By Kevin E. Noonan --
The Federal Circuit continued its explication both of the contours of obviousness for pharmaceutical formulations after KSR Int'l Co. v. Teleflex Inc. as well as how it exercises its supervisory powers over the U.S. Patent and Trademark Office after Dickinson v. Zurko, in a decision last Friday, In re Huai-Hunk Kao et al. The subject matter was controlled-release oxymorphone formulations, assigned to Endo Pharmaceuticals Inc. in three applications: U.S. Application Nos. 11/680,432 (Kao, Baichwal, McCall and Lee, inventors), 12/167,859 (Kao, Baichwal, McCall and Lee, inventors), and 11/766,740 (Ahdieh, inventor). All claims at issue were rejected as being obvious.
Controlled-release formulations are important for opioid drugs such as oxymorphone (at left) because these drugs undergo significant "first pass" metabolism by the liver, and repeated administration of immediate release formulations have deleterious side effects. The three applications rejected by the U.S. Patent and Trademark Office provided controlled-release formulations that overcame these limitations.
All the applications had been filed under the PTO's Accelerated Examination Program, which limited the claims that were argued on appeal. Claim 1 of the '432 application reads as follows:
1. An analgesically effective controlled release pharmaceutical composition with a twelve hour dosing interval in the form of a tablet, comprising oxymorphone or a pharmaceutically acceptable salt thereof as the sole active ingredient in the tablet and a controlled release delivery system comprising at least one pharmaceutical excipient, wherein upon placement of the composition in an in vitro dissolution test comprising USP Paddle Method at 50 rpm in 500 ml media having a pH of 1.2 to 6.8 at 37oC, about 15% to about 50%, by weight, of the oxymorphone or salt thereof is released from the tablet at about 1 hour in the test.
This claim was rejected for being obvious over International Publication No. WO 01/08661 ("the Maloney reference"), alone or in combination with U.S. Patent No. 5,047,248. According to the Examiner, the Maloney reference discloses every element of the claim except the dissolution rate, and the Examiner required Applicants to demonstrate that the practice of the formulations disclosed by Maloney did not (inherently?) produce that dissolution rate. In response, Applicants submitted declarations distinguishing the Maloney reference on the grounds that it disclosed oxycodone that showed a "markedly different bioavailability profile" than oxymorphone. In addition, the method used to demonstrate the dissolution rate in the Maloney reference was different from the method used by Applicants, and the dissolution rates were not comparable. Finally, Applicants asserted that their claimed formulations showed an unexpected result -- multiple peaks in blood concentration of the drug using the claimed formulation as well as commercial success of Endo's drug product. The Examiner, affirmed by the Board, rejected these arguments and distinctions, finding that the claims were obvious because the Maloney reference disclosed oxymorphone formulations as "preferred embodiments" and the dissolution rates in the reference overlapped with the range of rates in the '432 application claims. The Board also rejected Applicants' profferred evidence of secondary considerations because that evidence was not "commensurate in scope" with the claimed invention.
The '859 application claimed methods of relieving pain using controlled release delivery of oxymorphone:
8. A method for treating pain in a human subject in need of acute or chronic pain relief, comprising the steps of:
(a) providing a solid oral dosage form comprising about 5 mg to about 80 mg oxymorphone or a pharmaceutically acceptable salt thereof in a controlled release delivery system with a release rate profile designed to provide an adequate blood plasma level over at least 12 hours to provide sustained pain relief over this same period, the sys- tem comprising a filler and a hydrophilic material, wherein oxymorphone is the sole active ingredient; and,
(b) administering the dosage form to the subject, wherein the oxymorphone Cmax is at least about 50% higher when the dosage form is administered to the subject under fed versus fasted conditions.
The Maloney reference was also asserted by the Examiner against the claims of the '859 application in support of an obviousness determination, substantially consistent with the ground asserted against the '432 application claims. The Examiner, affirmed by the Board also discounted evidence of secondary considerations because that evidence was not commensurate in scope with the '859 application claims.
The claims of the '740 application were also rejected for obviousness:
21. A method of providing extended pain relief to patients in need thereof, comprising:
providing information that the average bioavailability of oxymorphone in an oral extended release formulation designed to have a 12 hour dosing cycle is increased by at least about 26% for subjects with renal impairment compared to that for healthy subjects, and
providing a therapeutically effective amount of such an extended release oral dosage form of oxymorphone or its pharmaceutically acceptable salt thereof.
The obviousness rejection of these claims was based on the Maloney reference, in light of U.S. Patent Application Publication No. 2002/0032581, which disclosed a clinical evaluation kit. As with the other two applications, evidence regarding secondary considerations was not persuasive in overcoming the obviousness rejections.
The Federal Circuit, in an opinion by Judge Linn, joined by Judge Moore and Chief Judge Rader, vacated and remanded the Board's obviousness rejection of the '432 application claims but affirmed the rejection of the '859 and '740 applications. The Board's opinion affirming rejection of the '432 application claims on obviousness was vacated as not being supported by substantial evidence. The PTO had based its obviousness determination on the disclosure in the Maloney reference that the formulation being prepared with oxymorphone as well as the "equivalence" of the two types of dissolution tests used by the art and the Applicants. The Federal Circuit opinion accepts the Office's contention that it would have been obvious to substitute oxymorphone for oxycodone based on the disclosure of the reference that oxymorphone is a preferred embodiment. However, where the Office's argument fails according to the opinion is in the determination that the formulation disclosed in the Maloney reference would have the dissolution properties required in the claim. This is due to the differences in the assay method (the "paddle" method versus the "basket" method) and the failure of the Office to establish this by substantial evidence, particularly in view of the declaration from the Applicant to the contrary. The deficiency in the Board's decision is that "there is a lack of direct factual support in the record for the view that the claimed range of dissolution rates actually overlaps with the dissolution rate disclosed in [the] Maloney [reference], a premise upon which the Board's reasoning is founded."
The Office tried to use evidence to support the correlation from a declaration submitted by Applicants, but erred according to the opinion because it:
[R]elied on four data points from an exhibit correlating the dissolution rates of Opana® ER, when tested by both methods, and Maloney's Formula 6, tested only by the Basket Method, and concluded, without any reasoning, that because the Basket Method dissolution in the first hour for Opana® ER was 1.3 times faster than the dissolution rate of the Paddle Method for Opana® ER, this correlation would also hold for Maloney's Formula 6.
This conclusion was formed in the face of express statements from the declarant that "there is no general correlation between the Basket and Paddle Methods," a statement supported by scientific literature citations. The opinion states that the record is devoid of any evidence or reasoning why the declarant's statements are not accurate. Since "substantial evidence" is "such evidence as a reasonable mind might accept as adequate to support a conclusion" (citing Consol. Edison Co. v. Nat'l Labor Relations Bd., 305 U.S. 197, 229 (1938)), the Office's unsupported conclusion does not meet the standard according to the Federal Circuit.
However, the opinion also states that the importance of the dissolution range in the claim to the obviousness issue (i.e., whether this distinction would be sufficient to render the claims non-obvious) was not before the Court, and the panel directed the Board to consider this question on remand, citing to Ormco Corp. v. Align Technology, Inc., 463 F.3d 1299, 1311 (Fed. Cir. 2006), for the principle that "overlap between [a] claimed range and [the] prior art gives rise to a presumption of obviousness where claimed range and prior art value are insubstantially different." The panel also cited to one of the Supreme Court's most cogent statements of its obviousness jurisprudence in this regard:
When there is . . . market pressure to solve a problem and there are a finite number of identified, predictable solutions, a person of ordinary skill in the art has good reason to pursue the known options within his or her technical grasp. If this leads to the anticipated success, it is likely the product not of innovation but of ordinary skill and common sense. KSR Intern. Co. v. Teleflex Inc., 550 U.S. 398, 402-403 (2007).
With regard to secondary considerations, the Board was not persuaded that Applicants' evidence of secondary considerations raised in support of the non-obviousness of any of the claims at issue, on the grounds that the evidence of unexpected results and commercial success were "not commensurate with the scope of the claims." The panel opinion stated that the Office must consider evidence of secondary considerations when asserted, and that the evidence thereof "must be reasonably commensurate with the scope of the claims," citing In re Tiffin, 448 F.2d 791, 792 (CCPA 1971), and In re Hiniker, 150 F.3d 1362, 1369 (Fed. Cir. 1998). While this does not require an applicant to "test every embodiment" within the scope of the claim to demonstrate secondary considerations, there must be sufficient evidence presented that would "show a correlation" throughout the scope of the claims according to the Court, citing In re Greenfield, 571 F.2d 1185, 1189 (CCPA 1978), and In re Cescon, 474 F.2d 1331, 1334 (CCPA 1973).
However, the Court characterized as "a more fundamental requirement" that there be a nexus between the evidence asserted and the "merits of the claimed invention." Wyers v. Master Lock Co., 616 F.3d 1231, 1246 (Fed. Cir. 2010) (emphasis in original). Thus, the opinion states that where the proffered "secondary consideration" is the consequence of something "other than what is both claimed and novel in the claim," a nexus is not established, citing Tokai Corp. v. Easton Enters., Inc., 632 F.3d 1358, 1369 (Fed. Cir. 2011), Ormco Corp., and In re Woodruff, 919 F.2d 1575, 1578 (Fed. Cir. 1990).
For the '432 patent, the panel found that there was not substantial evidence (indeed, there was no evidence) supporting the Board's conclusion that the asserted unexpected result (that the formulation caused "multiple peaks of oxymorphone blood concentration") "must be caused by some component of that particular disclosed controlled-release formulation." This formed another basis for remand to the Board to "determine whether there is a nexus between the unexpected in vivo concentration profile and aspects of the claimed invention not already present in the prior art." "[F]or the unexpected in vivo concentration profile of the applicant's product to have substantial weight, there must be a nexus to some aspect of the claim not already in the prior art, such as the claimed range of dissolution rates, as against other unclaimed prior-art dissolution rates."
Regarding the evidence of commercial success, the opinion reasserted the principle that not every embodiment of a claimed invention must be sold to demonstrate unexpected results ("'[i]t seems unlikely that a company would sell a product containing multiple, redundant embodiments of the patented invention . . . . Under the [Office's] logic, there would never be commercial success evidence for a claim that covers more than one embodiment," citing In re Glatt Air Techniques, Inc., 630 F.3d. 1026, 1030 (Fed. Cir 2011)), but found that "the record is nearly silent on whether the commercial success was caused by the merits of the invention as distinct from the prior art," forming yet another factual issue to be determined by the Office on remand.
Turning to the '859 and '740 applications, here the Court was not persuaded that the Board had erred in determining that these claims were obvious. With regard to the '859 application, the panel agreed that the increased efficacy of administering the claimed oxymorphone formulations with food was an inherent property of the drug not limited to the claimed controlled-release formulations, relying on King Pharmaceuticals, Inc. v. Eon Labs, Inc., 616 F.3d 1267, 1275-76 (Fed. Cir. 2010), to support this proposition. The Court also agreed that the 12-hour effectiveness limitation was disclosed in the Maloney reference. Finally, the Court agreed with the Board, saying that "[s]ubstantial evidence supports the Board's finding that Maloney teaches a controlled release formulation using both hydrophobic and hydrophilic materials" as required by the claims at issue.
While the Court faulted the Board for failing to give proper weight to the secondary considerations asserted in support of the non-obviousness of the claims of the '859 patent, here the panel affirmed the obviousness rejection because there was "a strong showing of obviousness," consistent with the Court's post-KSR practice of discounting secondary considerations when the evidence supporting an obviousness rejection seems compelling (see "Pharmastem Therapeutics, Inc. v. Viacell, Inc. (Fed. Cir. 2007)"; This is an ironic treatment of the secondary, or "objective" indicia of non-obviousness, which were intended by the Supreme Court under Graham v. John Deere Co. to rebut an obviousness determination under just those circumstances where unavoidable hindsight might lead to an erroneous conclusion.)
Finally, the opinion addresses the obviousness rejection of the '740 application, which was also affirmed. The Applicant asserted that the "information" regarding an "undiscovered correlation between renal failure and bioavailability" rendered the claims non-obvious. The panel considered this argument to be the same argument it rejected in King Pharmaceuticals, which also involved increasing oral bioavailability using information unappreciated in the prior art (in King, administering metaxalone with food). This case is not "meaningfully distinct," the panel states, because "informing someone of the correlation cannot confer patentability absent a functional relationship between the informing and administering steps," citing In re Ngai, 367 F.3d 1336, 1338 (Fed. Cir. 2004), and General Elec. Co. v. Jewel Incandescent Lamp Co., 326 U.S. 242, 249 (1945). The opinion states that at least one basis for its decision regarding the obviousness of the '740 application's claim at issue is that "there is no requirement in the claim that the dosage be adjusted in response to the informing step." In addition, "because there is no indication of who is to be informed or to whom the drug is to be administered, the claim would presumably cover a situation where a doctor informs patient A of the correlation and administers a therapeutically effective dose of controlled release oxymorphone to patient B," i.e., "there is no functional relationship between the two steps in the method." Since merely administering controlled release oxymorphone is "squarely present in the prior art," the Board properly determined that the claims of the '740 application were obvious.
While the Court believed that the Board had erroneously failed to give proper weight to evidence of secondary considerations with regard to the '740 application claims, this error was harmless because the Applicant failed to establish the required nexus between the claimed invention and the asserted unexpected results or commercial success.
These results, while not inconsistent with prior precedent illustrate nicely how the Court is applying the rubrics set forth by the Supreme Court in KSR and how the outcome has changed due to that decision. Arguably, for at least the '859 and '740 applications there was no teaching, suggestion or motivation to provide formulations having the specifically claimed components (as claimed in the '859 application) or with the benefit of understanding the correlation between bioavailability and renal failure (as claimed in the '740 application), and these claims might otherwise have issued without the renewed focus on the predictability of the claimed method (or the common sense of the skilled artisan at arriving at these methods). Even with regard to the '432 application, the panel appears to believe it necessary to remind the Board of KSR's emphasis on predictability in deciding whether a claim is obvious. This opinion reinforces the appearance that the Federal Circuit has understood the Supreme Court's interpretation of the appellate court's mandate and is doing what it can to comply.
In re Kao (Fed. Cir. 2011)
Panel: Chief Judge Rader and Circuit Judges Linn and Moore
Opinion by Circuit Judge Linn