More than the mere look of a compound is required to establish obviousness
| January 22, 2019
Amerigen Pharmaceuticals v. UCB Pharma GMBH
January 11, 2019
Before Lourie, Chen and Stoll. Opinion by Lourie.
Summary
Amerigen appeals an inter parties review Decision by the U.S. Patent and trademark Office Patent Trial and Appeal Board (hereinafter “the Board”) that the U.S. Patent No. 6,858,650 (hereinafter ‘650) was not unpatentable as obviousness. The CAFC held that there was substantial evidence to support the Board’s findings. The CAFC affirmed the Board’s findings.
Details
The U.S. Patent No. 6,858,650 (hereinafter ‘650) claims some chemical derivative of 3,3‑diphenylpropylamines, including fesoterodine. Fesoterodine, an antimuscarinic drug with the following chemical structure:
“Fesoterodine is a prodrug of the active compound 5-hydroxymethyl tolterodine (hereinafter “5‑HMT”). A prodrug is an inactive molecule that, once inside the body, transforms to an active therapeutic agent.
5‑HMT is a metabolite of the compound tolterodine, an older antimusarinic drug….” Id. at 3. 5-HMT is an active metabolite, which has its own antimuscaranic activity and can contribute to the therapeutic effect of tolterodine. Tolterodine is converted to 5-HMT, once ingested by a patient, by cytochrome P450 2D6 (hereinafter “CYP2D6”). CYP2D6 converts the methyl group at the 5-position of the benzene ring of tolterodine to a hydroxylmethyl group in 5‑HMT. The following is the chemical structures of tolterodine and 5-HMT.
A noted distinction between 5-HMT and fesoterodine is present at the 2-position of the benzene ring. In fesoterodine, an isobutyryl ester is at the 2-position. In 5-HMT, the 2-postion is a hydroxyl group.
An inter partes review (IPR) of ‘650 was brought by Mylan Pharmaceuticals Inc. The Board instituted the review based on “(1)obviousness over the Detrol Label, Postlind, Bundgaard, Bundgaard PCT, and Berge; and (2) obviousness over Brynne, Bundgaard, Bundgaard PCT, and Johansson.” Id. at 4. After the institution of the IPR, Amerigen joined as a party to the proceeding.
In the IPR, Petitioners argued that there was sufficient motivation for a skilled artisan to modify 5-HMT. Petitioners’ Expert testified that 5-HMT had insufficient lipophilicity and this would cause bioavailability problems. Id. at 7. The Expert, citing Brynne as support, stated that tolerodine is 10-fold more lipophilic than 5-HMT. UCB argued that there was no basis to allege modification of 5-HMT due to a bioavailability issue. UCB argued that none of the cited art suggested an issue regarding absorption by 5-HMT and further argued that “the lipophilicity of 5-HMT relative to tolterodine…did not show that 5-HMT had a bioavailability problem.” Id. at 7. Further, UCB’s Expert testified to an analysis of 5‑HMT using the Rule of 5 by Lipinski, which assesses 4 inherent properties of a compound to predict a potential bioavailability problem, and found that none of properties indicated a bioavailability problem for 5-HMT. Id. at 7. Petitioner’s Expert agreed that a skilled artisan would use the Rule of 5 to determine if there a potential bioavailability problem.
The Board held that, while a skilled artisan would have reason to choose 5-HMT as a lead compound, said artisan would not have been motivated to modify 5-HMT to achieve a prodrug wherein the 2-position hydroxyl group is replaced with an alkyl ester of six or fewer carbons. Id. at 6 and 7. Moreover, the Board, crediting UCB’s Expert, held that a skilled artisan would not have been motivated to modify 5‑HMT due to a bioavailability issue. Further, the Board, found that:
- Since there is no bioavailability issue, a skilled artisan would not have any reason or motivation to achieve a 5-HMT prodrug;
- Designing a prodrug is difficult since a skilled artisan must consider toxicity, bioavailability, and other drug characteristics of two compounds, rather than just one;
- Petitioners failed to establish that an ester of 5-HMT would be inactive, an essential characteristic of a prodrug; and
- Petitioners did not present any prodrugs in the same chemical class, with the same mechanism of action or the in the same field of treatment.
Id. at 8. The Board concluded that it would not have been obvious to develop a prodrug of 5‑HMT. Furthermore, the Board held that achieving the compounds claimed in the ‘650 patent would not have been a matter of routine optimization; none of the cited art disclosed the molecule fesoterodine and that there were too many possibilities of molecular modifications of 5-HMT consistent with a prodrug design to render obvious the compounds claimed in the ‘650 patent. The Board, relying upon UCB’s Expert, held that a skilled artisan may consider esterifying the hydroxy groups at the 2-position and the 5-postion, but that even if said artisan only considered esterification of the 2-position hydroxy, there was not reason or motivation to achieve an ester of six carbons or less and further, even if all possible esters were limited to only alkyl esters of 6 carbons or less at the 2-position, there would still be 86 possibilities disclosed. The Board held it would not be routine to test each of the 86 possibilities. Id. at 9.
Amerigen appealed the holding of the Board and argued before the CAFC that the Board’s holding was improper because:
- The Board did not understand the argument regarding lipophilicity and that a skilled artisan would have motivation to increase lipophilicity of 5-HMT for its own sake (motivation)
- An excessive burden was place upon Petitioner to establish a motivation to make 5-HMT a prodrug (burden)
- The Board did not give sufficient consideration to their routine optimization argument (routine optimization)
Id. at 16 and 17. Further, Amerigen argued that the Board did not give sufficient consideration to their argument regarding the effect of a patent claiming 5-HMT. UCB argued that Amerigen did not present a legal error committed by the Board and that the Board’s findings were supported by substantial evidence. (Side Note – UCB also argued that Amerigen lacked standing to bring an appeal. The CAFC held that Amerigen had standing. This issue is not addressed herein).
The CAFC affirmed the Board’s decision, finding that there was sufficient evidence to support their factual findings. “A finding is supported by substantial evidence if a reasonable mind might accept the evidence as adequate to support the finding. Consol. Edison Co. v. NLRB, 305 U.S. 197, 229 (1938).” Id. at 17.
Regarding Amerigen’s first argument (motivation), the CAFC concluded that there was substantial evidence to support the Board’s holding that there is no reason or motivation to modify 5-HMT to increase lipophilicity. The CAFC noted the Board’s holding that UCB’s Expert “better addressed the bioavailability issue and that lipophilicity of 5-HMT relative to tolterodine did not demonstrate a bioavailability problem. We agree with UCB that a reasonable fact finder could have weighted Dr. Roush’s (UCB Expert) testimony over Dr. Patterson’s (Petitioner’s Exert).” Id. at 19. The CAFC also noted the Rule of 5 assessment of 5-HMT by UCB’s Expert that found that there was “no reason to suspect that 5-HMT would possess poor oral absorption.” Id. at 19.
Before the CAFC, Amerigen argued that “there need not be a specific problem with bioavailability of 5-HMT for one of ordinary skill in the art to be motivated to modify 5-HMT to further improve its bioavailability.” Id. at 19. The CAFC determined that this was merely a conclusory argument that was insufficient to overcome the substantial evidence that supported the Board’s holding.
Regarding Amerigen’s second argument (burden), the CAFC held that the Board correctly found that Petitioners did not meet their burden of proof (“In an IPR, the petitioner has the burden of proving unpatentability by a preponderance of the evidence. 35 U.S.C. § 316(e).” Id. at 18.) Relying upon Bundgaard, the Board noted that a prodrug is an inactive drug. The Board also noted that Petitioners failed to present any evidence that an ester of 5-HMT would be inactive. The CAFC held that the “Board sensibly found that a skilled artisan would ‘seek some degree of certainty that a prodrug of a particular molecule would be inactive before embarking on the process of attempting to create the prodrug’ and the petitioners failed to provide any such certainty.” Id. at 21.
Before the CAFC, Amerigen argued that the Board impermissible placed too high of a burden on Petitioners by requiring them to present a prodrug that was analogous to 5-HMT. The Board had noted that Petitioners did not present any evidence of a prodrug that would be analogous to 5-HMT. The CAFC held that the Board did not commit an error. The Board did not require such evidence but merely found the lack of such evidence to further support UCB’s position. The CAFC held that the Board inquiring as to the existence or not of a prodrug, similar to the claimed compounds, is not a dispositive error.
Regarding Amerigen’s third argument (routine optimization), the CAFC held that there was sufficient substantial evidence to support the Board’s holding that the cited art did not render obvious achieving the claimed monoester substitution solely at the 2-position of a 5-HMT and that Amerigen did not establish a discernible error in the Board’s analysis.
The Board had found 1) in view of Bundgaard, a skilled artisan would consider diester substitutions as well as other prodrug moieties, 2) a skilled artisan would consider modifying the 5-position and/or the 2‑position, and 3) Bundgaard did not disclose isobutyryl ester of fesoterodine. The Board held it would not have been routine for a skilled artisan to achieve the claimed molecular modification to 5-HMT to achieve the claimed compounds of the ‘650 patent. Before the CAFC, Amerigen argued that “Bundgaard disclosed esters as prototypical prodrug moieties and that modifying the 2-position alone would have been the most obvious choice.” Id. at 22. The CAFC noted that the Board considered the disclosure of ester prodrugs by Bundgaard but also considered the disclosure by Bundgaard of many other prodrug substitutions. UCB’s Expert testified to at least 6 categories of additional substitutions. The Board held that modifications at the 5-position was as likely as modifications at the 2-position since the cited art “did not indicate a preference for either the 2- or 5-position, and the inventors themselves considered modifying the 5-position.” Id. at 22. The Board dismissed as unpersuasive testimony by Petitioner’s Expert that modifying only the 5-position would pose a risk of transesterification since the risk was not sufficiently explained.
Lastly, before the CAFC, Amerigen argued that the Board did not give sufficient weight to the Petitioner’s argument, presented in a single-sentence footnote in the petition, that a skilled artisan would have been motivated to modify 5-HMT because 5-HMT was patented at the time of invention. The CAFC held that even if a patent of 5-HMT provided a commercial motivation to modify 5‑HMT, such a motivation did not render the claimed compounds of the ‘650 patent obvious. The CAFC held that Amerigen did not meet its burden that “the ‘prior art would have suggested making the specific molecular modifications necessary to achieve the claimed invention.” Takeda Chem. Indus., Ltd. v. Alapharm Pty., Ltd., 492 F.3d 1350, 1356 (Fed. Cir. 2007) (emphasis added) (quoting In re Deuel, 51 F.3d 1552, 1558 (Fed. Cir. 1995)). A general motivation to modify 5-HMT based on a prior patent would not suffice….” Id. at 23.
The CAFC, affirming the holding of the Board, stated that “[A]ny compound may look obvious once someone has made it and found it to be useful, but working backwards from that compound, with the benefit of hindsight, once one is aware of it does not render it obvious.” Id. at 23.
Take away
- Ensure that there is a clearly identified reason for making the proposed modification. General assertions for making a proposed modification may not establish a prima facie case of obviousness
a. Ensure that the clearly identified reason is logical. Furthermore, ensure the alleged reason has a correlation to the cited feature.
2. Consider the breadth of the possibilities for a substitution presented in the cited art. The disclosure regarding a specific substitution may be exponentially greater when one considers more than one reference and/or more than one possible location of said substitution, e. 2‑position and/or 5-position of a benzene ring.
Issuance date or expiration date as the reference point for obviousness-type double patenting?
| January 11, 2019
Novartis Pharmaceutical Corp. v. Breckenridge Pharmaceutical Inc., et al
December 7, 2018
Before Prost, Wallach, and Chen. Opinion by Chen.
Summary
The Federal Circuit reversed the district court’s decision to invalidate U.S. Patent No. 5,665, 772 based on obviousness-type double patenting because a change in patent term law should not truncate the term statutorily as assigned to the pre-URAA ‘722 patent.
Details
Novartis owns U.S. Patent No. 5,665,772 (hereafter ‘722 patent), which claims the compound everolimus, and U.S. Patent No. 6,440,990 (hereafter ‘990 patent), which is directed to some methods of treatment using everolimus and some pharmaceutical compositions including everolimus. Everolimus is an active ingredient in Zortress® and Afinitor®, which are famous drugs for treating certain cancers and preventing rejection in kidney and liver transplantations. Plaintiff Novartis sues Defendants Breckenridge for infringing ‘772 patent after Defendants sought FDA approval to market generic versions of Zortress® and Afinitor®.
The only question before the district court was whether the ‘990 patent could serve as an obviousness-type double patenting reference against the ‘772 patent? The ‘772 patent was filed on April 7, 1995 and issued on September 9, 1997. Because it was filed before June 8, 1995, the URAA’s effective date, the patent term is 17 years from the issuance date. Furthermore, Novartis obtained a five-year patent term extension under 35 U.S.C. §156 of the Hatch-Waxman Act. So the actual expiration date for the ‘722 patent is September 9, 2019. The ‘990 patent was filed on May 23, 1997 and issued on August 27, 2002. Because it was filed after the URAA’s effective date and claimed the same priority as the ‘722 patent from a September 24, 1993 PCT filing date. So the expiration date for the ‘990 patent is September 24, 2013. The following diagram illustrates the dates for each patent:
That is, the ‘990 patent issues later, but expired earlier, than the ‘772 patent. There is a terminal disclaimer filed in ‘990 patent.
Defendants relied heavily on decision in a previous federal circuit case, Gilead Sciences, Inc., v. Natco Pharma Ltd. 753 F. 3d 1208 (Fed. Cir. 2014). The following diagram illustrates the relevant dates of two patents in dispute:
Gilead held that the proper reference point for an obviousness-type double patenting inquiry is the expiration dates, rather than the issuance dates, of the patents in question. Thus, a patent (‘375 patent) that issues after but expires before another patent (‘483 patent) can qualify as a double patenting reference against the earlier-issuing, but later-expiring patent (‘483 patent). However, the Federal Circuit distinguishes this case from Gilead because the two patents in Gilead were all filed post-URAA while, in the present case, one patent was filed pre-URAA and the other patent was filed post-URAA. The URAA transition statute changed the term of a U.S. patent from 17 years from the issuance date to 20 years from the filing date of the earliest U.S. or PCT application to which priority is claimed, excluding provisional applications.
Defendants also relied on another previous case, Abbvie, Inc. v. Mathilda & Terence Kennedy Institute of Rheumatology Trust, 764 F. 3d 1366 (Fed. Cir. 2014). The following diagram illustrates the relevant dates of two patents in dispute:
AbbVie also held that claims of the ‘422 patent (second issued, second-expiring) were invalid over the ‘766 patent (first-issued, first-expiring) for obviousness type double patenting. The court explained that the patent owner had impermissibly sought an undue patent term extension for its later-expiring, patentably indistinct claims by choosing to claim different priority dates for its patent applications. However, the Federal Circuit distinguishes this case from Abbvie because the two patents in Abbvie were all filed post-URAA.
The Federal Circuit’s rationale seems to place a lot of weight on the fact that Novartis did not engage in any gamesmanship such as the structuring of priority claims among related patents to obtain the benefit of one patent gaining a later expiration date. Furthermore, the URAA transition statute expressly provides that the term of a patent issuing from an application filed before June 8, 1995 shall be the greater of the 20-year term from the earliest priority date or 17 years from grant, subject to any terminal disclaimers. Thus, the Federal Circuit applies traditional, pre-URAA obviousness-type double patenting practice to the pre-URAA patent. That is, the ‘772 patent’s issuance date is used as the reference point for the obviousness-type double patenting analysis. Since the ‘990 patent is issued later than the ‘772 patent, the ‘990 patent is not a proper obviousness-type double patenting reference for the ‘772 patent.
Furthermore, the Federal Circuit considers that the holding is consistent with the core principle underlying the double patenting doctrine: giving one invention and nonobvious variants of that invention the same patent term. Here, critically, Novartis did not seek to extend its patent rights over its invention beyond one patent term, 17 years from issuance of the ‘772 patent.
Take away
- Is issuance date or expiration date as the reference point for obviousness-type double patenting? It depends. If the challenged patent is filed before June 8, 1995, the reference point for obviousness-type double patenting is the issuance date. If the challenged patent is filed after June 8, 1995, the reference point for obviousness-type double patenting is the expiration date.
