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 .
Application Status
The preliminary amendments filed 10 May 2024 are acknowledged and have been entered. Claims 3-8 are amended. Claims 1-13 are pending and being examined on the merits.
Priority
The application is a 371 PCT of US2022/079700 filed 11/11/2022 which claims priority to application 63/278,317 filed 11/11/2021.
Information Disclosure Statement
The information disclosure statement filed 5/10/2024 and 03/05/2024 have been considered.
Specification
The use of the term Molecular Devices, GraphPad, Applied Biosystems, Agilent Technologies, Thermo Fisher Scientific, Millipore, Bio-Rad, Cell Signaling Technology and Molecular Probes, to name a few, which is a trade name or a mark used in commerce, has been noted in this application. The term should be accompanied by the generic terminology; furthermore the term should be capitalized wherever it appears or, where appropriate, include a proper symbol indicating use in commerce such as ™, SM , or ® following the term. A cursory review of the specification has revealed these trademarks or names. It would be remedial to check the specification for additional trademarks or names and amend all upon amendment.
Although the use of trade names and marks used in commerce (i.e., trademarks, service marks, certification marks, and collective marks) are permissible in patent applications, the proprietary nature of the marks should be respected and every effort made to prevent their use in any manner which might adversely affect their validity as commercial marks.
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.
Claims 4, 9-10, and 12-13 are 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.
Claim 4 recites “the AMPKα inhibitor comprises Dorsomorphin.” However, neither claim 4 nor independent claim 1, from which claim 4 depends, previously introduces an AMPKα inhibitor. Consequently, the recitation “the AMPKα inhibitor” lacks antecedent basis. It is unclear whether dorsomorphin is intended to be an additional inhibitor in the composition of claim 1 or is intended to replace one of the ULK1, HDAC, or mTOR inhibitors required by claim 1.
Claim 9 depends from claim 8, which requires that the mTOR inhibitor comprise rapamycin or a rapalog. Claim 9 further recites that “the mTOR inhibitor comprises everolimus.” It is unclear whether everolimus is intended to further specify the rapalog required by claim 8 or whether everolimus is intended to be an additional mTOR inhibitor administered in combination with rapamycin or another rapalog. Although everolimus is a rapalog, the present wording does not expressly distinguish between these interpretations. Accordingly, the scope of claim 9 is unclear. Applicants are required to clarify whether everolimus is the rapalog recited in claim 8 or is an additional mTOR inhibitor.
Claim 10 depends from claim 8, which requires that the mTOR inhibitor comprise rapamycin or a rapalog. Claim 10 further recites that “the mTOR inhibitor comprises RapaLink.” Because RapaLink is neither rapamycin nor a rapalog, it is unclear whether RapaLink is intended to replace the rapamycin or rapalog required by claim 8 or whether the composition is intended to comprise RapaLink in addition to the rapamycin or rapalog inherited from claim 8. Consequently, the claim does not clearly identify whether one or multiple mTOR inhibitors are required. Applicants are required to clarify whether RapaLink is an additional inhibitor or is intended to replace the rapamycin or rapalog required by claim 8.
Claims 12 and 13 recite methods of treatment but depend from claim 7, which is directed to a pharmaceutical composition. Consequently, the claims incorporate the limitations of a pharmaceutical composition while purporting to further define a method of treatment. It is unclear whether applicants intend to claim a pharmaceutical composition having the recited administration characteristics or a method of administering the composition.
The following is a quotation of 35 U.S.C. 112(d):
(d) REFERENCE IN DEPENDENT FORMS.—Subject to subsection (e), a claim in dependent form shall contain a reference to a claim previously set forth and then specify a further limitation of the subject matter claimed. A claim in dependent form shall be construed to incorporate by reference all the limitations of the claim to which it refers.
The following is a quotation of pre-AIA 35 U.S.C. 112, fourth paragraph:
Subject to the following paragraph [i.e., the fifth paragraph of pre-AIA 35 U.S.C. 112], a claim in dependent form shall contain a reference to a claim previously set forth and then specify a further limitation of the subject matter claimed. A claim in dependent form shall be construed to incorporate by reference all the limitations of the claim to which it refers.
Claims 4, 10, 12 and 13 are rejected under 35 U.S.C. 112(d) or pre-AIA 35 U.S.C. 112, 4th paragraph, as being of improper dependent form for failing to further limit the subject matter of the claim upon which it depends, or for failing to include all the limitations of the claim upon which it depends.
Claim 4 depends from claim 1 and recites “wherein the AMPKα inhibitor comprises Dorsomorphin.” However, claim 1 requires a composition comprising a STAT3 inhibitor and one or more of a ULK1 inhibitor, an HDAC inhibitor, or an mTOR inhibitor in a pharmaceutically acceptable carrier. Claim 1 does not recite an AMPKα inhibitor. Furthermore, the specification describes AMPKα inhibition as an alternative to ULK1, HDAC, or mTOR inhibition rather than expressly identifying dorsomorphin as an additional component of the composition recited in claim 1. Accordingly, insofar as claim 4 is intended to substitute an AMPKα inhibitor for the ULK1, HDAC, or mTOR inhibitor required by claim 1, claim 4 fails to retain all the limitations of the claim from which it depends.
Claim 10 depends from claim 8, which requires that the mTOR inhibitor comprise rapamycin or a rapalog. However, claim 10 specifies that the mTOR inhibitor comprises RapaLink. In the event that the RapaLink is the mTOR inhibitor (see 112(b) rejection above), RapaLink is not a rapalog and is distinct from rapamycin. Accordingly, to the extent claim 10 identifies RapaLink as a replacement for the rapamycin or rapalog required by claim 8, claim 10 fails to retain the limitation of the parent claim and therefore does not properly further limit its subject matter.
Claims 12 and 13 depend from claim 7, which is directed to a pharmaceutical composition. However, claims 12 and 13 recite methods involving administration of inhibitors. Accordingly, claims 12 and 13 do not properly further limit the pharmaceutical composition of claim 7, but instead introduce subject matter directed to a different statutory class.
Applicant may cancel the claim(s), amend the claim(s) to place the claim(s) in proper dependent form, rewrite the claim(s) in independent form, or present a sufficient showing that the dependent claim(s) complies with the statutory requirements.
The following is a quotation of the first paragraph of 35 U.S.C. 112(a):
(a) IN GENERAL.—The specification shall contain a written description of the invention, and of the manner and process of making and using it, in such full, clear, concise, and exact terms as to enable any person skilled in the art to which it pertains, or with which it is most nearly connected, to make and use the same, and shall set forth the best mode contemplated by the inventor or joint inventor of carrying out the invention.
The following is a quotation of the first paragraph of pre-AIA 35 U.S.C. 112:
The specification shall contain a written description of the invention, and of the manner and process of making and using it, in such full, clear, concise, and exact terms as to enable any person skilled in the art to which it pertains, or with which it is most nearly connected, to make and use the same, and shall set forth the best mode contemplated by the inventor of carrying out his invention.
Claims 1-13 are rejected under 35 U.S.C. 112(a) or 35 U.S.C. 112 (pre-AIA ), first paragraph, as failing to comply with the written description requirement. The claim(s) contains subject matter which was not described in the specification in such a way as to reasonably convey to one skilled in the relevant art that the inventor or a joint inventor, or for applications subject to pre-AIA 35 U.S.C. 112, the inventor(s), at the time the application was filed, had possession of the claimed invention.
For claims drawn to a genus, MPEP § 2163 states the written description requirement for a claimed genus may be satisfied through sufficient description of a representative number of species by actual reduction to practice, reduction to drawings, or by disclosure of relevant, identifying characteristics, i.e., structure or other physical and/or chemical properties, by functional characteristics coupled with a known or disclosed correlation between function and structure, or by a combination of such identifying characteristics, sufficient to show the applicant was in possession of the claimed genus. See Eli Lilly, 119 F.3d at 1568, 43 USPQ2d at 1406.
Claim 1 is directed to a pharmaceutical composition comprising a STAT3 inhibitor and one or more additional inhibitors selected from the recited inhibitor classes, together with a pharmaceutically acceptable carrier. The STAT3 inhibitor is defined by its inhibitory function rather than by a particular chemical structure, sequence, or mechanism of action. The additional inhibitors likewise encompass structurally and mechanistically diverse agents. The claim therefore encompasses numerous combinations of inhibitors, including combinations having different molecular structures, selectivities, mechanisms of action, and biological effects. Dependent claims 2–10 further specify particular inhibitors or inhibitor subclasses but retain the limitations of claim 1. Claim 11 is directed to a method of treating glioblastoma in a subject by administering a STAT3 inhibitor in combination with one or more inhibitors selected from the recited additional inhibitor classes. The claim encompasses multiple pharmacological combinations without restricting the STAT3 inhibitor to a particular compound, the additional inhibitor to a particular experimentally demonstrated species, or the glioblastoma to a particular molecular or signaling phenotype. The specification, while describing particular STAT3 inhibitors and additional inhibitors, does not adequately demonstrate possession of the full scope of pharmaceutical compositions comprising the broadly claimed combinations of functionally defined inhibitors.
The specification identifies numerous direct and indirect STAT3 inhibitors, including peptides, small molecules, oligonucleotides, and inhibitors of upstream signaling pathways [pp. 9–11, Table 1]. The specification also identifies ULK1 inhibitors having different structures and inhibitory properties [pp. 15–18], AMPK inhibitors [pp. 18–19], HDAC inhibitors [pp. 19–20], and mTOR inhibitors [pp. 20–22]. However, the working examples principally employ genetic deletion of STAT3 or expression of phosphorylation-defective STAT3 mutants, followed by treatment with MRT68921 or ULK1 knockdown using siRNA [pp. 33–36 and 42–44; Figs. 6–7]. The specification does not provide working examples of pharmaceutical compositions containing representative combinations across the full range of claimed inhibitor classes. Nor does it identify a common structural characteristic or an established structure-function relationship demonstrating that the broadly recited inhibitors are interchangeable within the claimed combinations. The working examples do not demonstrate administration of the full range of claimed pharmacological combinations to subjects having glioblastoma. The experiments principally rely on genetic STAT3 deletion or expression of STAT3 phosphorylation-defective mutants rather than administration of a pharmacological STAT3 inhibitor.
The prior art establishes that inhibitors directed to the same molecular target may exhibit different selectivity profiles and biological effects. Petherick (Petherick et al., Journal of Biological Chemistry 290.18 (2015): 11376-11383) demonstrate that MRT68921 inhibits ULK1 but also inhibits additional kinases, including TBK1/IKKε and AMPK-related kinases, and employed knockout cells and a drug-resistant ULK1 mutant to determine the contribution of ULK1 inhibition to the observed effects on autophagy [Results; Fig. 2A–C]. Martin (Martin et al. Martin, Katie R., et al. Iscience 8 (2018): 74-84) further demonstrates differences in selectivity among ULK1 inhibitors, reporting that ULK-101 exhibited greater selectivity than SBI-0206965 and identifying cross-reactivity of MRT68921 with AMPK [Discussion; Table S1]. These teachings establish that members of a functionally defined inhibitor class are not necessarily interchangeable with respect to their pharmacological activities. Accordingly, the experimental activity of a particular ULK1 inhibitor does not, without further evidence, establish that all inhibitors encompassed by the claimed genus possess equivalent biological properties.
The specification identifies numerous individual inhibitors but does not establish that applicants possessed the full range of claimed pharmaceutical combinations as an integrated genus. In particular, the demonstrated biological effects of genetic STAT3 deletion combined with ULK1 inhibition do not establish possession of pharmaceutical combinations containing every class of STAT3 inhibitor and every additional inhibitor encompassed by claim 1. The disclosure does not identify representative combinations spanning the claimed structural and mechanistic diversity or establish characteristics demonstrating that the disclosed combinations are representative of the full genus. Accordingly, the specification does not adequately demonstrate possession of the full scope of the claimed genus and the claimed method of treating glioblastoma.
Claims 2–10 narrow the claimed compositions, but the disclosure of an individual inhibitor does not, by itself, establish possession of every combination remaining within the dependent claim. Each dependent claim retains the deficiency to the extent that it continues to encompass an inadequately described combination genus.
Dependent claims. Claims 12 and 13 recite administration characteristics but do not restrict the treatment method to particular inhibitors or a glioblastoma population shown to respond to treatment. Concurrent administration or administration in a single composition does not, by itself, establish possession of the full therapeutic genus. Therefore, upon correction of their dependencies to claim 11, claims 12 and 13 would retain the written-description deficiency to the extent that they continue to encompass the same unsupported therapeutic alternatives.
Claim 11 is rejected under 35 U.S.C. 112(a) or 35 U.S.C. 112 (pre-AIA ), first paragraph, because the specification, while being enabling for suppressing autophagy and inducing apoptosis through ULK1 inhibition in selected STAT3-deficient glioblastoma cells using MRT68921 treatment and ULK1 knockdown in STAT3-knockout or STAT3-mutant experimental models, does not reasonably provide enablement for the full scope of treating glioblastoma subjects using every pharmacological STAT3 inhibitor in combination with the broadly recited additional inhibitor classes. The specification does not enable any person skilled in the art to which it pertains, or with which it is most nearly connected, to make and use the invention commensurate in scope with these claims.
Nature of the invention
The claimed invention concerns treating glioblastoma through combined pharmacological inhibition of STAT3 and one or more additional signaling pathways. The method requires that administration of the inhibitors produce a therapeutic effect against glioblastoma. The therapeutic effect depends on complex biological interactions involving STAT3 signaling, AMPKα activity, ULK1 activity, autophagy, apoptosis, and tumor-cell survival. The specification demonstrates that STAT3 deletion activates autophagy and that ULK1 inhibition can suppress this response and promote apoptosis in certain experimental models [pp. 36–45; Figs. 1–7]. However, pharmacological inhibition of STAT3 is not necessarily equivalent to complete genetic deletion of STAT3 or expression of phosphorylation-defective STAT3 mutants. Accordingly, the therapeutic response cannot be assumed to be uniform across all claimed inhibitor combinations.
Breadth of claims
Claim 11 encompasses treating glioblastoma using a STAT3 inhibitor combined with one or more inhibitors selected from the recited additional classes. The claim is not limited to a particular STAT3 inhibitor, a particular additional inhibitor, a defined degree of target inhibition, a specific dosage or administration schedule, or a glioblastoma population having a demonstrated responsive signaling phenotype. The claim therefore encompasses numerous pharmacological combinations having different molecular structures, inhibitory selectivities, pharmacokinetic properties, and biological effects. The breadth of the claim substantially exceeds the particular experimental interventions and cellular models investigated in the specification.
Guidance from the specification
The specification identifies numerous inhibitors and provides conventional pharmaceutical formulation and administration guidance [Specification, pp. 9–30]. The working examples demonstrate that STAT3 deletion increases autophagy and that treatment with MRT68921 or ULK1 siRNA suppresses autophagy and promotes apoptosis in selected STAT3-deficient glioblastoma cells [pp. 42–45; Figs. 6–7]. However, the examples do not demonstrate therapeutic efficacy in a subject using the full range of claimed pharmacological combinations. The specification does not provide a validated method for determining which STAT3 inhibitors reproduce the relevant effects of genetic STAT3 deletion, which additional inhibitors produce the required therapeutic response, or which glioblastoma populations respond to each combination. Thus, although the specification provides guidance concerning a particular mechanistic pathway, it does not provide sufficient guidance for practicing the full scope of the claimed treatment method.
State of the art
The state of the art demonstrates that the therapeutic consequences of combining inhibitors of STAT3 and other signaling pathways were not uniformly predictable. Miyata (Miyata et al. Cancer Genomics-Proteomics 14.1 (2017): 83-91) investigated the STAT3 inhibitor STX-0119 in combination with the mTOR inhibitor rapamycin in temozolomide-resistant glioblastoma cells and demonstrated significant inhibition of cell proliferation in vitro [Results, cell proliferation assay; Fig. 2]. However, the authors reported that the corresponding in vivo combination study did not demonstrate a statistically significant additive inhibitory effect and identified rapamycin dosage as a possible explanation requiring further investigation [pp. 86-87, bridging para; Fig. 5; pg. 89, col. 2, para 3]. Furthermore, Petherick demonstrated that MRT68921 inhibits additional kinases besides ULK1, including TBK1/IKKε and AMPK-related kinases [Results; Fig. 2A]. Martin demonstrated differences in the selectivity profiles of pharmacological ULK1 inhibitors [Discussion; Table S1]. Collectively, these teachings establish that inhibitor identity, selectivity, dosage, and experimental context can materially affect the observed biological response. Accordingly, therapeutic activity observed with one pharmacological combination cannot automatically be extrapolated to every inhibitor combination encompassed by the claimed method.
Experimentation required
In view of the differences in inhibitor selectivity and therapeutic responses established in the prior art, practicing the full scope of claim 11 would require determining which pharmacological STAT3 inhibitors reproduce the relevant biological effects, identifying compatible additional inhibitors, establishing effective concentrations and administration schedules, and evaluating whether each combination produces a therapeutic effect in glioblastoma. The prior art support the conclusion that identifying an inhibitor combination and demonstrating cellular activity do not necessarily establish its therapeutic efficacy in a subject. The specification does not provide a generally applicable method for predicting which of the broadly claimed combinations will produce the required therapeutic response, leaving the skilled artisan to determine the efficacy of combinations extending beyond the disclosed experimental models. Such experimentation would involve more than routine confirmation of an established therapeutic relationship because the specification demonstrates that the relevant signaling responses vary between glioblastoma cell lines. The disclosure does not provide a generally applicable method for predicting which combinations will be therapeutically effective across the full scope of the claim.
The specification provides experimental support for the proposition that inhibition of ULK1 can suppress autophagy and promote apoptosis in certain STAT3-deficient glioblastoma cells. However, the disclosure does not establish that the full range of claimed pharmacological combinations can be used to treat glioblastoma without undue experimentation. In particular, the disclosed effects of genetic STAT3 deletion or mutation cannot automatically be extrapolated to every pharmacological STAT3 inhibitor, and the demonstrated effects of ULK1 inhibition do not establish therapeutic efficacy for every additional inhibitor class encompassed by the claim. Accordingly, the specification does not enable the full scope of claim 11.
Claims 12 and 13 recite administration characteristics but do not restrict the method to a particular pharmacological combination demonstrated to treat glioblastoma. Concurrent administration or administration in a single composition does not resolve the lack of guidance concerning which inhibitor combinations provide the required therapeutic effect. Therefore, upon correction of their dependencies to claim 11, claims 12 and 13 would retain the scope-of-enablement deficiency.
Claim Rejections - 35 USC § 102
The following is a quotation of the appropriate paragraphs of 35 U.S.C. 102 that form the basis for the rejections under this section made in this Office action:
A person shall be entitled to a patent unless –
(a)(1) the claimed invention was patented, described in a printed publication, or in public use, on sale, or otherwise available to the public before the effective filing date of the claimed invention.
(a)(2) the claimed invention was described in a patent issued under section 151, or in an application for patent published or deemed published under section 122(b), in which the patent or application, as the case may be, names another inventor and was effectively filed before the effective filing date of the claimed invention.
Claims 1, 8-9 and 11-13 are rejected under 35 U.S.C. 102(a)(1) as being anticipated by Reuveni et al. (US 2018/0028475 A1, published February 1, 2018).
Regarding claim 1, Reuveni teaches a pharmaceutical combination comprising an IRS/STAT3 dual modulator and an inhibitor of mammalian target of rapamycin (mTOR) [0260]–[0261]. Reuveni expressly teaches that the disclosed compounds inhibit STAT3 phosphorylation in cancer cells [0226] and demonstrates that compounds A and D inhibit STAT3 phosphorylation in intact cells in a dose-dependent manner [0116; Fig. 6]. Reuveni further teaches that combining an IRS/STAT3 dual modulator with an mTOR inhibitor provides an anticancer therapeutic effect [0260]–[0262]. Reuveni teaches that the components of the combination may be administered in one pharmaceutical composition containing a pharmaceutically acceptable carrier or excipient [0323]. Accordingly, Reuveni discloses a composition comprising a STAT3 inhibitor and an mTOR inhibitor in a pharmaceutically acceptable carrier.
Regarding claims 8-9, Reuveni teaches a pharmaceutical combination comprising a STAT3-inhibitory compound and an mTOR inhibitor [0116; 0226; 0260]–[0261]. Reuveni expressly identifies rapamycin and everolimus as mTOR inhibitors and teaches that everolimus is a preferred mTOR inhibitor [0269]. Reuveni specifically discloses an embodiment in which compound D is combined with everolimus (Afinitor) [0271]. Reuveni further teaches administering the combination in one pharmaceutical composition containing a pharmaceutically acceptable carrier or excipient [0323].
Regarding claim 11, Reuveni teaches compounds that inhibit STAT3 phosphorylation in cancer cells [0226]. Reuveni expressly teaches combining an IRS/STAT3 dual modulator with an mTOR inhibitor [0260]–[0261] and discloses a method of treating cancer comprising administering a therapeutically effective amount of the combination to a subject in need thereof [0262]. Reuveni identifies rapamycin and everolimus as suitable mTOR inhibitors [0269]. Reuveni expressly identifies glioblastoma among the cancers treatable using the disclosed combinations [0315]. Accordingly, Reuveni teaches administering an effective amount of a STAT3 inhibitor and an mTOR inhibitor to a subject for treating glioblastoma.
Regarding claim 12, Reuveni teaches the method of treating cancer by administering a therapeutically effective amount of a STAT3-inhibitory compound and an mTOR inhibitor [0262] and identifies glioblastoma as a cancer treatable by the disclosed combinations [0315]. Reuveni further teaches that the components may be administered together in one pharmaceutical composition [0323]. Administration of both inhibitors in the same composition provides concurrent administration of the inhibitors.
Regarding claim 13, Reuveni teaches treating cancer by administering a therapeutically effective amount of a combination comprising a STAT3-inhibitory compound and an mTOR inhibitor [0226; 0260]–[0262]. Reuveni expressly identifies glioblastoma among the cancers treatable using the disclosed combinations [0315]. Reuveni further teaches that the components of the combination may be administered in one pharmaceutical composition containing a pharmaceutically acceptable carrier or excipient [0323].
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.
The factual inquiries for establishing a background for determining obviousness under 35 U.S.C. 103 are summarized as follows:
1. Determining the scope and contents of the prior art.
2. Ascertaining the differences between the prior art and the claims at issue.
3. Resolving the level of ordinary skill in the pertinent art.
4. Considering objective evidence present in the application indicating obviousness or nonobviousness.
This application currently names joint inventors. In considering patentability of the claims the examiner presumes that the subject matter of the various claims was commonly owned as of the effective filing date of the claimed invention(s) absent any evidence to the contrary. Applicant is advised of the obligation under 37 CFR 1.56 to point out the inventor and effective filing dates of each claim that was not commonly owned as of the effective filing date of the later invention in order for the examiner to consider the applicability of 35 U.S.C. 102(b)(2)(C) for any potential 35 U.S.C. 102(a)(2) prior art against the later invention.
Claim 2 is rejected under 35 U.S.C. 103 as being unpatentable over Reuveni et al. (US 2018/0028475 A1, published February 1, 2018), as applied to claim 1, in view of MacDonald (US 2021/0145806 A1, published May 20, 2021).
The teachings of Reuveni are discussed above as applied to claim 1, Reuveni teaches a pharmaceutical composition comprising a STAT3-inhibitory compound and an mTOR inhibitor. Reuveni explains that its compounds inhibit STAT3 phosphorylation in cancer cells [0226], expressly teaches combining an IRS/STAT3 dual modulator with an mTOR inhibitor [0260]–[0262], and identifies rapamycin and everolimus as suitable mTOR inhibitors [0269]. Reuveni further teaches administering the combination in one pharmaceutical composition containing a pharmaceutically acceptable carrier or excipient [0323].
Reuveni does not expressly identify WP1066 as the STAT3 inhibitor.
MacDonald teaches that WP1066 is a STAT3 inhibitor for treating brain cancer [0006]–[0007]. MacDonald further teaches pharmaceutical compositions comprising WP1066, another therapeutic inhibitor, and a pharmaceutically acceptable excipient [0014]–[0016]. MacDonald reports that WP1066 inhibits proliferation of medulloblastoma cells and that combination treatment with WP1066 and fisetin significantly decreases proliferation and inhibits colony formation [0021; 0033]–[0035].
It would have been obvious to a person of ordinary skill in the art before the effective filing date to substitute the known STAT3 inhibitor WP1066 for Reuveni's STAT3-inhibitory compound to provide an alternative STAT3 inhibitor in the pharmaceutical composition. MacDonald expressly identifies WP1066 as a STAT3 inhibitor, demonstrates its inhibitory activity in brain cancer cells, and teaches its incorporation into pharmaceutical compositions with another therapeutic inhibitor. The skilled artisan would reasonably have expected the substituted compound to provide STAT3 inhibitory activity.
Claim 3 is rejected under 35 U.S.C. 103 as being unpatentable over Reuveni et al. (US 2018/0028475 A1, published February 1, 2018), as applied to claim 1,in view of Petherick (Petherick et al. Journal of Biological Chemistry 290.18 (2015): 11376-11383).
The teachings of Reuveni are discussed above as applied to claim 1, Reuveni teaches a pharmaceutical composition comprising a STAT3-inhibitory compound and an mTOR inhibitor [0226; 0260]–[0262]. Reuveni identifies rapamycin and everolimus as mTOR inhibitors [0269] and teaches administering the combination in one pharmaceutical composition containing a pharmaceutically acceptable carrier or excipient [0323].
Reuveni does not expressly teach including MRT68921 as a ULK1 inhibitor.
Petherick teaches that inhibition of mTOR activates the ULK1 kinase complex and induces autophagy [p. 11376, Introduction]. Petherick explains that autophagy can function as a cancer-cell survival mechanism, allowing tumor cells to cope with metabolic demands and damage caused by chemotherapy, and identifies autophagy inhibition as a potential therapeutic approach [p. 11376, Introduction]. Petherick further identifies MRT68921 as a potent ULK1 inhibitor, reporting an IC₅₀ of 2.9 nM against ULK1, and demonstrates that MRT68921 reduces ULK1 activity and blocks autophagic flux in cells [p. 11377, Results; Fig. 1A–B].
It would have been obvious to a person of ordinary skill in the art to incorporate MRT68921 into Reuveni's STAT3 inhibitor/mTOR inhibitor composition to suppress the ULK1-mediated autophagic response associated with mTOR inhibition. Petherick expressly identifies mTOR inhibition as a trigger for ULK1 activation and demonstrates that MRT68921 blocks ULK1 activity and autophagic flux. The skilled artisan therefore would have had a reason to combine these teachings and a reasonable expectation of obtaining ULK1 inhibition and suppression of autophagy.
Claims 5-7 are rejected under 35 U.S.C. 103 as being unpatentable over MacDonald (US 2021/0145806 A1, published May 20, 2021) in view of Hull (Hull et al. BioMed research international 2016.1 (2016): 8797206).
Regarding claims 5-6, MacDonald teaches treating brain cancer using a combination of a STAT3 inhibitor and a YB-1 inhibitor, specifically identifying WP1066 and fisetin [0006]–[0007]. MacDonald further teaches administering these inhibitors in combination with an additional chemotherapy agent and expressly identifies vorinostat among the suitable agents [0010]. MacDonald teaches pharmaceutical compositions containing WP1066, fisetin, and a pharmaceutically acceptable excipient [0015]–[0016].
MacDonald do not expressly identify the HDAC isoforms inhibited by vorinostat.
Hull teaches that vorinostat, also known as SAHA, is an HDAC inhibitor [p. 3, §3.1]. Hull's Table 1 reports inhibitory activity of vorinostat against HDAC1, HDAC2, HDAC3, and HDAC6 [p. 4, Table 1].
It would have been obvious to a person of ordinary skill in the art to select vorinostat as the additional chemotherapy agent expressly contemplated by MacDonald and prepare the combined agents in a pharmaceutical formulation using the excipients disclosed by MacDonald. MacDonald identifies the particular additional agent and teaches pharmaceutical formulations containing the underlying inhibitors, while Hull establishes that vorinostat inhibits the HDAC isoforms claimed. The skilled artisan would reasonably have expected vorinostat to provide HDAC inhibitory activity in the modified composition.
Regarding claim 7, Hull teaches that trichostatin A, also known as TSA, is an HDAC inhibitor and reports inhibitory activity against HDAC1, HDAC2, HDAC3, and HDAC6 [p. 4, Table 1]. Hull identifies vorinostat as another HDAC inhibitor having activity against these isoforms [p. 4, Table 1]. It would have been obvious to a person of ordinary skill in the art to consider trichostatin A as an alternative to vorinostat in MacDonald's contemplated combination because Hull identifies both compounds as known HDAC inhibitors with overlapping activity against HDAC1, HDAC2, HDAC3, and HDAC6. The skilled artisan would have reasonably expected trichostatin A to provide HDAC inhibitory activity in the modified composition.
Conclusion
No claims allowed.
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/TIFFANY NICOLE GROOMS/Examiner, Art Unit 1637
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