DETAILED ACTION
Notice of Pre-AIA or AIA Status
The present application, filed on or after March 16, 2013, is being examined under the first inventor to file provisions of the AIA .
Claim Status
Claims 28, 30-34, 37-44 and 47-51 are pending. Claims 28, 30-34, 37-44 and 47-51 are rejected.
Response to Amendment/Arguments
On pages 6-10 of the remarks filed July 28th, 2025, Applicant traverses the USC 103 rejection of claims 28, 30-34, 37-44 and 47 and notes that claims 28 and 39 were amended to recite that “the nucleic acid inhibitor molecule is administered in a therapeutically effective amount to knock down hCAS mRNA expression levels.” Applicant asserts that administration of delta-tocotrienol and a therapeutically effective amount of nucleic acid inhibitor molecule to knock down hCAS mRNA expression confers unexpected results. Whether or not the data suggests the presence of unexpected results, the instant claims as drafted do not adequately distinguish the instant methods of treatment from the combined teachings of the prior art. The newly added limitation “to knock down” hCAS mRNA expression levels is an intended effect. The current claim construction of claims 28 and 39 not does not require any particular level of knockdown effect to be achieved. Even if the instant claims were to specify that the nucleic acid inhibitor molecule is an hCAS-specific RNA interference molecule, use of small interfering RNA (siRNA) to knock down hCAS for cancer treatment is known. Despite the new limitation simply serving as an intended effect the instant claims are newly rejected in light of prior art that provides a motivation for using siRNA to treat pancreatic cancer.
Applicant argues that cited references do not recognize certain mechanisms discussed in the instant application; however, the prior art is not required to provide an underlying mechanism to support the disclosed methods nor is the prior art required to provide the same motivation for performing a method. Regarding claims 48-51, the combined teachings of the prior art provide a method of treating pancreatic cancer by administering delta-tocotrienol and a nucleic acid inhibitor molecule, and teach that hCAS is strongly positive in certain pancreatic cancer lines. This provides a motivation for administering the combination to subjects with pancreatic cancer wherein a person of ordinary skill could expect to encounter a population of subjects with pancreatic cancer that comprises overexpression of hCAS given that hCAS was identified as being strongly positive in pancreatic cancer cells. Claim 48 is open-ended and does not exclude the administration of a secondary agent such as the nucleic acid inhibitor molecule of claim 1. Furthermore, the fact that claim 48 identifies a patient population that includes some targets not mentioned by the prior art and excludes others that the prior art method is directed to does not overcome the rejection because an overlap remains between the subjects of the instant claim and the prior art. Claims 50-51 are further rejected under 35 USC 103 as applied to claims 28, 30-34, 39-44 and 48-49. Claims 50-51 remain rejected for obviousness wherein parent claim 48 was rejected for the reasons noted above and the teachings of Ames et al. provide a motivation for administering aspirin in combination with delta-tocotrienol to the subjects defined in the rejection of claims 28, 30-34, 39-44 and 48-49.
Claim Rejections - 35 USC § 103
The following is a quotation of 35 U.S.C. 103 which forms the basis for all obviousness rejections set forth in this Office action:
A patent for a claimed invention may not be obtained, notwithstanding that the claimed invention is not identically disclosed as set forth in section 102, if the differences between the claimed invention and the prior art are such that the claimed invention as a whole would have been obvious before the effective filing date of the claimed invention to a person having ordinary skill in the art to which the claimed invention pertains. Patentability shall not be negated by the manner in which the invention was made.
Claims 28, 30-34, 39-44 and 48-49 are rejected under 35 U.S.C. 103 as being unpatentable over WO0234072 by Troup et al. in view of Husain et. al. In: Proceedings of the 101st Annual Meeting of the American Association for Cancer Research; 2011 Apr 17-21; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2011;71(8 Suppl): Abstract nr 1667. cited in the IDS filed June 11th, 2024. and Husain et. al. In: Proceedings of the 101st Annual Meeting of the American Association for Cancer Research; 2010 Apr 17-21; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2010;70(8 Suppl):Abstract nr 1612.
Determining the scope and contents of the prior art. (See MPEP § 2141.01)
The prior art discloses a ”Synergistic combination of delta tocols and polyphenols” (title). Troup et al. disclose a composition containing delta-tocotrienol (page 3).
The prior art reports that the composition may be administered prevent or slow the progression of diseases associated with free radical damage such as pancreatic cancer and to counteract the effect of reactive oxygen species resulting from treatment with neoplastic drugs which would embrace preventing recurrence of pancreatic cancer and anti-cancer treatment maintenance following anti-cancer treatment of pancreatic cancer, in accordance with instant claims 28 and 39 (page 15).
Regarding instant claims 30-33 and 40-43, the prior art discloses daily doses up to 2000 mg which embraces the 400 and 800 mg doses of the instant claims (page 7). Troup et al. further note that the daily dosage may be provided through multiple dosages.
Instant claims 34 and 44 are directed towards the method of preventing cancer recurrence and/or anti-cancer treatment maintenance wherein δ-tocotrienol is administered for 6 months. A person of skill would have been motivated to administer the compound for extended periods of time to reduce the likelihood of recurrence.
Ascertainment of the differences between the prior art and the claims. (See MPEP § 2141.02)
The prior art discloses a method of preventing cancer recurrence after undergoing cancer treatment by administering delta-tocotrienol; however, the prior art does not teach the method wherein a nucleic acid inhibitor is administered to knock down hCAS mRNA expression levels.
Finding of prima facie obviousness --- rationale and motivation (See MPEP § 2141.02)
Husain et al. disclose (title) “Abstract 1667: In vitro and in vivo validation of CSE1L/hCAS as a potential molecular target in pancreatic cancer”. Specifically, the prior art teaches (Results) “[p]ancreatic ductal carcinomas (PCA) were hCAS strongly positive. Normal pancreatic ducts (ND) were hCAS weakly positive. hCAS KD-MiaPaCa-2 tumor growth was retarded in mice compared to Scr-MiaPaCa-2 tumors. hCAS KD-MiaPaCa-2 tumors showed hCAS depletion, lower proliferative index, increased caspase-3 immunostaining and PARP1 cleavage.” Husain et al. conclude (Conclusion) “[t]his is the first report of hCAS expression in human pancreatic cancer. Our data suggest that hCAS is a regulator of cell proliferation, cell cycle regulation and apoptosis. hCAS may represent a potential chemopreventive and therapeutic target for human pancreatic cancer.”
Husain et al. also disclose (title) “Abstract 1612: Validation of CSE1L/hCAS as a potential therapeutic target in pancreatic cancer”. Specifically, the prior art reports that effects of hCAS knockdown using small interfering RNA (siRNA) oligonucleotides were investigated in MiaPaCa-2 human pancreatic cancer cells (Methods). Husain et al. explain (Results):
hCAS protein expression increased in pancreatic cancer cell lines relative to the immortalized pancreatic ductal epithelial cell line. Immunohistochemical staining of a human pancreatic tumor tissue microarray showed that hCAS expression was higher in pancreatic tumors compared with their normal counterparts. There was increasing nuclear to cytoplasmic staining with progression from normal pancreatic duct to increasing grade of pancreatic intraductal neoplasia to invasive pancreatic cancer. Treatment with hCAS targeting small interfering RNAs effectively reduced pancreatic cell growth in tissue culture, induced apoptosis, and inhibited growth in soft agar.
Accordingly, a person of ordinary skill in the art would have been motivated to modify the method of preventing pancreatic cancer recurrence disclosed by Troup et al. to administer hCAS targeting siRNA because hCAS is strongly positive in pancreatic cancers and hCAS knockdown was shown to reduce pancreatic cancer cell growth and induce apoptosis as taught by Husain et al. The limitation “to knock down” hCAS mRNA expression levels is an intended effect. The current claim construction of claims 28 and 39 does not require any particular level of knockdown effect to be achieved and nor does it specify a sequence for a particular hCAS RNAi compound therefore the instant claim is obvious in view of the combination of the prior art.
Additionally, the method of decreasing hCAS levels in a cell by administering delta-tocotrienol and a nucleic acid inhibitor molecule that reduces hCAS mRNA expression levels is embraced by this method because administration of the compounds to a subject would result in the compounds coming into contact with cells (corresponding to instant claim 48). A person of ordinary skill could expect to encounter a population of subjects with pancreatic cancer that comprises overexpression of hCAS given that hCAS was identified as being strongly positive in pancreatic cancer cells.
Claims 37-38, 47 and 50-51 are rejected under 35 U.S.C. 103 as being unpatentable over WO0234072 by Troup et al. in view of Husain et. al. In: Proceedings of the 101st Annual Meeting of the American Association for Cancer Research; 2011 Apr 17-21; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2011;71(8 Suppl): Abstract nr 1667. cited in the IDS filed June 11th, 2024. and Husain et. al. In: Proceedings of the 101st Annual Meeting of the American Association for Cancer Research; 2010 Apr 17-21; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2010;70(8 Suppl): Abstract nr 1612. as applied to claims 28, 30-34, 39-44 and 48-49 above, and further in view of US 20040102421 A1 by Ames et al.
Troup et al. and Husain et al. in combination disclose method of preventing cancer recurrence and/or anti-cancer treatment maintenance by administering δ-tocotrienol with a nucleic acid inhibitor molecule; however, the prior art does not teach the method further comprising administering an NSAID or COX-2 inhibitor.
Ames et al. disclose (page 9, claim 1):
[a] medicament comprising predetermined amounts of a phytyl substituted chromanol and an inhibitor of prostaglandin E2 (PGE2) formation, wherein: said medicament is in unit dosage form suitable for pharmaceutical administration; said phytyl substituted chromanol is selected from the group consisting of gamma-tocopherol, delta-tocopherol, gamma-tocotrienol and delta-tocotrienol; and said PGE2 inhibitor is selected from the group consisting of an omega-3 fatty acid cyclooxygenase substrate and a non-steroidal anti-inflammatory drug (NSAID) cyclooxygenase inhibitor.
Claim 11 on page 9 specifies the medicament wherein the PGE2 inhibitor is cyclooxygenase-2 (COX-2) selective inhibitor corresponding to instant claims 37-38 and 47. Table 1 on page 3 discloses aspirin as a suitable NSAID cyclooxygenase inhibitor.
Claim 13 (page 9) of the prior art discloses a method of inhibiting inflammation comprising the medicament. Ames et al. further disclose “[t]hese subject medicaments can also be used to treat and prevent chronic diseases associated with inflammation such as cancer and cardiovascular disorders” (page 1, paragraph 0008).
Accordingly, a person of ordinary skill in the art would have been motivated to modify the method of preventing cancer reoccurrence and/or anti-cancer treatment maintenance taught by Troup et al., Freier and Husain et al. to include administration of aspirin disclosed by Ames et al. for improved cancer treatment outcomes. Additionally, the method of decreasing hCAS levels in a cell by administering delta-tocotrienol and aspirin required by instant claims 50-51 would by embraced by this combined method.
Double Patenting
The nonstatutory double patenting rejection is based on a judicially created doctrine grounded in public policy (a policy reflected in the statute) so as to prevent the unjustified or improper timewise extension of the “right to exclude” granted by a patent and to prevent possible harassment by multiple assignees. A nonstatutory double patenting rejection is appropriate where the conflicting claims are not identical, but at least one examined application claim is not patentably distinct from the reference claim(s) because the examined application claim is either anticipated by, or would have been obvious over, the reference claim(s). See, e.g., In re Berg, 140 F.3d 1428, 46 USPQ2d 1226 (Fed. Cir. 1998); In re Goodman, 11 F.3d 1046, 29 USPQ2d 2010 (Fed. Cir. 1993); In re Longi, 759 F.2d 887, 225 USPQ 645 (Fed. Cir. 1985); In re Van Ornum, 686 F.2d 937, 214 USPQ 761 (CCPA 1982); In re Vogel, 422 F.2d 438, 164 USPQ 619 (CCPA 1970); In re Thorington, 418 F.2d 528, 163 USPQ 644 (CCPA 1969).
A timely filed terminal disclaimer in compliance with 37 CFR 1.321(c) or 1.321(d) may be used to overcome an actual or provisional rejection based on nonstatutory double patenting provided the reference application or patent either is shown to be commonly owned with the examined application, or claims an invention made as a result of activities undertaken within the scope of a joint research agreement. See MPEP § 717.02 for applications subject to examination under the first inventor to file provisions of the AIA as explained in MPEP § 2159. See MPEP § 2146 et seq. for applications not subject to examination under the first inventor to file provisions of the AIA . A terminal disclaimer must be signed in compliance with 37 CFR 1.321(b).
The filing of a terminal disclaimer by itself is not a complete reply to a nonstatutory double patenting (NSDP) rejection. A complete reply requires that the terminal disclaimer be accompanied by a reply requesting reconsideration of the prior Office action. Even where the NSDP rejection is provisional the reply must be complete. See MPEP § 804, subsection I.B.1. For a reply to a non-final Office action, see 37 CFR 1.111(a). For a reply to final Office action, see 37 CFR 1.113(c). A request for reconsideration while not provided for in 37 CFR 1.113(c) may be filed after final for consideration. See MPEP §§ 706.07(e) and 714.13.
The USPTO Internet website contains terminal disclaimer forms which may be used. Please visit www.uspto.gov/patent/patents-forms. The actual filing date of the application in which the form is filed determines what form (e.g., PTO/SB/25, PTO/SB/26, PTO/AIA /25, or PTO/AIA /26) should be used. A web-based eTerminal Disclaimer may be filled out completely online using web-screens. An eTerminal Disclaimer that meets all requirements is auto-processed and approved immediately upon submission. For more information about eTerminal Disclaimers, refer to www.uspto.gov/patents/apply/applying-online/eterminal-disclaimer.
Claims 28, 30-34, 37-44 and 47-51 are rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1-14 of U.S. Patent No. 8846653 and claims 1-9 of U.S. Patent No. 8288369 in view of WO0234072 by Troup et al. in view of Husain et. al. In: Proceedings of the 101st Annual Meeting of the American Association for Cancer Research; 2011 Apr 17-21; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2011;71(8 Suppl): Abstract nr 1667. cited in the IDS filed June 11th, 2024., Husain et. al. In: Proceedings of the 101st Annual Meeting of the American Association for Cancer Research; 2010 Apr 17-21; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2010;70(8 Suppl):Abstract nr 1612. and US 20040102421 A1 by Ames et al.
The patents disclose a method of treating pancreatic cancer comprising administering a therapeutically effective amount of delta-tocotrienol where treating embraces preventing the recurrence of said cancer, which serves as the basis of a rationale under 35 USC 103. The teachings and rationale of Troup et al., Husain et al. and Ames et al. relative to claims 28, 30-34, 37-44 and 47-51 as discussed above are incorporated here by reference. The instant claims are deemed to be obvious variants of the subject matter of the patents for the same reasons as under 35 USC 103.
Claims 28, 30-34, 37-44 and 47-51 are provisionally rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1-10 of copending Application No. 18833013 in view of WO0234072 by Troup et al. in view of Husain et. al. In: Proceedings of the 101st Annual Meeting of the American Association for Cancer Research; 2011 Apr 17-21; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2011;71(8 Suppl): Abstract nr 1667. cited in the IDS filed June 11th, 2024., Husain et. al. In: Proceedings of the 101st Annual Meeting of the American Association for Cancer Research; 2010 Apr 17-21; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2010;70(8 Suppl):Abstract nr 1612., and US 20040102421 A1 by Ames et al.
Copending claims 2-3 recite a method of inhibiting progression of pancreatic cancer following surgical removal or anti-cancer treatment by administering a composition comprising delta-tocotrienol which serves as the basis of a rationale under 35 USC 103. The teachings and rationale of Troup et al., Husain et al. and Ames et al. relative to claims 28, 30-34, 37-44 and 47-51 as discussed above are incorporated here by reference. The instant claims are deemed to be obvious variants of the subject matter of the copending application for the same reasons as under 35 USC 103.
This is a provisional nonstatutory double patenting rejection.
Conclusion
Applicant's amendment necessitated the new ground(s) of rejection presented in this Office action. Accordingly, THIS ACTION IS MADE FINAL. See MPEP § 706.07(a). Applicant is reminded of the extension of time policy as set forth in 37 CFR 1.136(a).
A shortened statutory period for reply to this final action is set to expire THREE MONTHS from the mailing date of this action. In the event a first reply is filed within TWO MONTHS of the mailing date of this final action and the advisory action is not mailed until after the end of the THREE-MONTH shortened statutory period, then the shortened statutory period will expire on the date the advisory action is mailed, and any nonprovisional extension fee (37 CFR 1.17(a)) pursuant to 37 CFR 1.136(a) will be calculated from the mailing date of the advisory action. In no event, however, will the statutory period for reply expire later than SIX MONTHS from the mailing date of this final action.
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/A.A.C./Examiner, Art Unit 1626
/JOSEPH K MCKANE/Supervisory Patent Examiner, Art Unit 1626