Ex Parte Salamone et alDownload PDFPatent Trial and Appeal BoardJul 22, 201612767034 (P.T.A.B. Jul. 22, 2016) Copy Citation UNITED STA TES p A TENT AND TRADEMARK OFFICE APPLICATION NO. FILING DATE 121767,034 04/26/2010 26345 7590 07/26/2016 GIBBONS P.C. ONE GATEWAY CENTER NEW ARK, NJ 07102 FIRST NAMED INVENTOR Salvatore J. Salamone UNITED STATES DEPARTMENT OF COMMERCE United States Patent and Trademark Office Address: COMMISSIONER FOR PATENTS P.O. Box 1450 Alexandria, Virginia 22313-1450 www .uspto.gov ATTORNEY DOCKET NO. CONFIRMATION NO. 105529-52543 2ND DIV 2829 EXAMINER HAQ, SHAFIQUL ART UNIT PAPER NUMBER 1678 NOTIFICATION DATE DELIVERY MODE 07/26/2016 ELECTRONIC Please find below and/or attached an Office communication concerning this application or proceeding. The time period for reply, if any, is set in the attached communication. Notice of the Office communication was sent electronically on above-indicated "Notification Date" to the following e-mail address( es): IPDocket@gibbonslaw.com PTOL-90A (Rev. 04/07) UNITED STATES PATENT AND TRADEMARK OFFICE BEFORE THE PATENT TRIAL AND APPEAL BOARD Exparte SALVATORE J. SALAMONE, JODI BLAKE COURTNEY, and DENNIS STOCKER Appeal2013-008011 Application 12/767,034 Technology Center 1600 Before JEFFREY N. FREDMAN, JOHN G. NEW, and CHRISTOPHER G. PAULRAJ, Administrative Patent Judges. PAULRAJ, Administrative Patent Judge. DECISION ON APPEAL This is an appeal1under35 U.S.C. § 134 involving claims drawn to an immunogen. The Examiner rejected the claims for being indefinite and obvious. We have jurisdiction under 35 U.S.C. § 6(b). We reverse both pending rejections. 1 Appellants identify the Real Party in Interest as Saladax Biomedical Inc. (see Appeal Br. 3). Appeal2013-008011 Application 12/767,034 STATEMENT OF THE CASE Background According to the Specification, "[t]he invention relates to the field of immunological assays for determining the presence and/or quantifying the amount of 5-fluoro-uracil [ 5-FU] in human biological samples in order to rapidly determine optimal drug concentrations during chemotherapy." Spec. 1: 8-11. 5-FU is a common cytotoxic agent used for treatment of breast and colorectal cancer, with the following formula: 0 Spec. 1-2. 5-FU is a type ofhapten, a protein-free substance that is incapable of stimulating antibody formation but can react with antibodies formed by coupling the hapten to a high molecular weight immunogenic carrier and injecting to a human or animal subject. Id. at 9-10. The Specification notes that "5-FU can be administered in its pro-drug form as tegafur," which, "when administered to a patient, is generally absorbed and metabolized into 5-FU by the patient at different rates." Id. at 3--4. However, "in monitoring the level of 5-FU in patients by means of an immunoassay, it is important that the immunoassay be able to distinguish between tegafur, the inactive substance, and 5-FU, the active substance, into 5 which tegafur metabolizes," and "[t]he problem with antibodies to 5-FU is 2 Appeal2013-008011 Application 12/767,034 that they could be cross-reactive with tegafur making these immunoassays not useful." Id. at 4. The Specification discloses that a new class of antibodies specific for 5-FU are produced by immunogens formed as conjugates of an immunogenic polyamine polymer. Id. at 5. The Specification discloses that the antibodies produced by using such immunogens "are substantially selectively reactive to 5-FU so as to bind to 5-FU without any substantial cross reactivity to tegafur, as well as, to other interfering pyrimidine bases, uracil and cytosine." Id. at 4. The Claims Claims 37, 38, 42, 43, and 46 are under appeal, and are reproduced in the Claims Appendix of the Appeal Brief. Independent claim 3 7 is representative and reads as follows: 37. An immunogen containing an immunogenic carrier containing a polyamine polymer linked to a compound of the formula: 0 F H II-A wherein Y is an organic spacing group; X is a terminal functional group involved in the binding to said polyamine polymer; and p is an integer from 0 to 1. Appeal Br. 21 (Claims App'x). 3 Appeal2013-008011 Application 12/767,034 The Re} ections The Examiner has rejected the claims as follows: I. Claim 46 under 35 U.S.C. § 112 (pre-AIA), second paragraph, as being indefinite; II. Claims 37, 38, 42, 43, and 46 under 35 U.S.C. § 103(a) as being unpatentable over the combination of Yoshida, 2 Fujiwara, 3 Nolli,4 Marunaka,5 and Pischel. 6 Final Office Action dated Nov. 15, 2012 ("Final Act."). DISCUSSION Rejection I -Indefiniteness The Examiner finds that claim 46 is indefinite because "[t]he definition for the R4 is missing and thus it is unclear what linkages is/are intended to be encompassed by the linkage -NH-(C=R4)-." Final Act. 2-3. Appellants argue that the R4 in claim 46 is defined in claim 42 because "[c]laim 46 is dependent upon claim 42," and "[t]herefore, it includes all of the limitations of claim 42 which not need be stated is claim 2 Yoshida et al., Clinical significance of monitoring serum levels of 5- fluorouracil by continuous infusion in patients with advanced colonic cancer, 26 Cancer Chemotherapy and Pharmacology 352-354 (1990) ("Yoshida"). 3 Fujiwara et al., Enzyme Immunoassay for the Quantification of Mitomycin C Using fJ-Galactosidase as a Label, 42 Cancer Research 1487-1491 (1982) ("Fujiwara"). 4 Nolli and Parenti, Antibodies against the antibiotics: an overview, 27 Ann. 1st Super. Sanita 149-154 (1991) ("Nolli"). 5 Marunaka, Mass Spectra of N-Substituted Derivatives of 5-Fluorouracil, 8 Biomedical Mass Spectrometry 105-110 (1981). 6 Pischel et al., Synthesis and Biological Activity of N-substituted 5- Fluroruracil-1-Acetamides, 4 7 Collection Czechoslovak Chem. Commun. 2806-2813 (1982) ("Pischel"). 4 Appeal2013-008011 Application 12/767,034 46." Appeal Br. 7. In claim 42, R4 is defined as being oxygen or sulfur. We are persuaded by Appellants' representation that the R4 in claim 46 is the same R4 as recited in claim 42 as being either oxygen or sulfur. Accordingly, we reverse the indefiniteness rejection. Rejection II - Obviousness A. Findings of Fact FF 1. Yoshida teaches that 5-FU is an anticancer drug, and the monitoring of serum concentrations of 5-FU using an HPLC method. Yoshida, 352 (Summary). FF2. Fujiwara teaches that a "mitomycin C (MMC) antibody was produced following immunization of rabbits with a MMC-bovine serum albumin conjugate, which was newly synthesized by coupling MMC to mercaptosuccinylated bovine serum albumin via a cross- linker, N-maleoyl aminobutyric acid." Fujiwara, 1487 (Abstract)). "An antibody against MMC was produced in each of 3 rabbits immunized with a MMC-BSA conjugate and was detected by the reaction of diluted antiserum with MMC-B-gal conjugate." Id. at 1488 (Results, "Antibody Response"). FF3. Nolli teaches generally that small molecules, such as antibiotic haptens, be made immunogenic by conjugation with carrier proteins or synthetic polypeptides. Nolli, 151. Nolli further teaches different immunogenic carriers and potential positions on the hapten (e.g., carboxyl groups) for linking to the carriers. Id.; Table 3. FF4. Marunaka discloses that 5-FU and its derivatives have been widely used in cancer chemotherapy. Marunaka, 105 5 Appeal2013-008011 Application 12/767,034 (Introduction). Marunaka further teaches a 5-FU derivative compound 15 having reactive carboxylic acid ester substituent that satisfies the requirements of formula II-A. Id. at 106. FPS. Pischel discloses 5-FU and its derivatives are in clinical use the chemotherapy of cancer. Pischel, 2806. Pischel further teaches 5-FU derivative compound III having reactive carboxylic acid group substituent that satisfies the requirements of formula II-A. Id. at 2807. B. Analysis The Examiner asserts that: given the fact that 5-fluoro-uracil is well-established as an anticancer drug and its detection in blood is important for establishing optimal effective dose in a patient (Yoshida et al), one of ordinary skill in the art would be motivated to substitute the [H]PLC detection of 5-flurouracil with an immunoassay detection in view of the teaching of Fujiwara et al and Nolli et al because both Fujiwara et al [and] Nolli et al teach that immunogenic detection is advantageous for being possessing reasonable sensitivity, accuracy, precision and significant degree of specificity (Fujiwara et al and Nolli et al). As evidenced by Fujiwara et al and Nolli et al, once a drug is established, it is obvious to make corresponding antibody for high sensitive detection/assay of the drug and thus it would be obvious to one of ordinary skill in the art to consider providing corresponding antibody to 5-fluorouracil drug in accordance with the reasoning set forth in Ex parte Erlich, 3 USPQ2d 1011 (1987), in particular, paragraph [5] of page 1016. Final Act. 4-5; Ans. 3--4. The Examiner further asserts that: One of ordinary skill in the art would also be motivated to utilize the 5-fluorouracil derivatives of Marunaka and Pischel et al because Marunaka and Pischel et al disclose derivatives having reactive group, such as carboxylic acid group and 6 Appeal2013-008011 Application 12/767,034 carboxylic acid e[ s ]ters, suitable for conjugating to a carrier in view of the teaching ofNolli et al. Reasonable expectation of success in obtaining monoclonal antibody against 5-fluoro- uracil comes from Nolli et al's teaching of the conventional preparation methods of immunogenic carrier to activated drug haptens, immunogens, tracers, and corresponding antibodies using reactive groups on the hapten (e.g. amine group) and since the amino group on the 5-fluoro-uracil is a potential reactive functional group for the drug, one of ordinary skill in the art would be motivated to try the anime groups on the drug for conjugation of immunogenic carrier. Further, once a compound has been established as a potential drug for therapeutic application, one of ordinary skill in the art would be motivated to establish an [a ]ssay to monitor the drug concentration in blood, urine and other body fluids and tissues which are essential for studying pharmacology and pharmacokinetics of the drug and to establish therapeutic level of the drug in various body compartments. Final Act. 5-6; Ans. 4. We determine that the Examiner has not made a prima facie showing of obviousness. Yoshida, Marunaka, and Pischel do not teach or suggest any need to formulate an immunogenic conjugate of 5-FU with a polyamine polymer, much less the particular conjugate of formula II-A recited in claim 37. In particular, we agree with Appellants that although "Marunaka and Pischel disclose the compound of formula II-A" among other 5-FU derivatives, "there is no disclosure or teaching in Marunaka and Pischel of forming a conjugate with this compound," and "none of the references teach any immunogen structurally related to 5-fluoro-uracil or the haptens of formula II-A." Appeal Br. 7-8, 12; see also Reply Br. 4 ("Nothing in Marunaka or Pischel teach selecting the specific 5-FU derivative from among their many 5-FU derivatives they disclose for conjugating to an 7 Appeal2013-008011 Application 12/767,034 immunogenic carrier to produce the claimed immunogenic conjugates."). We further agree with Appellants' argument that "[n]either the Nolli nor Fujiwara references teach that the hap ten of formula II-A disclosed in Marunaka and Pischel could be conjugated in any manner with an immunogen to produce a conjugate for making an antibody for use in a 5- fluoro-uracil immunoassay." Appeal Br. 12-13. As further noted by Appellants, "[w]hile Fujiwara and Nolli provide generalized teachings for the production of antibodies to non antigenic drugs, their non-antigenic drugs or immunogens for forming antibodies are no way structurally related to 5-fluoro-uracil or the 5-FU derivatives of Marunaka and Pischel." Reply Br. 3. Ex parte Erlich, cited by the Examiner, is distinguishable insofar as the large molecule human fibroblast interferon at issue in that case was a known antigen, unlike the record established regarding the small molecule hapten 5-FU. See Ex parte Erlich, 3 USPQ2d 1011, 1015 (BPAI 1986) ("From our analysis, we find that it would have been obvious to ... form monoclonal antibodies specific for human fibroblast interferon since human fibroblast interferon was a known antigen ... of unquestioned research interest as an antiviral or antitumor agent."). Moreover, the Examiner has not taken into account the data in the Specification and Appellants' argument that the claimed "immunogen provides a new class of antibodies which are selectively reactive with [ 5-FU] without having any substantial cross-reactivity to tegafur as well as other cross-interfering pyrimidine bases." Reply Br. 3. In particular, the Specification includes data showing that "it is when the immunogen is formed from the compound of formula II-A, rather than II-B, an antibody is 8 Appeal2013-008011 Application 12/767,034 produced which does not cross-react with Tegafur," and "[i]t is through the antibody provided from the immunogen of the compound of the formula II- A and the reagent carrier provided from the compound of II-A or II -B, that produces an accurate immunoassay for 5-FU to monitor patients being treated with 5-FU." Spec. 51; Tables 1and2. These results show that not all conjugates of 5-FU derivatives will function effectively in an immunoassay. We therefore reverse the obvious rejection. SUMMARY We reverse the rejection of claim 46 under 35 U.S.C. § 112 (pre- AIA), second paragraph for indefiniteness; We reverse the rejection of claims 38, 42, 43, and 46 under 35 U.S.C. § 103(a) as being unpatentable over the combination of Yoshida, Fujiwara, Nolli, Marunaka, and Pischel. REVERSED 9 Copy with citationCopy as parenthetical citation