DETAILED ACTION
Status of Application
The response filed 10/27/2025 has been received, entered and carefully considered. The response affects the instant application accordingly:
Claims 1, 4-5, 7, 10-11, 14-15 have been amended.
Applicant had previously elected Group I and the species for the Src protein tyrosine inhibitor to be bafetinib, the species of ACYL inhibitor to be BMS303141, the PI3K inhibitor to be LY294002, and the pharmaceutical composition form to be an oral dosage form with the specific form of a tablet.
To address the breath claimed, the Src protein tyrosine inhibitor was expanded to include AZ628, sorafenib, curcumin, bosutinib, dasatinib, KX2-391, and soracatinib; the ACYL inhibitor was expanded to include SB-204990 and (-)hydroxycitrate; the PI3K inhibitor was expanded to include XL765 (Voxtalisib), BKM120 (buparlisib), and ARQ-197 (i.e. CW147 class of MET inhibitors) of Vali. The tablet form was expanded to include capsules.
Claims 1-16, 18-19, 28-29 are pending.
Claims 1-15 are present for examination at this time.
The present application, filed on or after March 16, 2013, is being examined under the first inventor to file provisions of the AIA .
All grounds not addressed in the action are withdrawn or moot as a result of amendment.
New grounds of rejection are set forth in the current office action as a result of amendment.
Claim Objections
Claims 4-5 and 15 are objected to because of the following informalities: the claim now recites “PBK inhibitor” rather than the previous “PI3K inhibitor” which appears to be a typographical error. Appropriate correction is required.
Claim 7 is objected to because of the following informalities: the claim recites “saracatinhib” and review of the specification demonstrates that the Lyn tyrosine kinase inhibitor is written as soracantinib wherein is a typographical error as to the correct spelling soracatinhib/saracantinib as a Lyn tyrosine kinase inhibitor. Appropriate correction is required.
New Grounds of Rejection
Due to the amendment of the claims the new grounds of rejection are applied:
Claim Rejections - 35 USC § 112
The following is a quotation of 35 U.S.C. 112(b):
(b) CONCLUSION.—The specification shall conclude with one or more claims particularly pointing out and distinctly claiming the subject matter which the inventor or a joint inventor regards as the invention.
The following is a quotation of 35 U.S.C. 112 (pre-AIA ), second paragraph:
The specification shall conclude with one or more claims particularly pointing out and distinctly claiming the subject matter which the applicant regards as his invention.
Claim 14 is rejected under 35 U.S.C. 112(b) or 35 U.S.C. 112 (pre-AIA ), second paragraph, as being indefinite for failing to particularly point out and distinctly claim the subject matter which the inventor or a joint inventor (or for applications subject to pre-AIA 35 U.S.C. 112, the applicant), regards as the invention.
The claims recites “according to claim 12 or claim H) which is unclear as the clams previous recited “according to claim 12” and there is no “claim H”. It does not allow one to ascertain the metes and bounds of the claims as written. For purposes of examination, it is treated as “according to claim 12”.
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 1-3, 5-10, 12-15 are rejected under 35 U.S.C. 103 as being unpatentable over Vali et al. (U.S. Pat. Pub. 2016/0058751).
Rejection:
Vali et al. teaches a pharmaceutical composition comprising a combination of actives for the treatment of cancer (abstract). The actives include a kinase inhibitor and an inhibitor of an enzyme involved in lipid metabolism and an excipient [3]. The combination can comprise at least one member of a first group and at least one member of a second group; where the first group is selected from a Raf inhibitor and a c-MET inhibitor, and the second group is selected from a HMG CoA reductase inhibitor or ATP Citrate Lyase (ACLY) inhibitor or farnesyltransferase inhibitor or geranylgeranyltransferase inhibitor or farnesyl diphosphate synthatase inhibitors [395]. The RAF inhibitors include AZ628 and sorafenib (CW137 class [135], are also known inhibitors of Lyn tyrosine kinase see specification and Li et al.). The c-MET inhibitors include ARQ-197 and crizotinib [136], and MET inhibitors (CW147 class) inhibit MET signaling and decrease MET-mediated RAS, PI3K and SRC activation (inhibitors of SRC and PI3K [204]). The ATP citrate lyase (ACLY) inhibitors include SB 204990 and BMS-303141 [153]. The pharmaceutical dosage unit form can be a tablet or a capsule [343, 345, 369]. The compound (Raf inhibitor, c-MET inhibitor, ATP Citrate Lyase inhibitor) is present in the composition in a range from about 1mg-2000mg including about 50mg-100mg [373] and about 50mg [374]. Combinations of actives are taught such as sorafenib and BMS-303141 (Example 8-13, ACLY and Raf inhibitor that is also a Lyn inhibitor in assay media) and ARQ-197 and BMS-303141 (Example 20-21, ACLY and MET inhibitor with Src/PI3K inhibition [204] in assay media), and a dosage form comprising combination of actives (claims 133-138).
While Vali et al. does not expressly exemplify the pharmaceutical composition comprising the combination of actives like ARQ-197 and BMS-30314 (ACLY inhibitor and MET inhibitor with Src/PI3K inhibition), or sorafenib and BMS-303141 and ARQ-197 (Raf/Lyn inhibitor and MET inhibitor with Src/PI3K inhibition and ACLY inhibitor [359]); but does expressly teach the combinations and exemplified combining the actives and claims it wherein it would be prima facie obvious to exemplify the pharmaceutical composition in the amounts taught with a reasonable expectation of success absent evidence of criticality for the claimed values. As the same components are present in the composition which is in the recited oral form, the composition is capable of the recited future intended use as it is the natural result of the combination of the recited actives in the composition form.
Response to Arguments:
Applicant's arguments are centered on the assertion that Vali is silent to the newly discovered dual regulation mechanism of ACLY and provides no teaching that a Src family kinase directly phosphorylates ACLY; or that PI4K pathway phospholipid bind directly to ACLY; where one would not have motivation to combine a Src family kinase inhibitor, a PI3K inhibitor and an ACLY inhibitor to inhibit this specific mechanism as the mechanism itself was not known to the art. This is fully considered but not persuasive. The claims are composition claims not method of use claims wherein as the same components are present in the composition which is in the recited oral form, the composition is capable of the recited future intended use as it is the natural result of the combination of the recited actives in the composition form. The prior art has a different reason for combining the actives than Applicant and the fact that Applicant has recognized another advantage which would flow naturally from following the suggestion of the prior art cannot be the basis for patentability when the differences would otherwise be obvious.
Accordingly, the rejection stands.
Claim 4 is rejected under 35 U.S.C. 103 as being unpatentable over Vali et al. (U.S. Pat. Pub. 2016/0058751) as applied to claims 1-3, 5-10, 12-15 above, in view of Goldman et al. (U.S. Pat. 2015/0374692).
Rejection:
The teachings of Vali et al. are addressed above.
Vali et al. does not expressly recite the instant claimed PI3K inhibitors but does teach a pharmaceutical composition with the combination of actives including RAF/Lyn/Src inhibitors like AZ628 and sorafenib, and ACLY inhibitors, and MET inhibitors (CW147 class) which can inhibit RAS/PI3K/SRC [204] for cancer treatment.
Goldman et al. teaches that compositions containing a combination of PI3K inhibitor and Src/lyn inhibitors help reduce the development of drug-resistant cancer cells (abstract, [8, 10,12, 25]). The PI3K inhibitor include XL765 (Voxtalisib) and LY294002 ([25, 42] Figure 4B).
Wherein it would be obvious to one of ordinary skill in the art before the effective filing date of the claimed invention to incorporate a PI3K like XL765 (Voxtalisib) or LY294002 in the composition as suggested by Goldman et al. and produce the claimed invention; as Vali et al. is directed to a composition comprising a combination of actives like AZ628 and sorafenib (RAF/Lyn/Src inhibitors) and ACLY inhibitors and MET inhibitors, useful for cancer treatment and the inclusion of actives like PI3K like XL765 (Voxtalisib) or LY294002 to combine with the Src/Lyn inhibitors of Vali, or even the addition of another Src inhibitor to reduce the development of drug resistant cancer cells is desirable with a reasonable expectation of success.
Response to Arguments:
Applicant's arguments are centered on the arguments presented to Vali, that Goldman is directed to dual PI3K-Src regimens to reducing the development of drug resistant cancer cells while Vai is to therapies for RAS mutated cancers which does not teach the claimed combination especially with the inclusion of an ACLY inhibitor which goes to the assertion that one of skill in the art would not have been motivated to combine a primary anti-tumor therapy with a secondary anti-resistance strategy by adding an ACLY inhibitor without a reasonable expectation of success, and that neither reference provides a teaching/rationale that ACLY inhibitor would enhance/complement PI3K/Src inhibition within Goldman’s framework.
This is fully considered but not persuasive.
Applicant’s arguments to Vali are addressed above. Applicant’s argument that Goldman is to PI3K-Src regimens for reducing drug resistance cancer cells and that Vali is to RAS mutated cancers where the reference do not teach the claimed combination with an ACLY inhibitor is not persuasive and not representative of the prior art. Contrary to Applicant’s assertion, as addressed above Vali does teach the inclusion of ACLY inhibitors in the pharmaceutical composition in combination with actives including RAF/Lyn/Src inhibitors like AZ628 and sorafenib, and MET inhibitors (CW147 class) which can inhibit RAS/PI3K/SRC [204] for cancer treatment. Goldman et al. is presented merely to show that a combination of PI3K inhibitor and Src/lyn inhibitors help reduce the development of drug-resistant cancer cells and known PI3K inhibitors include XL765 (Voxtalisib) and LY294002; wherein the inclusion of additional actives like PI3K like XL765 (Voxtalisib) or LY294002 to combine with the Src/Lyn inhibitors of Vali, or even the addition of another Src inhibitor for their additive effect to reduce the development of drug resistant cancer cells is desirable with a reasonable expectation of success particularly as Vali already teaches combination drug treatment.
As for the assertion that neither reference provides a teaching/rationale that ACLY inhibitor would enhance/complement PI3K/Src inhibition within Goldman’s framework, this is not persuasive as the argument is for Goldman to be the primary reference when Vali is the primary reference which already teaches the inclusion of ACLY inhibitors in combination with other active wherein the inclusion of other actives for their additive effect is prima facie obvious with a reasonable expectation of success. The prior art rejection has a different reason for combining the actives than Applicant and the fact that Applicant has recognized another advantage which would flow naturally from following the suggestion of the prior art cannot be the basis for patentability when the differences would otherwise be obvious.
Accordingly, the rejection stands.
Claim 11 is rejected under 35 U.S.C. 103 as being unpatentable over Vali et al. (U.S. Pat. Pub. 2016/0058751) as applied to claims 1-3, 5-10, 12-15 above, in view of Winfield et al. (Oral unit dosage forms-Container for tablets, Containers for capsules).
Rejection:
The teachings of Vali et al. are addressed above.
Vali et al. does not explicitly teach the packaging of the tablet/capsule but does teach the composition to be in a tablet/capsule form.
Winfield et al. teaches that containers for tablets include blister packs and container like amber glass/plastic containers (protects product e.g. from light, airtight), and similar containers for capsules.
Wherein it would be obvious to one of ordinary skill in the art before the effective filing date of the claimed invention package the tablets/capsules in blister packs or containers/bottles as suggested by Winfield et al. and produce the claimed invention; as it is prima facie obvious to have tablets/capsules in the conventional packaging with a reasonable expectation of success.
Response to Arguments:
Applicant's arguments are those to Vali which are addressed above.
Accordingly, the rejection stands.
Claims 1-10, 12-15 are rejected under 35 U.S.C. 103 as being unpatentable over Monje-Deisseroth et al. (U.S. Pat. 2016/0222100) in view of Thompson et al. (EP 2633856).
Rejection:
Monje-Deisseroth et al. teaches a pharmaceutical composition comprising excipients/carrier and therapeutic agents that inhibit neuronal activity-regulated protein for glioma treatment including small molecules of LY294002 (PI3K inhibitor), BKM120 (buparlisib, AN2025, PI3K inhibitor), curcumin (an inhibitor of Src), and bosutinib (Src/Lyn inhibitor, abstract, [31,147-149, 152, 158, 164]. Monje-Deisseroth et al. teaches that “a” and “an include plurals [78], wherein a composition containing an agent includes plural agents ([147] the composition has a combination of agents). The composition can be oral dosage forms like tablet and capsules [152, 158, 164], and the dose of the small molecule active agent can be from 100ug/kg-1mg/kg ([182], 100ug/kg-1mg/kg in standard man 70kg=7mg-70mg falling within the claimed range). Monje-Deisseroth et al. teaches that it can be combined with other actives ([188], see full document specifically areas cited).
Monje-Deisseroth et al. does not expressly teach the inclusion of an ATP citrate lyase (ACLY) inhibitor but does teach a pharmaceutical composition like a tablet/capsule comprising actives like LY294002 and bosutinib for treating glioma; and combination with other actives.
Thompson et al. teaches that ATP citrate lyase (ACLY) inhibitors like SB-204990 and (-)hydroxycitrate are useful for treating gliomas ([79 item 9], claim 7 and 11, figure 4). The inhibitors can be at a dose of about 25-500mg for the average human (70kg) ([62], falling within the claimed range), and can be in tablets/capsule [54].
Wherein it would be obvious to one of ordinary skill in the art before the effective filing date of the claimed invention to incorporate an ACLY inhibitor like SB-204990 at its known effective dose in the composition containing actives for treating glioma like LY294002 and bosutinib as suggested by Thompson et al. and produce the claimed invention; as it is It is obvious to combine the actives for the composition, each of which is taught by prior art to be useful for same purpose for their additive effect as the prior art addresses combination treatment with a reasonable expectation of success.
While the prior art does not teach the exact claimed values for the dependent amounts of ACLY inhibitor, PI3K inhibitor, and Src inhibitor in a capsule; they are embraced as the prior art teaches the dose of the ACLY inhibitor to be about 25-500mg, and the dose of the PI3K inhibitor and Src inhibitor to be 7mg-70mg (100ug/kg-1mg/kg in standard man 70kg=7mg-70mg) – wherein it would be prima facie obvious to optimize within the taught range as a means of attaining the desired therapeutic profile and arrive at the claimed values with a reasonable expectation of success absent evidence of criticality for the claimed amounts.
Response to Arguments:
Applicant's arguments are centered on the assertion that Monje-Deisseroth et al. is directed to a different disease as it is to gliomas and not general oncology while Thompson et al. is to general anti-cancer strategy by targeting ACLY and one of skill in the art would not look to a glioma therapy for general metabolic inhibitor combination as the rational is different where the combination is hindsight.
This has been fully considered but not persuasive. The claims are composition claims, not method of use claims. Wherein as contrary to Applicant’s assertion, the composition does not have to be to general oncology. Monje-Deisseroth et al. teaches a pharmaceutical composition like a tablet/capsule comprising actives such as LY294002 (PI3K inhibitor), BKM120 (buparlisib, AN2025, PI3K inhibitor), curcumin (an inhibitor of Src), and bosutinib (Src/Lyn inhibitor) for treating glioma; and combination with other actives; and contrary to Applicant’s assertion that Thompson et al. is to general oncology and to a different rational, this is not the case as - Thompson teaches that ATP citrate lyase (ACLY) inhibitors like SB-204990 and (-)hydroxycitrate are useful for treating gliomas ([79 item 9], claim 7 and 11, figure 4); wherein it is prima facie obvious to combine the actives for the composition, each of which is taught by prior art to be useful for same purpose for their additive effect as the prior art addresses combination treatment with a reasonable expectation of success. In response to applicant's argument that the examiner's conclusion of obviousness is based upon improper hindsight reasoning, it must be recognized that any judgment on obviousness is in a sense necessarily a reconstruction based upon hindsight reasoning. But so long as it takes into account only knowledge which was within the level of ordinary skill at the time the claimed invention was made, and does not include knowledge gleaned only from the applicant's disclosure, such a reconstruction is proper. See In re McLaughlin, 443 F.2d 1392, 170 USPQ 209 (CCPA 1971).
Accordingly, the rejection stands.
Claim 11 is rejected under 35 U.S.C. 103 as being unpatentable Monje-Deisseroth et al. (U.S. Pat. 2016/0222100) in view of Thompson et al. (EP 2633856) as applied to claims 1-10, 12-15 above, in view of Winfield et al. (Oral unit dosage forms-Container for tablets, Containers for capsules).
Rejection:
The teachings of Monje-Deisseroth et al. in view of Thompson et al. are addressed above.
Monje-Deisseroth et al. in view of Thompson et al. does not explicitly teach the packaging of the tablet/capsule but does teach the composition to be in a tablet/capsule form.
Winfield et al. teaches that containers for tablets include blister packs and container like amber glass/plastic containers (protects product e.g. from light, airtight), and similar containers for capsules.
Wherein it would be obvious to one of ordinary skill in the art before the effective filing date of the claimed invention package the tablets/capsules in blister packs or containers/bottles as suggested by Winfield et al. and produce the claimed invention; as it is prima facie obvious to have tablets/capsules in the conventional packaging with a reasonable expectation of success.
Response to Arguments:
Applicant's arguments are to Monje-Deisseroth and Thompson which are addressed above.
Accordingly, the rejection stands.
Claims 1-10, 12-15 are rejected under 35 U.S.C. 103 as being unpatentable over Thompson et al. (EP 2633856) in view of Goldman et al. (U.S. Pat. 2015/0374692).
Rejection:
Thompson et al. teaches a composition comprising ATP citrate lyase (ACLY) inhibitors like SB-204990 and (-)hydroxycitrate are useful for treating cancer ([79 item 9], claim 7 and 11, figure 4). The inhibitors can be at a dose of about 25-500mg for the average human (70kg) ([62], falling within the claimed range), be in tablets/capsule [54], part of combination therapy, and with chemotherapeutics, to prolong the survival of the patient ([20, 44-47], see full document specifically areas cited).
Thompson et al. does not expressly teach the inclusion of PI3K inhibitors and Src/lyn kinase inhibitors but does teach a pharmaceutical composition comprising ACLY inhibitors for treating cancer.
Goldman et al. teaches a combination of PI3K inhibitors and Src/lyn kinase inhibitors for reducing the development of drug-resistant cancer cells (abstract, [8, 10,12, 25]). The PI3K inhibitor include XL765 (Voxtalisib) and LY294002 ([25, 42] Figure 4B). The Src family kinase inhibitors include bosutinib, dasatinib, KX2-391, saracatinib [46]. Additional agents can be included [104] and pharmaceutical forms include tablets and capsules [99], the effective dose of the active includes 0.1mg/kg and 0.5mg/kg and 1mg/kg ([105], standard human 70kg so 0.1mg/kgx70kg=7mg, 0.5mg/kgx70kg=35mg, 1mg/kgx70kg=70mg, falling with the claimed ranges and values (i.e. 35mg is about 37.5mg, 70mg is about 75mg, see full document specifically areas cited).
Wherein it would be obvious to one of ordinary skill in the art before the effective filing date of the claimed invention to incorporate PI3K inhibitors like LY294002 and Src/lyn kinase inhibitors like bosutinib at its known effective dose in the tablet/capsule composition as suggested by Goldman et al. and produce the claimed invention; as it is It is obvious to incorporate actives that would reduce the development of drug resistant cancer cells in a composition for treating cancer which is desirable for their additive effect with a reasonable expectation of success.
While the prior art does not teach the exact claimed values for the dependent amounts of ACLY inhibitor in a capsule; it is embraced as the prior art teaches the dose of the ACLY inhibitor to be about 25-500mg wherein it would be prima facie obvious to optimize within the taught range as a means of attaining the desired therapeutic profile and arrive at the claimed values with a reasonable expectation of success absent evidence of criticality for the claimed amounts.
Response to Arguments:
Applicant's arguments are the assertion that Thompson relates to a primary metabolic therapy by inhibiting ACLY while Goldman is to a secondary therapy to overcome acquired dry resistance by combing PI3K and Src inhibitor where one would not be motivated to combine these teaching which are to different problem at different stages of cancer treatment, and the assertion of hindsight.
This is fully considered but not persuasive. Thompson compositions with ACLY inhibitors for teaches treating cancer and combination therapy where the inclusion of additional actives are expressly taught to prolong the survival of the patient, and Goldman et al. teaches that the combination of PI3K inhibitors and Src/lyn kinase inhibitors reduce the development of drug-resistant cancer cells which is desirable; wherein it would be obvious to one of ordinary skill in the art to incorporate PI3K inhibitors and Src/lyn kinase inhibitors and produce the claimed invention; as it is It is obvious to incorporate actives that would reduce the development of drug resistant cancer cells in a composition for treating cancer for their additive effect and prolong the survival of the patient with a reasonable expectation of success. In response to applicant's argument that the examiner's conclusion of obviousness is based upon improper hindsight reasoning, it must be recognized that any judgment on obviousness is in a sense necessarily a reconstruction based upon hindsight reasoning. But so long as it takes into account only knowledge which was within the level of ordinary skill at the time the claimed invention was made, and does not include knowledge gleaned only from the applicant's disclosure, such a reconstruction is proper. See In re McLaughlin, 443 F.2d 1392, 170 USPQ 209 (CCPA 1971).
Accordingly, the rejection stands.
Claim 11 is rejected under 35 U.S.C. 103 as being unpatentable Thompson et al. (EP 2633856) in view of Goldman et al. (U.S. Pat. 2015/0374692 as applied to claims 1-10, 12-15 above, further in view of Winfield et al. (Oral unit dosage forms-Container for tablets, Containers for capsules).
Rejection:
The teachings of Thompson et al. in view of Goldman et al. are addressed above.
Thompson et al. in view of Goldman et al. does not explicitly teach the packaging of the tablet/capsule but does teach the composition to be in a tablet/capsule form.
Winfield et al. teaches that containers for tablets include blister packs and container like amber glass/plastic containers (protects product e.g. from light, airtight), and similar containers for capsules.
Wherein it would be obvious to one of ordinary skill in the art before the effective filing date of the claimed invention package the tablets/capsules in blister packs or containers/bottles as suggested by Winfield et al. and produce the claimed invention; as it is prima facie obvious to have tablets/capsules in the conventional packaging with a reasonable expectation of success.
Response to Arguments:
Applicant's arguments are to Thompson et al. in view of Goldman which is addressed above.
Accordingly, the rejection stands.
Conclusion
Claims 1-15 are rejected.
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.
Any inquiry concerning this communication or earlier communications from the examiner should be directed to GIGI GEORGIANA HUANG whose telephone number is (571)272-9073. The examiner can normally be reached Monday-Thursday 9:00-5:00pm.
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/GIGI G HUANG/Primary Examiner, Art Unit 1613