Ex Parte KwongDownload PDFPatent Trial and Appeal BoardMay 9, 201411549347 (P.T.A.B. May. 9, 2014) Copy Citation UNITED STATES PATENT AND TRADEMARK OFFICE 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 APPLICATION NO. FILING DATE FIRST NAMED INVENTOR ATTORNEY DOCKET NO. CONFIRMATION NO. 11/549,347 10/13/2006 Yok-Lam Kwong UHK 00231 6827 23579 7590 05/09/2014 Pabst Patent Group LLP 1545 PEACHTREE STREET NE SUITE 320 ATLANTA, GA 30309 EXAMINER CHOI, FRANK I ART UNIT PAPER NUMBER 1616 MAIL DATE DELIVERY MODE 05/09/2014 PAPER 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. PTOL-90A (Rev. 04/07) UNITED STATES PATENT AND TRADEMARK OFFICE ____________ BEFORE THE PATENT TRIAL AND APPEAL BOARD ____________ Ex parte YOK-LAM KWONG ____________ Appeal 2012-008942 Application 11/549,347 Technology Center 1600 ____________ Before DONALD E. ADAMS, ERICA A. FRANKLIN, and SUSAN L. C. MITCHELL, Administrative Patent Judges. ADAMS, Administrative Patent Judge. DECISION ON APPEAL1 This appeal2 under 35 U.S.C. § 134 involves claims 1, 5, 6, 8, 11, and 12 (App. Br.3 2). Examiner entered a rejection under 35 U.S.C. § 103(a). We have jurisdiction under 35 U.S.C. § 6(b). We affirm. STATEMENT OF THE CASE The claims are directed to a method for inhibiting human female genital tract cancer or digestive tract cancer cells in a patient. Claim 1 is 1 The Real Party in Interest is The University of Hong Kong (App. Br. 2). 2 This Appeal is related to Appeal No. 2012-005618, Application No. 11/871,068. 3 Appellant’s “Second Appeal Brief,” entered into the record December 29, 2011. Appeal 2012-008942 Application 11/549,347 2 representative and is reproduced in the Claims Appendix of Appellant’s Brief. Claims 1, 5, 6, 8, 11, and 12 stand rejected under 35 U.S.C. § 103(a) as unpatentable over the combination of Warrell,4 Ellison,5 Kwong,6 Aono,7 Park,8 Moustafa,9 Arber,10 Xie,11 Rojewski,12 and either of Chen13 or Cao.14 4 Warrell, Jr. et al., US 2002/0013371 A1, published Jan. 31, 2002. 5 Ellison et al., US 6,875,451 B2, patented Apr. 5, 2005. 6 Yok-Lam Kwong, Arsenic trioxide in the treatment of haematological malignancies, 3 EXPERT OPIN. DRUG SAF. 589-597 (2004). 7 Aono et al., Study on Normal Ranges of Blood Urea Nitrogen and Serum Creatinine Levels in the Community-Dwelling Elderly Subjects Elderly 70 or Over – Correlation Between Age and Renal Function, 3 JAPAN J. GERIATRICS 232-236 (1994). 8 Park et al., Arsenic trioxide inhibits the growth of A498 renal cell carcinoma cells via cell cycle arrest or apoptosis, 300 BIOCHEMICAL AND BIOPHYSICAL RESEARCH COMMUNICATIONS 230-235 (2003). 9 Moustafa et al., Cyclin D1 is essential for neoplastic transformation induced by both E6/E7 and E6/E7/ErbB-2 cooperation in normal cells, 23 ONCOGENE 5252-5256 (2004). 10 Arber et al., Antisense to Cyclin D1 Inhibits the Growth and Tumorigenicity of Human Colon Cancer Cells, 57 CANCER RESEARCH 1569- 1574 (1997). 11 Xie, Arsenic trioxide (As2O3) induced apoptosis and its mechanisms in a human esophageal squamous carcinoma cell line, 115 CHINESE MEDICAL JOURNAL 280-285 (2002). 12 Rojewski, Dual effects of arsenic trioxide (As2O3) on non-acute promyelocytic leukaemia myeloid cell lines: induction of apoptosis and inhibition of proliferation, 116 BRITISH JOURNAL OF HAEMATOLOGY 555-563 (2002). 13 Chen, US 2006/0275504 A1, published Dec. 7, 2006. 14 Cao et al., Study on ascorbic acid enhancing arsenic trioxide to induce apoptosis in cervical cancer HELA cells, 24 JOURNAL OF SOUTHEAST UNIVERSITY (MEDICAL SCIENCE EDITION) 294-299 (2005). Appeal 2012-008942 Application 11/549,347 3 ISSUE Does the preponderance of evidence relied upon by Examiner support a conclusion of obviousness? FACTUAL FINDINGS (FF) FF 1. Warrell suggests the treatment of a variety of leukemia, lymphoma and solid tumors, including digestive tract cancer, “in humans by oral administration of [a therapeutically effective and non-lethal amount of] arsenic trioxide” (Ans. 6; Warrell Abstract, 4: ¶ [0052], 5: ¶ [0064] (“According to . . . [Warrell’s] invention, the arsenic compounds and their physiologically acceptable solvates may be formulated for oral or parenteral administration”), 5: ¶ [0065], and ¶ [0075]). FF 2. Warrell suggests the administration of arsenic trioxide, for treatment of “conditions described herein,” at a “preferred total daily dose . . . from about 2.5 to about 40 mg of arsenic trioxide” and that this dosage can “vary according to the age, body weight, condition and response of the individual patient” (Warrell 6: ¶ [0070]; see also id. (“the daily dose ranges of arsenic trioxide for the conditions described herein are generally from about 0.05 to about 5 mg per kg body weight administered in divided doses administered parenterally or orally or topically”); id. at [0074] (the attending physician would know how to adjust the dosage to attain the required therapeutic effect and safety); Ans. 6). FF 3. Warrell suggests that “any suitable route of administration may be employed for providing the patient with an effective dosage of an arsenic compound” and exemplifies the intravenous administration of arsenic trioxide to treat colon cancer (Warrell 6: ¶ [0075] and 12: ¶¶ [0131]-[0132]). Appeal 2012-008942 Application 11/549,347 4 FF 4. Examiner finds that Warrell fails to suggest “treatment of female genital tract cancer, a method of inhibiting cyclin D1 production by contacting a cancer cell with[] arsenic trioxide, producing a level of from 2-4 micromolar, the use of 5 mg/day in subjects over 70 years old or [arsenic trioxide in] combination with ascorbic acid” (Ans. 9). FF 5. Ellison suggests the oral administration of arsenic trioxide in the treatment of gastrointestinal tract, including esophageal, colon and stomach; and urogenital tract, including carcinoma of the cervix, tumors (Ellison, col. 9, l. 36 - col. 10, l. 25; Ans. 6; see also Ellison, col. 14, ll. 8-13 (“In general, the total daily dose ranges for the conditions described herein are generally from about 10 µg to about 200 mg administered in divided doses administered . . . orally,” and may “vary according to the age, body weight, condition and response of the individual patient”)). FF 6. Examiner finds that Kwong suggests [T]hat oral arsenic trioxide is effectively comparable to intravenous arsenic trioxide, that at therapeutic doses arsenic trioxide has much fewer side effects than standard chemotherapy and is a remarkably safe medication to use, and that renal excretion is a major route of elimination of arsenic and . . . half the standard dose [or ]5 mg/day[] should be used in patients with impaired renal function (Ans. 6; Kwong 591: col. 1, ll. 12-23 and 593: col. 2, ll. 5-8). FF 7. Examiner relies on Aono to suggest “that decline in renal function correlated with age after the seventh decade” (Ans. 7). FF 8. Examiner relies on Park to suggest that “renal cell . . . susceptibility to arsenic trioxide was similar to that in other solid tumors, such as ovarian, colon and cervical cancer, [and] that arsenic trioxide decreased levels of cyclin D1 in renal cancer cells” (Ans. 7; Park 230: Abstract (“arsenic Appeal 2012-008942 Application 11/549,347 5 trioxide . . . decreased the levels of . . . cyclin D1”); 231: col. 2, ll. 44-54; and 233: col. 1, ll. 6-8 (“A498 cells treated with arsenic trioxide resulted in a down-regulation of . . . cyclin D1”)). FF 9. Examiner relies on Moustafa to suggest “that cyclin D1 is overexpressed in different types of human cancer, including cervical cancer . . . [and] that antisense cyclin D1 led to the inhibition of cyclin D1 expression and cell growth of squamous cell carcinomas both in vitro and in vivo” (Ans. 7). FF 10. Examiner relies on Arber to suggest [T]hat increased expression of the cyclin D1 gene has been found in several types of human cancer, including . . . colon . . . and squamous carcinomas of the esophagus . . . . [T]hat inhibition of the expression of cyclin D1 in colonic tumor cells that overexpress this gene tends to revert their transformed phenotype and inhibits their tumorigenicity which may be of clinical significance . . . [and] that therapeutic agents directed against cyclin D1 . . . activity might be useful in the therapy of the subset of human colon tumors that overexpress cyclin D1. (Id. at 7-8; Arber 1569: col. 1, l. 28 – col. 2, l. 4 and 1573: col. 2, ll. 23-34.) FF 11. Examiner relies on Xie to suggest “that arsenic trioxide at a concentration of 1, 2 and 4 micromole/L markedly inhibited the growth and survival of human esophageal squamous carcinoma cell line,” EC8712, which was used as a model of the apoptotoic effect arsenic trioxide had on human solid tumor cells (Ans. 8; Xie 280: Abstract). FF 12. Examiner relies on Rojewski to suggest that [C]ell lines of leukaemia and lymphoma responded to arsenic trioxide at concentrations, up to 5 micromole/L, that are achievable by administration of well-tolerated doses of arsenic trioxide in clinical studies . . . [and that the] apoptosis-inducing effects of arsenic trioxide in non-acute promyelocytic leukaemia are in agreement with several reports about apoptotic Appeal 2012-008942 Application 11/549,347 6 effects of arsenic trioxide even in non-haemopoietic cells such as cervical cancer cell line, gastric cell lines and ovary cancer cell lines. (Ans. 8; see Rojewski 559, col. 2, l. 55 - 560, col. 1, l. 6.) FF 13. Examiner relies on Chen to suggest “treatment of solid tumors, such as colon, rectal and ovarian cancer with a combination of arsenic trioxide, ascorbic acid and vitamin K3” administered in an oral formulation (Ans. 8; Chen 3: ¶¶ [0031]-[0035]). FF 14. Examiner relies on Cao to suggest “that ascorbic acid enhances the ability of arsenic trioxide at concentration[s] of 2 and 5 micromole/L to induce apoptosis in a cervical cancer cell line” (Ans. 8; Cao 299: Abstract). FF 15. Kwong suggests that “oral arsenic trioxide achieves a lower peak plasma arsenic level, [therefore,] the prolongation of QT interval, which depends on the plasma arsenic, might be expected to be less serious” (Kwong 592: col. 2, ll. 18-21). ANALYSIS Based on the combination of Warrell, Ellison, Kwong, Aono, Park, Moustafa, Arber, Xie, Rojewski, and either of Chen or Cao, Examiner concludes that, at the time Appellant’s invention, Appellant’s claimed invention, “as a whole, would have been prima facie obvious to one of ordinary skill in the art at the time the invention was made, because every element of the invention has been collectively taught by the combined teachings of the references” (Ans. 11). Appeal 2012-008942 Application 11/549,347 7 Claim 1: The prior art suggests the oral administration of a safe (i.e., non- lethal) and therapeutically effective daily dose of arsenic trioxide for the treatment of a variety of leukemia, lymphoma and solid tumors, including digestive tract cancer and tumors of the gastrointestinal tract, including esophageal, colon and stomach; and urogenital tract, including carcinoma of the cervix (FF 1 and 5). For the treatment of the forgoing conditions, the prior art suggests the oral administration of a total daily dose of arsenic trioxide that is generally from about 10 µg to about 200 mg administered in divided doses, or generally from about 0.05 to about 5 mg per kg body weight (FF 2 and 5; Ans. 15; Cf. Appellant’s Claim 1). There is no evidence on this record to support a conclusion that the administration of the dosage suggested by the prior art, which is based on an amount per kilogram of body weight, would not “produce a level of from two to four micromolar” as that phrase is used in Appellant’s claims. In this regard, we recognize Examiner’s finding that “concentrations[] up to 5 micromole/L . . . are achievable by administration of well-tolerated doses of arsenic trioxide in clinical studies” (FF 12; see also FF 11 (“arsenic trioxide at a concentration of 1, 2, and 4 micromole/L markedly inhibited the growth and survival of [a] human esophageal squamous carcinoma cell line” used as a model of the apoptotic effect arsenic trioxide had on human solid tumor cells)). Therefore, we are not persuaded by Appellant’s intimation that the prior art relied upon by Examiner fails to suggest a safe, therapeutically effective oral dosage of arsenic trioxide, that falls with the scope of Appellant’s claim 1, for the in vivo treatment of a cancer within the scope of Appellant’s claim 1 (App. Br. 22-24; Reply Br. 5 and 8-11). Appeal 2012-008942 Application 11/549,347 8 Claim 1 does not require the arsenic trioxide to operate through a particular mechanism (e.g., inhibiting overexpression of cyclin D1) (see Appellant’s Claim 1; Cf. Appellant’s Claim 8). Therefore, we are not persuaded by Appellant’s contentions regarding cyclin D1 (App. Br. 23; Reply Br. 8-9). For the reasons set forth above, we recognize, but are not persuaded by, Appellant’s evidence of unexpected results that show no more than what a person of ordinary skill in this art would have reasonably expected from the application of the method suggested by the combination of prior art relied upon by Examiner (see, e.g., FF 1-2; Cf. App. Br. 24; Reply Br. 9-11). We are also not persuaded by Appellant’s contention that “Appellant made the unexpected discovery that an oral formulation of arsenic trioxide causes a smaller prolongation of QT intervals,” which was also suggested by the prior art (see Reply Br. 10; Cf. FF 15). Claim 5: Claim 5 depends from and further limits the cancer cell of Appellant’s claim 1 to a human female genital tract cancer (Appellant’s Claim 5). The prior art relied upon by Examiner suggests the oral administration of arsenic trioxide for the treatment of human female genital tract cancers (FF 5). Appellant failed to establish an evidentiary basis on this record to support a conclusion that the dosage suggested by the prior art is not commensurate in scope with Appellant’s claimed invention (see FF 2 and 5). Therefore, we are not persuaded by Appellant’s contention that “one of ordinary skill in the art would [not] expect success in using an orally administered dose of Appeal 2012-008942 Application 11/549,347 9 arsenic trioxide to treat cancer of the human female genital tract” (App. Br. 24-25; Reply Br. 12). Claim 5 does not require the arsenic trioxide to operate through a particular mechanism, therefore we are not persuaded by Appellant’s contention “that none of the cited references disclose or suggest that cancers of the human female genital tract overexpress cyclin D1” (App. Br. 24; see Appellant’s Claim 5; Cf. Appellant’s Claim 8). Claim 8: Claim 8 depends from and further limits claim 1 to require that growth is inhibited by inhibiting overexpression of cyclin D1 (see Appellant’s Claim 8). The prior art relied upon by Examiner established that “cyclin D1 is overexpressed in different types of human cancer” and that arsenic trioxide decreased cyclin D1 levels in cancer cells (FF 8-10). The combination of references relied upon by Examiner supports a conclusion that oral administration of arsenic trioxide, at a dosage commensurate in scope with Appellant’s claimed invention, is effective in the treatment of human digestive tract and female genital tract cancers, including those that over express cyclin D1 (see, e.g., FF 1-5 and 8-10). Accordingly, we are not persuaded by Appellant’s contentions that “the mechanism whereby arsenic trioxide inhibited cell proliferation and/or induced apoptosis was controversial and unclear” and that “[t]here is no reason why one of ordinary skill in the art would expect success in using an orally administered dose of arsenic trioxide to treat the claimed cancers” (App. Br. 25; Reply Br. 12). Appeal 2012-008942 Application 11/549,347 10 Claim 11: Claim 11 depends from and further limits the arsenic trioxide dosage of Appellant’s claim 1 to 10 mg/day administered to subjects below 70 years old with normal renal function or 5 mg/day administered to subjects over 70 years old (see Appellant’s claim 11). Aono suggests “that decline in renal function correlated with age after the seventh decade” (FF 7). Kwong suggests the use of an arsenic trioxide dosage of 5 mg/day in patients with impaired renal function, which Kwong suggests is half the standard dose, e.g., 10 mg/day (FF 6). In combination, the prior art suggests the administration of arsenic trioxide at a dosage of: (a) 5 mg/day for subjects over 70 years of age who are expected to have a decline in, or otherwise impaired, renal function and (b) 10 mg/day for subjects below 70 years of age with normal renal function. Therefore, we are not persuaded by Appellant’s contention that while Aono suggests “that a decline in renal function correlates with age after age 70 . . . simply saying that one should adjust for age is merely an invitation to experiment, not guidance” (App. Br. 25; Reply Br. 12-13). We recognize, but are not persuaded by, Appellant’s contention that Kwong fails to address cancer of human female genital tract or digestive tract (id.). While Kwong suggests the treatment of haematological malignancies, e.g., “leukaemia,” Warrell suggests the treatment of leukemia and digestive tract cancer cells in patients at dosages that correspond to those suggested by Kwong (FF 1, 2, and 6; see also FF 5 (wherein Ellison suggests the treatment of female genital tract cancer with an arsenic trioxide dosage that corresponds to the dosage suggested by Kwong)). Appeal 2012-008942 Application 11/549,347 11 Claim 12: Claim 12 depends from and further limits claim 1 to comprise administration of ascorbic acid with the arsenic trioxide (see Appellant’s Claim 12). Examiner relies on Chen to suggest “treatment of solid tumors, such as colon, rectal and ovarian cancer with a combination of arsenic trioxide, ascorbic acid and vitamin K3” administered in an oral formulation (FF 13; see generally FF 14 (“ascorbic acid enhances the ability of arsenic trioxide at concentration[s] of 2 and 5 micromole/L to induce apoptosis in a cervical cancer cell line”)). In sum, the combination of references relied upon by Examiner supports a conclusion that oral administration of arsenic trioxide in combination with ascorbic acid, at a dosage commensurate in scope with Appellant’s claimed invention, is effective in the treatment of human digestive tract and female genital tract cancers (see, e.g., FF 1-10 and 13). For the foregoing reasons we are not persuaded by Appellant’s contention that the combination of references relied upon by Examiner fails to establish “that ascorbic acid can be added to an oral arsenic trioxide formulation and effectively treat cancer in vivo, without producing debilitating side-effects, possibly death” (App. Br. 26; Reply Br. 13). CONCLUSION OF LAW The preponderance of evidence relied upon by Examiner supports a conclusion of obviousness. The rejection of claims 1, 5, 8, 11, and 12 under 35 U.S.C. § 103(a) as unpatentable over the combination of Warrell, Ellison, Kwong, Aono, Park, Moustafa, Arber, Xie, Rojewski, and either of Chen or Cao is affirmed. Claim 6 falls with claim 1. Appeal 2012-008942 Application 11/549,347 12 TIME PERIOD FOR RESPONSE No time period for taking any subsequent action in connection with this appeal may be extended under 37 C.F.R. § 1.136(a). AFFIRMED cdc Copy with citationCopy as parenthetical citation