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.