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IN RE BRANA
51 F.3d 1560 (1995)
In re Miguel F. BRANA, Jose M.C. Berlanga, Marina M. Moset, Erich Schlick and Gerhard Keilhauer.
93-1393.
United States Court of Appeals, Federal Circuit.
March 30, 1995.
Malcolm J. MacDonald, Keil & MacDonald, Washington, DC, argued, for appellant. With him on the brief was Herbert B. Keil. Of counsel was David S. Nagy.
Fred E. McKelvey, Sol., Office of Sol., Arlington, VA, argued, for appellee. With him on the brief were Albin F. Drost, Deputy Sol., Richard E. Schafer, Teddy S. Gron, Joseph G. Piccolo and Richard L. Torczon, Associate Sols.
Before PLAGER, LOURIE, and RADER, Circuit Judges.
PLAGER, Circuit Judge. Miguel F. Brana, et al. (applicants), appeal the March 19, 1993 decision of the United States Patent and Trademark Office (PTO) Board of Patent Appeals and Interferences (Board), in Appeal No. 92-1196. The Board affirmed the examiner's rejection of claims 10-13 of patent application Serial No. 533,944 under 35 U.S.C. § 112 ¶ 1 (1988).1 The examiner's rejection, upon which the Board relied in rendering its decision, was based specifically on a challenge to the utility of the claimed compounds and the amount of experimentation necessary to use the compounds. We conclude the Board erred, and reverse. I. BACKGROUNDOn June 30, 1988, applicants filed patent application Serial No. 213,690 (the '690 application)2 directed to 5-nitrobenzo[de]isoquinoline-1,3-dione compounds, for use as antitumor substances, having the following formula: [Image in original not included.] where n is 1 or 2, R1 and R2 are identical or different and are each hydrogen, C1-C6-alkyl, C1-C6-hydroxyalkyl, pyrrolidinyl, morpholino, piperidinyl or piperacinyl, and R3 and R4 are identical or different and are each hydrogen, C1-C6-alkyl, C1-C6-acyl, C2-C7-alkoxycarbonyl, ureyl, aminocarbonyl or C2-C7-alkylaminocarbonyl. These claimed compounds differ from several prior art benzo[de]isoquinoline-1,3-dione compounds due to the presence of a nitro group (O2N) at the 5-position and an amino or other amino group (NR3R4) at the 8-position of the isoquinoline ring. The specification states that these non-symmetrical substitutions at the 5- and 8- positions produce compounds with "a better action and a better action spectrum as antitumor substances" than known benzo[de]isoquinolines, namely those in K.D. Paull et al., Computer Assisted Structure-Activity Correlations, Drug Research, 34(II), 1243-46 (1984) (Paull). Paull describes a computer-assisted evaluation of benzo[de]isoquinoline-1,3-diones and related compounds which have been screened for antitumor activity by testing their efficacy in vivo3 against two specific implanted murine (i.e., utilizing mice as test subjects) lymphocytic leukemias, P388 and L1210.4 These two in vivo tests are
widely used by the National Cancer Institute (NCI) to measure the antitumor properties of a compound. Paull noted that one compound in particular, benzo[de]isoquinoline-1,3(2H)dione,5-amino-2(2-dimethyl-aminoe-thyl [sic]) (hereinafter "NSC 308847"), was found to show excellent activity against these two specific tumor models. Based on their analysis, compound NSC 308847 was selected for further studies by NCL. In addition to comparing the effectiveness of the claimed compounds with structurally similar compounds in Paull, applicants' patent specification illustrates the cytotoxicity of the claimed compounds against human tumor cells, in vitro,5 and concludes that these tests "had a good action."6
1. Unless otherwise noted, all United States Code citations are to the 1988 edition. 2. This is a divisional of patent application Serial No. 110,871 filed October 21, 1987. 3. In vivo means "[i]n the living body, referring to a process occurring therein." Steadman's Medical Dictionary 798 (25th ed. 1990). In vitro means "[i]n an artificial environment, referring to a process or reaction occurring therein, as in a test tube or culture media." Id. 4. The analysis in Paull consisted of grouping the previously-tested compounds into groups based on common structural features and cross-referencing the various groups, in light of the success rates of the group as a whole, to determine specific compounds that may be effective in treating tumors. 5. See supra note 3. 6. The specification does not state the specific type of human tumor cells used in this test. 7. The chemical compound in Zee-Cheng et al. is labeled a 3,6-disubstituted-1,8-naphthalimide and uses different numbering for the positions on the isoquinoline ring. The structure of this compound, however, is identical to that claimed by the applicants except for symmetrical substitutions at the 5-position and the 8-position of the isoquinoline ring. Zee-Cheng et al. teaches identical substitutions of amino or nitro groups while applicants claim a nitro group substitution at the 5-position and an amino group substitution at the 8-position. 8. HEp cells are derived from laryngeal cancer and HCT-29 cells from colon cancer. 9. The examiner's answer noted that the final rejection also could have been made under 35 U.S.C. § 101 for failure to disclose a practical utility. 10. The examiner subsequently filed two supplemental answers in response to arguments raised by the applicants in supplemental reply briefs. 11. See, e.g., Cross v. Iizuka,753 F.2d 1040, 224 USPQ 739 (Fed.Cir.1985); In re Langer,503 F.2d 1380, 183 USPQ 288 (CCPA 1974); In re Krimmel,292 F.2d 948, 130 USPQ 215 (CCPA 1961); In re Bergel,292 F.2d 958, 130 USPQ 205 (CCPA 1961). 12. This court's predecessor has determined that absence of utility can be the basis of a rejection under both 35 U.S.C. § 101 and § 112 ¶ 1. In re Jolles,628 F.2d 1322, 1326 n. 11, 206 USPQ 885, 889 n. 11 (CCPA 1980); In re Fouche,439 F.2d 1237, 1243, 169 USPQ 429, 434 (CCPA 1971) ("[I]f such compositions are in fact useless, appellant's specification cannot have taught how to use them."). Since the Board affirmed the examiner's rejection based solely on § 112 ¶ 1, however, our review is limited only to whether the application complies with § 112 ¶ 1. 13. The Board's decision did not expressly make any independent factual determinations or legal conclusions. Rather, the Board stated that it "agree[d] with the examiner's well reasoned, well stated and fully supported by citation of relevant precedent position in every particular, and any further comment which we might add would be redundant." Ex parte Brana et al., No. 92-1196 (Bd.Pat.App. & Int. March 19, 1993) at 2-3. Therefore, reference in this opinion to Board findings are actually arguments made by the examiner which have been expressly adopted by the Board. 14. Paull also found NSC 308847 to be effective against two other test models, B16 melanoma and Colon C872. 15. See Pazdur et al., Correlation of Murine Antitumor Models in Predicting Clinical Drug Activity in Non-Small Cell Lung Cancer: A Six Year Experience, 3 Proceedings Am.Soc.Clin.Oncology 219 (1984); Martin et al., Role of Murine Tumor Models in Cancer Research, 46 Cancer Research 2189 (April 1986). 16. As noted, this would appear to be a § 101 issue, rather than § 112. 17. See also In re Novak,306 F.2d 924, 928, 134 USPQ 335, 337 (CCPA 1962) (stating that it is proper for the examiner to request evidence to substantiate an asserted utility unless one with ordinary skill in the art would accept the allegations as obviously valid and correct); In re Chilowsky,229 F.2d 457, 462, 108 USPQ 321, 325 (CCPA 1956) ("[W]here the mode of operation alleged can be readily understood and conforms to the known laws of physics and chemistry ... no further evidence is required."). But see In re Marzocchi, 439 F.2d at 223, 169 USPQ at 369-70 ("In the field of chemistry generally there may be times when the well-known unpredictability of chemical reactions will alone be enough to create a reasonable doubt as to the accuracy of a particular broad statement put forward as enabling support for a claim. This will especially be the case where the statement is, on its face, contrary to generally accepted scientific principles."). 18. See supra note 15. 19. The declaration of Michael Kluge was signed and dated June 19, 1991. This declaration listed test results (i.e. antitumor activity) of the claimed compounds, in vivo, against L1210 tumor cells and concluded that these compounds would likely be clinically useful as anti-cancer agents. Enablement, or utility, is determined as of the application filing date. In re Glass,492 F.2d 1228, 1232, 181 USPQ 31, 34 (CCPA 1974). The Kluge declaration, though dated after applicants' filing date, can be used to substantiate any doubts as to the asserted utility since this pertains to the accuracy of a statement already in the specification. In re Marzocchi, 439 F.2d at 224 n. 4, 169 USPQ at 370 n. 4. It does not render an insufficient disclosure enabling, but instead goes to prove that the disclosure was in fact enabling when filed (i.e., demonstrated utility). 20. We note that this discussion is relevant to the earlier discussion as well. If we were to conclude that these in vivo tests are insufficient to establish usefulness for the claimed compounds, that would bear on the issue of whether one skilled in the art would, in light of the structurally similar compounds in Paull and Zee Cheng et al., have cause to doubt applicants' asserted usefulness for the compounds. 21. Congress enacted the Administrative Procedure Act (APA) on June 11, 1946. See 1 Kenneth Culp Davis, Administrative Law Treatise, § 1:7 (2d ed. 1978). The APA sets forth a framework for administrative agency procedure and provides judicial review for persons adversely affected by final agency actions. Chapter 7, codified at 5 U.S.C. § 701-706, contains the APA judicial review provisions, including the standard of review provision quoted above.
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