last month, the FDA released four new guidance documents providing insight on the FDA’s interpretation of provisions of the Biologics Price Competition and Innovation Act (“BPCIA”), as it amends the Public Health Service Act (“PHS Act”) and the Patient Protection and Affordable Care Act (“ACA”), among other statutes. Two of the documents relate to the “Deemed to be a License” provision in section 7002(e) of the BPCIA, and are covered in a separate post. The remaining two documents, which will be discussed here, address recommended practices for biosimilar development and meeting the application requirements for biosimilar and interchangeable products.[1]

The Questions and Answers on Biosimilar Development and the BPCI Act (Revision 1) guidance document is intended to enhance transparency of the FDA’s interpretation of the BPCIA by providing responses to common questions from prospective applicants and interested parties. The content is largely pulled from two of the FDA’s prior draft guidance documents issued in April 2015 and May 2015, respectively, with some updates and revisions.

In particular, the Q&A addresses questions regarding the permissible differences between a proposed biosimilar product and a reference product, as related to formulation and delivery device and the number of routes of administration, presentations (e.g., strengths or delivery devices), and conditions of use. One noteworthy change from the earlier drafts that spans several of the questions is the reference to a new January 2017 guidance document entitled “Considerations in Demonstrating Interchangeability With a Reference Product.” While the 2015 drafts included brief explanations about the FDA’s review process for interchangeable products as relevant to each question, the revised responses now direct applicants to the comprehensive 30-page guidance, which provides detailed suggestions for the development of and applications for a proposed interchangeable product specifically.

Other relevant differences between the drafts include: a change in the recommended length of time to retain reserve samples of the products used in comparative clinical studies intended to support a 351(k) application (now for at least 5 years following the date on which the 351(k) application is licensed, or, if such application is not licensed, at least 5 years following the date of completion of the studies); removal of the recommendations related specifically to retaining samples from multi-site studies and products intended for multi-dose administration; and an expanded definition of “publicly-available information” in relation to FDA’s previous determination that the reference product is safe, pure, and potent to include in a 351(k) application (the definition now includes “FDA-approved labeling for the reference product,” in addition to the types of information found in the “action package” for a Biologics License Application (“BLA”)). Lastly, while some Q&As were withdrawn and moved to the companion draft guidance document (addressed below), one  question relating to the permissibility of extrapolated clinical data was withdrawn entirely, and instead refers applicants with questions about the standards for clinical data to another guidance from April 2015, entitled “Scientific Considerations in Demonstrating Biosimilarity to a Reference Product.”

The companion document to Questions and Answers on Biosimilar Development and the BPCI Act (Revision 1) is New and Revised Draft Q&As on Biosimilar Development and the BPCI Act (Revision 2), which includes additional Q&As that address the requirements for pediatric assessments or investigations under the Pediatric Research Equity Act (“PREA”), the suggested support for post-approval manufacturing changes for a licensed biosimilar product, and the definition of “protein” in section 351(i)(1) of the PHS Act. Notably, the document also clarifies that a 351(k) application is not the appropriate vehicle to seek approval for routes of administration, dosage forms, strengths, or conditions of use that differ from those of the reference product, implying that sponsors must instead utilize the regular, unabbreviated pathway for licensure in those instances.

A new topic that the FDA addresses in this second guidance is the issue of when a reference product holder refuses to sell a product to a prospective applicant that is seeking to conduct studies to support approval of a biosimilar product, based on a belief that supplying the product for that purpose would violate the risk evaluation and mitigation strategy (REMS) with elements to assure safe use (ETASU) for the reference product. Noting that such incidents have occurred, the FDA proposes a solution where the prospective applicant may submit study protocols to the FDA and request a letter from the FDA stating that the proposed studies contain safety protections that would comply with the REMS. If the FDA finds that the safety protections are comparable to those in the REMS, the FDA would then notify the reference product holder with a separate letter indicating that the Agency would not consider the supply of the reference product to the prospective applicant for the required testing to be a violation of the REMS. The FDA hopes that this solution will help facilitate a prospective applicant’s access to the reference product for purposes of supporting the license application.

[1] The FDA clarifies that a “biosimilar” or “biosimilar product” refers to a product that the FDA has determined to be biosimilar to the reference product under sections 351(i)(2) and 351(k)(2) of the PHS Act, and that an “interchangeable biosimilar” or “interchangeable product” refers to a biosimilar product that the FDA has determined to be interchangeable with the reference product under sections 351(i)(3) and 351(k)(4) of the PHS Act.

The FDA recently proposed an amendment to its regulations defining the term “biological product.”  The proposed amendment incorporates changes made by the Biologics Price Competition and Innovation Act (BPCIA) into the FDA’s regulations, and provides the FDA’s interpretation of the statutory terms “protein” and “chemically synthesized polypeptide.”  The proposed definitions of the statutory terms are not too surprising because they are the same definitions that the FDA has provided in previously issued guidance documents.

The FDA’s proposed definition of “protein” is “any alpha amino acid polymer with a specific, defined sequence that is greater than 40 amino acids in size.”  The proposed definition of “chemically synthesized polypeptide” is “any alpha amino acid polymer that is made entirely by chemical synthesis and is greater than 40 amino acids but less than 100 amino acids in size.”  The proposed definitions for both terms include the proviso that if two or more chains of an amino acid polymer are associated with one another as they are in nature the size of the amino acid polymer will be based on the total number in the chain and is not limited by the number in a contiguous sequence.  The FDA also explains in the rulemaking document that if a product comprises amino acid chains that are associated in a manner not found in nature, then the FDA will conduct a fact-specific, case-by-case analysis to determine whether the size of the amino acid polymer should be determined by adding the total number of amino acids together, or if it should be based on the amino acid chain lengths in isolation.

The purpose of the proposed amendment is to clarify the statutory authority under which protein products are regulated.  In particular, the proposed amendment will help determine whether a product comprised of amino acids will be regulated under section 351 of the Public Health Service Act (PHSA), or section 505 of the Food, Drug, and Cosmetic Act (FD&C Act).  For example, under the proposed rule, an amino acid polymer with a specific, defined sequence less than 40 amino acids in size will be considered a peptide, and will be regulated under the FD&C Act instead of the PHSA.  In contrast, non-chemically synthesized proteins greater than 40 amino acids in length will be regulated by the PHSA.

The FDA also explains that the phrase “made entirely by chemical synthesis” in its proposed definition of “chemically synthesized polypeptide” means that the amino acids in the chain were added by a process that does not involve cell-based or cell-free recombinant DNA directed synthesis or recombinant RNA directed synthesis.  If that condition is met, and the product does not otherwise fall under the definition of biological product, such as by being a vaccine, then the chemically synthesized polypeptide product will be regulated under the FD&C Act.

The clarification provided by the proposed rule is important as the end of the BPCIA transition period draws near.  More specifically, on March 23, 2020, NDAs for certain biological products will be transitioned to BLAs as mandated by the BPCIA.  For this reason, it is not surprising that the FDA also released guidance on how it will interpret certain statutory provisions relating to that transition on the same day as it published its proposed rule.  The transition guidance documents will be discussed in a separate post.

Electronic or written comments on the FDA’s proposed amendment may be submitted until February 25, 2019.

Prior to 1994, the term of a U.S. patent was 17 years from the date of issuance.  When the Uruguay Round Agreements Act (“URAA”) changed the term to 20 years from the earliest nonprovisional priority date, it appeared that unpatentability due to obviousness type double patenting (“ODP”) would no longer be relevant since the patent term could no longer be extended by filing later applications claiming the same or similar subject matter. If an ODP rejection were made, a terminal disclaimer could be submitted based on a belief that no patent term would be lost.  However, in Gilead Sciences, Inc. v. Natco Pharma Ltd., 753 F.3d 1208 (Fed. Cir. 2014) (hereinafter Gilead), the Federal Circuit reaffirmed the relevance of ODP.

To recap, Gilead Sciences, Inc. owns U.S. Patent Nos. 5,763,483 (“the ’483 patent”) and 5,952,375 (“the ’375 patent”).  Both patents have the same inventors and disclose similar subject matter, but (1) were not examined by the same Examiner, (2) do not claim priority to a common patent application, and (3) have different expiration dates.  During the examination of the ’375 patent, a terminal disclaimer was filed disclaiming the term of the ’375 patent, which would have extended beyond the term of the first issued ’483 patent.  Gilead Sciences, Inc. argued that the ’375 patent could not be used as an ODP reference against the ’483 patent because the ’375 patent issued after the ’483 patent.  The Federal Circuit disagreed, concluding that the determining factor for ODP is the expiration date and not the issue date, since using the issue date as the determining factor would permit significant gamesmanship during prosecution.  In other words, separate applications with different priority claims could be used to ensure that specific claims issued from the application with the later priority date.  The decision in Gilead was affirmed in Abbvie v. Mathilda & Terence Kennedy Institute, 764 F. 3d 1366 (Fed. Cir. 2014) (hereinafter Abbvie) where the Federal Circuit stated that “[w]e now make explicit what was implicit in Gilead: the doctrine of obviousness-type double patenting continues to apply where two patents that claim the same invention have different expiration dates.”  Thus Gilead and Abbvie are different from an ODP analysis before the URAA where the term of a later issuing patent could not be used to shorten the term of an earlier issuing patent.

Two recent Federal Circuit decisions further clarify the ODP doctrine as it is applied post URAA.  In Novartis AG v. Ezra Ventures LLC (Fed. Cir. 2018), Novartis’ U.S. Patent No. 5,604,229 (“the ’229 patent”) was filed before the effective date of the URAA and thus had a term of 17 years from issuance (February 14, 2014). A patent term extension of five years pursuant to 35 USC §156, was obtained based on the time required for regulatory review, extending the term to February 18, 2019.  The ’229 patent claims a group of compounds including fingolimod.  Novartis also owns U.S. Patent No. 6,004,565 (“the ’565 patent”) directed to methods for administering fingolimod. The ’565 patent was filed after the effective date of the URAA and thus had a term of twenty years from its effective filing date (September 23, 2017). Ezra Ventures argued that (1) the extension of the ’229 patent  effectively extends the term of the ’565 patent  (since the method cannot be practiced without the product), thereby violating the requirement that only one patent be extended under 35 USC §156(c)(4), (2) the ’565 patent  should be applied as an ODP reference against the ’229 patent, and (3) there is an overriding policy concern that a patent owner should not be able to extend his rights through claims in a later-filed patent when the claims are not patentably distinct from claims in an earlier-filed patent.  The Federal Circuit found that there was no reason to read the term “effectively” as a modifier to “extend” in the language of 35 USC §156.  The court stated that the language in 35 USC §156(c)(4) referred to a legal extension with a certificate of extension recorded in the official file and considered as part of the original patent.  Though the method of the ’565 patent cannot be practiced during the extended term of the patent, this was found to be a “permissible consequence of the legal status conferred upon the ʼ229 patent by §156.”  Regarding the ’565 patent as an ODP reference against the ’229 patent, the Federal Circuit concluded that ODP does not invalidate a validly obtained patent term extension.  The court noted the contrast between 35 USC §156 and 35 USC §154, which expressly excludes patents which have been disclaimed beyond a specified date from term adjustment for PTO delays.  However, the Federal Circuit did not address patent term adjustment for a patent which has not been disclaimed beyond a specified date. The Federal Circuit also found that there was no potential gamesmanship issue through structuring of priority claims as in Gilead, and thus there were no overriding policy concerns.

In Novartis Pharmaceuticals Corp. v. Breckenridge Pharmaceutical Inc. (Fed. Cir. 2018), the Federal Circuit found that a post URAA patent was not a proper ODP reference for a pre-URAA patent with a five year patent term extension under 35 USC §156.  U.S.  Patent No. 5,665,772 (“the ’772 patent”) was filed and issued before U.S. Patent No. 6,440,990 (“the ’990 patent”), but both patents claimed the same priority date.  However, the ’990 patent expired before the ’772 patent  due to the post-URAA patent term of 20 years from the earliest effective filing date (September 23, 2013). The ’772 patent was filed before the effective date of the URAA and had a term of 17 years from issuance (September 9, 2014) plus a five year patent term extension under 35 USC §156 (September 9, 2019).  Though the Federal Circuit held in Gilead that the expiration date is the benchmark of obviousness type double patenting, the court found that the traditional obviousness type double patenting analysis based on the issue date should be applied to pre-URAA patents.  Under this analysis, the ’990 patent was not available as a double patenting reference against the ’772 patent.  The court’s reasoning was that the ’772 patent had a longer term due only to the change in the law, and did not involve gamesmanship during prosecution.  The Federal Circuit stated that “to require patent holders to truncate any portion of the statutorily assigned term of a pre-URAA patent that extends beyond the term of a post-URAA patent would be inconsistent with the URAA transition statute.” Thus, the court’s decision in both Gilead and Abbvie is limited to post-URAA patents.

Though none of the recent cases involved patent term adjustment, the decisions suggest that extensions of the term which are based on a statutory right should not be limited by later granted patents as long as gamesmanship is not involved.  Patent term adjustment is based on 35 USC §154(b) and thus following the rationale of the above discussed cases, ODP should not be available to invalidate a validly obtained patent term adjustment.  However, care must be taken to avoid anything which could be interpreted as gamesmanship, such as claiming different priority dates for the same or similar subject matter.

We previously wrote about Genentech’s U.S. Patent No. 6,407,213 (“the ’213 patent”) to Carter, first in October 2017, and more recently in March 2018. At the time of our last update, the ’213 patent had been at issue in six district court litigations, and had been the subject of ten filed IPR petitions, variously by Mylan Pharmaceuticals, Inc., Celltrion, Inc., Pfizer Inc., Boehringer Ingelheim Pharmaceuticals, Inc., and Samsung Bioepis Co., Ltd.

At that time, the two IPR proceedings brought by Mylan settled prior to institution; at least some grounds in the petitions by Celltrion, Pfizer, and Samsung Bioepis had been instituted; and the Boehringer Ingelheim petitions were pending.

Since then, there have been major developments not only in the litigations, but also with institutions, rehearings, and final written decisions in the IPRs. They are addressed below. One point that sticks out is that many of the actions appear to have settled, or otherwise been dismissed.

Beginning with actions that have terminated, soon after our previous article was published, the Boehringer Ingelheim petitions IPR2017-02031 and IPR017-02032 were both instituted on less than all grounds on March 29, 2018. However, in a request for rehearing based on the SAS Institute Supreme Court decision (which we covered in a post on our PTAB blog), both petitions were instituted as to all grounds in May 2018. Later filed requests for rehearing by Genentech were denied on the issue posed by SAS Institute. In the latest action, however, Boehringer Ingelheim requested adverse judgment as to both petitions, and both motions were granted on July 31, 2018.

Following the much earlier Mylan settlement (dismissed in March 2017), the Boehringer Ingelheim IPRs are the first sign that Genentech has begun attempting settlement with (at least some of) the various parties challenging its ’213 patent.

In May 2018, the case Celltrion v. Genentech, No. 4:18-cv-00274 (N.D. Cal.) was dismissed. The judge found that Celltrion’s declaratory judgment action failed to state a claim for relief, as Celltrion did not complete its obligations under the patent dance, and as such was not properly able to file a declaratory judgment action. Celltrion since appealed this decision to the Federal Circuit in July, and then voluntarily moved to dismiss the appeal in November. The dismissal was granted on November 30, 2018.

Next, in Genentech v. Pfizer, No. 1:17-cv-01672 (D.Del.), a stipulated dismissal due to settlement was entered on December 4, 2018.

As for actions which have reached determinations regarding the ’213 patent, Final Written Decisions were entered to both IPR2017-01374 by Celltrion and IPR2017-01488 by Pfizer on November 29, 2018. In each of these IPRs, 18 challenged claims were determined to be unpatentable, while 11 challenged claims survived. Of the surviving claims, 8 of the claims appear to have survived, at least in part, based on the defeat of two primary references (contained in all instituted grounds) as prior art by demonstration of support for the claims in the ’213 patent’s priority document, and by Genentech’s evidence of prior invention.

As for ongoing actions, in July, hearings were held as to both Celltrion petitions, IPR2017-01373 and IPR2017-01374, as well as both Pfizer petitions, IPR2017-01488 and IPR2017-01489 (and, by extension, the joined Samsung Bioepis petitions). As of this writing, Celltrion IPR2017-01373 and Pfizer IPR2017-01489 are both pending.

Of the pending litigation, many are currently around a similar stage. In Genentech v. Celltrion, No. 1:18-cv-00095 (D. Del.), a motion stipulating dismissal of certain of the patents alleged in the complaint was entered on October 17, 2018. Dismissal did not include the ’213 patent. The case as a whole remains ongoing, and is currently in the midst of discovery and claim construction.

Genentech v. Celltrion, No. 1:18-cv-01025 (D. Del.) was filed July 11, 2018. The parties have stipulated as to consolidation with the above action on December 3, 2018, but as of this writing, the stipulation does not appear to have been entered.

In Genentech v. Amgen, No. 1:17-cv-01407 (D.Del.) a claim based around Amgen first providing one date for its notice of commercial marketing, and then providing an earlier date was dismissed on April 17, 2018.  The matter was consolidated with another Genentech v. Amgen case, No. 1:17-cv-01471, in October, and the consolidated cases are currently in the discovery process.

An additional case against Amgen, Genentech v.  Amgen, No. 1:18-cv-00924 (D. Del.), was filed on June 21, 2018. A similar dismissal of certain of the patent infringement claims was made July 19, 2018. Otherwise, the case is ongoing, and is in the midst of discovery and claim construction.

The last litigation to be filed to date, Genentech v. Samsung Bioepis, No.  1:18-cv-01373 (D. Del), was filed on September 4, 2018. Discovery appears to have just begun following entry of scheduling orders, discovery orders, and protective orders in November 2018.

In sum, several IPRs and litigations are ongoing with the Carter ’213 patent at issue, but several cases have been dismissed or have apparently settled since our last update. Importantly, 18 claims of the ’213 patent have been found unpatentable by IPR proceedings brought by Celltrion and by Pfizer, and it will be interesting to see how this might impact the ongoing litigations.

As we previously reported, one of three Pfizer IPR petitions filed in April 2017 against Biogen-owned patents claiming methods of treatment with rituximab was instituted.  The instituted IPR is IPR2017-01168 regarding U.S. Patent No. 8,821,873 (the “’873 patent”), and the PTAB recently issued its Final Written Decision.

Adhering to its institution decision where it consolidated the two asserted grounds into a single ground consisting of five references, the Board found all claims unpatentable over a combination of:  (1)  Moreau (Moreau et al., Peripheral blood stem cell transplantation as front-line therapy in patients aged 61 to 65 years: a pilot study, 21 BONE MARROW TRANSPLANTATION 1193–96 (1998)); (2)  Link (Link et al., Phase II Pilot Study of the Safety and Efficacy of Rituximab in Combination with CHOP Chemotherapy in Patients with Previously Untreated Intermediate- or High-Grade NHL, Program/Proceedings, 17 AM. SOC. CLIN. ONCOL. 3a (Abstract 7) (1998)); (3)  McNeil (McNeil, Non-Hodgkin’s Lymphoma Trials In Elderly Look Beyond CHOP, 90 J. NAT. CANCER INST. 266–67 (1998)); (4)  Maloney (Maloney et al., IDEC-C2B8: Results of a Phase I Multiple-Dose Trial in Patients with Relapsed Non-Hodgkin’s Lymphoma, 15 J. Clin. Oncology 3266–3274 (1997)); and (5)  Coiffier (Coiffier et al., Rituximab (Anti-CD20 Monoclonal Antibody) for the Treatment of Patients with Relapsing or Refractory Aggressive Lymphoma: A Multicenter Phase II Study, 92 BLOOD 1927–32 (1998)).

The ’873 patent generally relates to a method of treating a patient over the age of 60 who has diffuse large cell lymphoma (“DLCL”) by administering anti-CD20 antibody (e.g., Rituxan®) and CHOP (cyclophosphamide, hydroxydaunorubicin/doxorubicin, vincristine, and prednisone/prednisolone) chemotherapy “wherein the anti-CD20 is administered in combination with stem cell transplantation.”  ’873 patent claim 1 (emphasis added).  Claim 4 further claims that the lymphoma is accompanied by bone marrow involvement.

Importantly, during claim construction the Board found that under the broadest reasonable interpretation standard, administering rituximab “in combination with stem cell transplantation,” would include administering the rituximab during induction, which it found was described as one of the “various stages of transplantation” in the specification.  FWD at 8 (finding that “in combination with stem cell transplantation” “means that the rituximab may be administered ‘at induction, in vivo purging, mobilization, conditioning, post-transplant reinfusion and at any other time during bone marrow or stem cell transplant for the purpose of improving the survival rate of transplant recipients”).  As a result, the Board agreed with Petitioner that administering rituximab at the induction of CHOP chemotherapy but before collecting and transplanting stem cells would fall within the scope of the ’873 patent claims requiring that the antibody be administered in combination with the stem cell transplantation.  Id.

In addition, the Board found that a person of ordinary skill in the art of would have at least an M.D. degree and more than a year of experience treating patients with NHL and would have familiarity with the published research and clinical trials directed to treating NHL patients.  Id. at 10.  Such a person could be an oncologist or hematologist.

With respect to obviousness, and consistent with its institution decision, the Board concluded that it was undisputed by the parties that the primary reference, Moreau, teaches all of the claim elements of claim 1 except for the use of rituximab.  FWD at 16.  The focus of the analysis, therefore, was whether “a person of ordinary skill in the art would have been motivated to combine rituximab with the CHOP in Moreau’s treatment method, and whether the person of ordinary skill in the art would have had a reasonable expectation of success in treating Moreau’s patient, i.e., a DLCL patient greater than 60 years old, by doing so.”  Id.  The Board found that there was sufficient motivation as well as a reasonable expectation of success.  Id. at 31.

Petitioner argued that because only half of Moreau’s DLCL patients had complete responses, there was motivation to combine another treatment with Moreau’s treatment that would increase efficacy and/or reduce toxicity.  Id. at 16-17.  The Board found that Petitioner had sufficiently demonstrated that a person of ordinary skill in the art would have understood from McNeil that an alternative to CHOP in elderly patients is the combination of CHOP and rituximab, that Link taught that CHOP plus rituximab may provide an increased response in DLCL patients, that Coiffier taught that rituximab has “significant anti-lymphoma activity in DLCL,” and that Maloney taught that rituximab does not impair bone marrow reserves.  Id. at 30.  Further, the Board found that rituximab was shown to be well-tolerated and well-tolerated when combined with CHOP, and therefore, it agreed with the Petitioner that it was reasonable to expect Moreau’s well-tolerated method of treatment to remain well-tolerated in combination with rituximab.  Id.

The Board also ruled on the parties’ motions to exclude.  It denied Petitioner’s motion to exclude exhibits as moot because it had not relied on the exhibits.  Id. at 34.  It also denied Patent Owner’s motion to exclude the 1997 Rituxan label.  Patent Owner argued that Petitioner had not established that the label existed and was available in 1997.  Id. at 34-35.  The Board noted that this issue related to the status of the exhibit as prior art and should have been raised in the briefing instead of in a motion to exclude.  Id. at 35.  It further found that Patent Owner failed to show that Petitioner had not sufficiently authenticated the exhibit and was not persuaded that the exhibit constituted hearsay.  Id.  The Board was likewise unpersuaded that other exhibits constituted hearsay and denied Patent Owner’s motion to exclude with respect to those exhibits.  Id.  And, it denied Patent Owner’s motion to exclude that was contingent upon the Board’s ruling on Petitioner’s motion to exclude given that the latter had been denied.  Id.  The Board also rejected Patent Owner’s arguments related to its motion to exclude the redirect testimony of Petitioner’s Reply declarant, Dr. Soiffer.

Given the foregoing, all claims of the ’873 patent have currently been held unpatentable.

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.