February 8, 2017

FUSTIBAL LLC (Petitioner)  v. BAYER HEALTHCARE LLC, (Patent Owner)

Case IPR2016-01490
Patent 8,637,553 B2

Link to PTAB Decision Denying Institution

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Regorafenib (API of STIVARGA®)

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Prior art compound = Sorafenib (Nexavar®)

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Summary

The Patent Trial and Appeal Board (PTAB) declined Fustibal’s petition to Institute an Inter Partes Review (IPR) trial of Bayer’s U.S. Patent 8,637,553 B2 claiming regorafenib (API of STIVARGA®).

The PTAB concluded that Fustibal did not establish a reasonable likelihood that Bayer’s claims are rendered as anticipated or obvious by the prior art.

At first glance, Fustibal’s petition looks strong because Bayer’s regorafenib merely differs from the prior art’s sorafenib by one fluorine on the center aromatic ring.  [Sorafenib does not have the extra fluorine] Fustibal argues that Bayer merely added fluorine as an obvious modification.

Fustibal challenged both regorafenib’s novelty and non-obviousness over the closest prior art publication WO 00/42012 to Riedl.

PTAB’s Deference to the Patent Examiner

The PTAB declined to second-guess the Patent Examiner because the examiner repeatedly reconsidered the prior art patent (Riedl) during prosecution and expressly allowed the claims over the prior art.

The patent examiner provided the following Reasons for Allowance:

“After a thorough search, the closest prior art, WO 00/42012 to Riedl, et al. was found to teach similar phenyl-urea derivatives as kinase inhibitors.  However, the WO document fails to teach or render obvious the instant claimed compounds according to Formula (I), and does not fairly suggest their salts or pharmaceutical compositions.”

The PTAB further declined to institute an IPR trial on the merits.

Anticipation / Novelty – §102

Even though the prior art recited a genus that would encompass regorafenib, the PTAB determined that the prior art genus was too vast to anticipate regorafenib.

• Where “the number of compounds actually disclosed by [the asserted prior art] numbers in the millions (including all proposed alternative substituents),” the prior art genus cannot anticipate a later species claim.  (Eli Lilly & Co. v. Zenith Goldline Pharm., Inc., 471 F.3d 1369, 1376 (Fed. Cir. 2006))
• Where a reference does not “clearly and unequivocally disclose the claimed compound,” to be anticipatory reference under 35 U.S.C. § 102, it must, nevertheless, “direct those skilled in the art to the compound without any need for picking, choosing, and combining various disclosures not directly related to each other by the teachings of the cited reference.”  In re Arkley, 455 F.2d 586, 587 (CCPA 1972).  For the reasons set forth at pages 9–16 of the Preliminarily Response, we agree with Patent Owner that the genus relied on by Petitioner, having “‘eight individual chemical compounds possible when substituting a halogen”—F, Cl, Br, or I—at position 2/2’ or 3/3’ of the central ring of sorafenib, does not exist in Riedl, and only results from Petitioner’s improper picking and choosing disparate aspects of the disclosure.  See Prelim. Resp. 13–15 (quoting Pet. 16).

Obviousness – § 103

As expected, the PTAB applied the two-prong inquiry [“lead compound analysis”] from Otsuka Pharm. Co. v. Sandoz, Inc., 678 F.3d 1280, 1291–93 (Fed. Cir. 2012) for determining whether a claimed compound would have been obvious over prior art compounds.  First, the PTAB determined whether a chemist of ordinary skill would have selected the asserted prior art compounds as lead compounds, or starting points, for further development efforts.  Second, the PTAB analyzed whether there was a reason to modify a lead compound to make the claimed compound with a reasonable expectation of success.

The PTAB noted that Fustibal’s petition did not include a “mandatory” lead compound analysis.  Fustibal merely assumed – without explanation – that a person of ordinary skill in the art would select sorafenib as a lead compound for modification.

The PTAB did not discern a reason to select from Sorafenib from the prior art Riedl reference because the reference does not highlight any of the vast number of disclosed compounds is having particularly beneficial properties or present any enzymatic or biological data.

No reason to modify Sorafenib by adding one fluorine to arrive at Regorafenib

Fustibal’s petition did not provide the necessary reasons why a chemist would modify the prior art in that particular manner. Even though the prior art discloses potential benefits of adding one or more fluorine atoms, the prior art merely indicates that the prior art compound can be halogenated.

The PTAB did not read the prior art to suggest that any fluorine substitution will result in improved pharmacological properties.  The PTAB agreed with the patent owner that if improvements by adding fluorine were always true, then “all pharmaceutical compounds would be fluorinated, which is plainly not the case.”  Meanwhile, the compound already had a trifluoromethyl group on it.  The petitioner could not explain why a chemist would add multiple additional fluorine atoms.

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Notes:

On November 22, 2013, the U. S. Food and Drug Administration approved sorafenib (NEXAVAR tablets, Bayer Healthcare Pharmaceuticals Inc.) for the treatment of locally recurrent or metastatic, progressive, differentiated thyroid carcinoma (DTC) refractory to radioactive iodine treatment. The FDA previously approved Sorafenib for treatment of renal cell carcinoma (2005) and hepatocellular carcinoma (2007).

http://www.fda.gov/Drugs/InformationOnDrugs/ApprovedDrugs/ucm376547.htm

The U.S. Food and Drug Administration approved Stivarga® (regorafenib) on September 27, 2012 to treat patients with colorectal cancer that has progressed after treatment and spread to other parts of the body (metastatic). http://www.fda.gov/NewsEvents/Newsroom/PressAnnouncements/ucm321271.htm