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 .
Status of the Claims
Claims 1-2, 4, 7-10, 12, 14-16, 18-20, 22, 25 and 33 are pending in the instant application and subject to examination herein.
Claim Interpretation
The following is a quotation of 35 U.S.C. 112(f):
(f) Element in Claim for a Combination. – An element in a claim for a combination may be expressed as a means or step for performing a specified function without the recital of structure, material, or acts in support thereof, and such claim shall be construed to cover the corresponding structure, material, or acts described in the specification and equivalents thereof.
The following is a quotation of pre-AIA 35 U.S.C. 112, sixth paragraph:
An element in a claim for a combination may be expressed as a means or step for performing a specified function without the recital of structure, material, or acts in support thereof, and such claim shall be construed to cover the corresponding structure, material, or acts described in the specification and equivalents thereof.
This application includes one or more claim limitations that do not use the word “means,” but are nonetheless being interpreted under 35 U.S.C. 112(f) or pre-AIA 35 U.S.C. 112, sixth paragraph, because the claim limitation(s) uses a generic placeholder that is coupled with functional language without reciting sufficient structure to perform the recited function and the generic placeholder is not preceded by a structural modifier. Such claim limitations is: an RNA Pol II targeting inhibitor comprising a cyclin-dependent kinase inhibitor “targeting CDK9”, in claims 1 and 19. The term “targeting CDK9” is understood as functional language that does not recite sufficient structure to perform the recited function.
Claim 1 is drawn to a method of inhibiting growth of, inhibiting replication of, or inducing cell death in a cell having a FET-fused oncogene, said method comprising introducing to the cell having the FET-fused oncogene an effective amount of a composition comprising an RNA Pol II targeting inhibitor comprising a cyclin-dependent kinase inhibitor targeting CDK91, and a DNA damaging agent comprising a topoisomerase poison, wherein the composition inhibits growth of the cell, inhibits replication of the cell, or induces cell death in the cell.
Claim 19 is drawn to a method of treating a patient with a tumor having a FET-fused oncogene, said method comprising: administering to the patient an effective amount of a composition comprising both an RNA Pol II targeting inhibitor comprising a cyclin-dependent kinase inhibitor targeting CDK92, and a DNA damaging agent comprising a topoisomerase poison, wherein the composition inhibits growth of the tumor, inhibits replication of cells in the tumor, or induces cell death in cells of the tumor.
Because this claim limitation is being interpreted under 35 U.S.C. 112(f) or pre-AIA 35 U.S.C. 112, sixth paragraph, it is being interpreted to cover the corresponding structure described in the specification as performing the claimed function, and equivalents thereof. The instant specification does not provide any definition for the term “targeting CDK9”, and a person of ordinary skill in the art would not immediately envisage the scope of the term. The SPEC provides exactly one mention of the term “targeting CDK9” in paragraph [0031], wherein the description of Applicant’s instant Figure 3A states “A standard DNA damaging chemotherapy (SN38 or irinotecan (Stewart et al., Cell Rep 2014), used to treat Ewing's sarcoma (A673 cells) was combined with a well-characterized transcription inhibitor targeting CDK9, flavopiridol.” Thus, the SPEC defines flavopiridol as an inhibitor “targeting CDK9” and provides no other definition or example of this limitation. Accordingly, the instant claims 1 and 19 and those claims dependent therefrom will be examined with limitation of an inhibitor “targeting CDK9” defined specifically as flavopiridol.
If applicant does not intend to have this/these limitation(s) interpreted under 35 U.S.C. 112(f) or pre-AIA 35 U.S.C. 112, sixth paragraph, applicant may: (1) amend the claim limitation(s) to avoid it/them being interpreted under 35 U.S.C. 112(f) or pre-AIA 35 U.S.C. 112, sixth paragraph (e.g., by reciting sufficient structure to perform the claimed function); or (2) present a sufficient showing that the claim limitation(s) recite(s) sufficient structure to perform the claimed function so as to avoid it/them being interpreted under 35 U.S.C. 112(f) or pre-AIA 35 U.S.C. 112, sixth paragraph.
Claim Rejections - 35 USC § 112(b) – Necessitated by Amendment
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 12 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.
Claim 12 recites the limitation " The method of claim 1, wherein the RNA Pol II targeting inhibitor is selected from: flavopiridol, DRB, dinaciclib, roscovitine, olomoucine II, or TG02." There is insufficient antecedent basis for this limitation in the claim, because claim 1 already limits the RNA Pol II targeting inhibitor to an inhibitor “targeting CDK9”, which, as discussed above (see “Claim Interpretation” section) is interpreted under 35 U.S.C. 112(f) to be limited to the specific agent flavopiridol. Thus, there is insufficient antecedent basis for claim 12 to claim the alternate agents DRB, roscovitine, olomoucine II, or TG02 as the RNA Pol II targeting inhibitor to be administered.
Claim Rejections - 35 USC § 102 - Withdrawn
The prior rejection of claims 1-2, 4, 7-8, 14-15, 19-20, 22 and 25 under 35 U.S.C. 102(a)(1) and 102(a)(2) as being anticipated by Dowless (Dowless, et al.; Clinical Cancer Research, v24, pp6028-6039; 2018) is withdrawn in response to Applicant’s amendment of claims 1, 7, 19 and 25.
The prior rejection of claims 1-2, 4, 7, 9-10, 14-15, 19-20, 22 and 25 under 35 U.S.C. 102(a)(1) as being anticipated by Iniguez (Iniguez, et al.; Cancer Cell, v33, pp.202-216; 2018) is withdrawn in response to Applicant’s amendment of claims 1, 7, 19 and 25.
The prior rejection of claims 1-2, 4, 7 and 12 under 35 U.S.C. 102(a)(1) as being anticipated by Shoemaker (Shoemaker, G. B.; Master’s Thesis, Health Physics, Georgetown University; 2015) is withdrawn in response to Applicant’s amendment of claims 1, 7, 19 and 25.
The prior rejection of claims 1-2, 4, 7-9, 12, 14-15, 19-20, 22, 25 and 33 under 35 U.S.C. 102(a)(1) as being anticipated by Mills (Mills, et al.; Cancer Research, v78, pp320-325; 2018) is withdrawn in response to Applicant’s amendment of claims 1, 7, 19 and 25.
Claim Rejections - 35 USC § 103 – Withdrawn
The prior rejection of claims 1-2, 4, 7-8, 14-15, 19-20, 22, 25 and 33 are rejected under 35 U.S.C. 103 as being unpatentable over Dowless (Dowless, et al.; Clinical Cancer Research, v24, pp6028-6039; 2018) in view of Gould (Gould, et al.; Nature Medicine, v21, pp431-439; 2015) is withdrawn in response to Applicant’s amendment of claims 1, 7, 19 and 25.
Claim Rejections - 35 USC § 103 - Maintained
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.
The prior rejection of claim 123 under 35 U.S.C. 103 as being unpatentable over Bernstein (Bernstein, M., et al.; The Oncologist, v11, pp503-519; 2006) in view of Li (Li, X., et al.; International Journal of Cancer, v116, pp385-396; 2005) is maintained.
Applicant has traversed the rejection on the grounds that a person of ordinary skill in the art would not have been motivated to modify the Bernstein prior art with the Li prior art because such a combination “overlooks the critical mechanistic distinction between actinomycin D and the presently claimed CDK9/Pol-II-specific inhibitors. Actinomycin D is not an RNA polymerase I I-specific agent; rather, it is a broad-spectrum transcriptional inhibitor that indiscriminately blocks multiple polymerases, including bacterial and phage polymerases as well as mammalian RNA Polymerases. By contrast, inhibitors such as flavopiridol exhibit a defined specificity for CDK9, which uniquely regulates transcriptional elongation by RNA Pol II. This specificity is particularly significant in the context of tumors harboring FET fusions. Thus, substituting actinomycin D with flavopiridol, as the Examiner suggests, is not a simple or routine exchange, but rather a mechanistically distinct approach that achieves a surprising therapeutic effect not taught or suggested by the prior art.” Additionally, Applicant has traversed the rejection based on an alleged requirement for concomitant administration of the DNA-damaging agent and a CDK9/Pol II-targeting inhibitor, which the cited prior art teaches against.
Applicant’s arguments have been considered, but are not found persuasive, for the following reasons:
Neither the prior-rejected nor currently-amended claims require that the CDK9-targeting RNA Polymerase II inhibitor is selective for CDK9;
Neither the prior-rejected nor currently-amended claims include any language requiring concomitant administration of the DNA damaging agent and RNA Polymerase II inhibitor;
The replacement of actinomycin D with flavopiridol represents a simple substitution of known equivalents (RNA Polymerase II inhibitors) to achieve a predictable result, and Applicant’s allegation that the mechanistic distinctions in the manner of RNA Pol II inhibition by the agents would make the them nonobvious alternatives for each other is not supported by the prior art, as it was known in the art that each of these agents achieves similar biological results, as for example, in the teaching of Blagosklonny (Blagosklonny, M. V.; Cell Cycle, v3, pp1537-1542; 2004). Blagosklonny teaches a review of the CDK inhibitor flavopiridol, including its mechanism and clinical potential, describing flavopiridol as “not just a second actinomycin D” which both distinguishes and likens flavopiridol to actinomycin D (Abstract). Blagosklonny teaches that actinomycin D and flavopiridol both inhibit RNA transcription, while they each do so by distinct mechanisms, with flavopiridol inhibiting CDK9 and thus blocking the elongation phase of RNA Polymerase II transcription, and actinomycin D blocking transcription by RNA Polymerase II by intercalating with DNA (page 1538 and pages 1537-1538, bridging paragraph), and Blagosklonny further teaches that both actinomycin D and flavopiridol exhibit both cytotoxicity and transcription inhibition aspects of their biological effects (page 1538). Blagosklonny teaches that “Like Actinomycin D and DRB (other inhibitors of transcription), flavopiridol downregulates thousands of mRNAs that have a short half-life” (page 1538). Blagosklonny further teaches that flavopiridol causes cell cycle arrest by inhibiting transcription and “Similarly for many years, inhibitors of RNA synthesis (actinomycin D and DRB) were used to arrest cell cycle. Transcription is absolutely necessary for cell cycle progression” (page 1538). Additionally, Blagosklonny teaches that Actinomycin D and flavopiridol share the property of potentiating drugs that target Tumor Necrosis Factor (TNF), thus turning apoptosis-reluctant cells into apoptosis prone cells (page 1538). Finally, Blagosklonny also teaches that actinomycin D and flavopiridol share the property of upregulating the transcription factor E2F-1 (page 1539) and share the common side effect of neutropenia which may be a side effect associated to the transcription inhibition by both agents (page 1540). Thus, it was known in the art that actinomycin D and flavopiridol are inherently similar transcription inhibitors with regard to the effects of transcription inhibition, per the teaching of Blagosklonny, and a person of ordinary skill in the art would have a reasonable expectation of similar results upon replacing one with the other in a combination therapy.
Reiterated rejection:
Bernstein teaches the combination of a DNA-damaging agents (radiation therapy and doxorubicin, a known topoisomerase poison per the instant claims and specification) with a transcription inhibitor (actinomycin D) for the inhibition of cell growth in Ewing’s Sarcoma cell lines having the EWS-FLI1 FET oncogene (pp510-512). Bernstein does not teach the use of a cyclin-dependent kinase inhibitor that targets CDK9 in combination with any of the standard four agents of the VACD regimen. However, Bernstein does teach that the VACD components can be substituted with other chemotherapy agents.
Li teaches the use of flavopiridol in the treatment of Ewing’s family tumor (EFT) cells, particularly cells expressing the EWS-FLI1 fusion gene (p385). Li reports that “flavopiridol efficiently suppressed the growth of EFT cells in vitro and in vivo by the inhibition of cyclinE/CDK2 kinase activity and the induction of apoptosis.” Combination therapy is standard therapy in cancer treatment, as evidenced by the four-component VACD regimen and its variations. It would have been obvious to a person of ordinary skill in the art to combine agents already shown to successfully inhibit Ewing’s sarcoma tumor cells to obtain a predictable result of increased inhibition, resulting in the practice of the method of claim 12 with a reasonable expectation of success.
Claim Rejections - 35 USC § 103 – Necessitated by Amendment
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.
Claims 1-2, 4, 7-10, 12, 14-16, 18-20, 22 and 25 are unpatentable over Bernstein in view of Blagosklonny and Li.
Claims 1-2, 4, 7-10, 12, 14-16, 18-20, 22 and 25 are rejected under 35 U.S.C. 103 as being unpatentable over Bernstein (Bernstein, M., et al.; The Oncologist, v11, pp503-519; 2006) in view of Blagosklonny (Blagosklonny, M. V.; Cell Cycle, v3, pp1537-1542; 2004) and Li (Li, X., et al.; International Journal of Cancer, v116, pp385-396; 2005).
Claim 1 is drawn to a method of inhibiting growth of, inhibiting replication of, or inducing cell death in a cell having a FET-fused oncogene, said method comprising introducing to the cell having the FET-fused oncogene an effective amount of a composition comprising an RNA Pol II targeting inhibitor comprising a cyclin-dependent kinase inhibitor targeting CDK9, and a DNA damaging agent comprising a topoisomerase poison, wherein the composition inhibits growth of the cell, inhibits replication of the cell, or induces cell death in the cell. As discussed above (see “Claim Interpretation” section), the limitation of an inhibitor “targeting CDK9” is being interpreted being interpreted under 35 U.S.C. 112(f) to refer directly to flavopiridol.
Bernstein teaches that Ewing’s Sarcoma is commonly traced to the EWS-FLI1 gene translocation (oncogene) in the tumor cells (pp506-507). Bernstein teaches the administration of the “VACD scheme” first reported in a clinical trial in 1974 and thereafter practiced in multiple additional clinical trials (pp510-512). The VACD scheme, which was administered to human patients with Ewing’s sarcoma, includes “a trial of radiation therapy given with a four-drug regimen consisting of vincristine, actinomycin D, cyclophosphamide, and doxorubicin used in combination”. Bernstein further notes that “The VACD scheme then became a standard therapy in numerous clinical trials”. As indicated in the instant Specification, doxorubicin is a topoisomerase poison (paragraph [0051]), and actinomycin D is a transcription inhibitor (paragraph [0054]) but does not meet the instant Specification provision of an inhibitor “targeting CDK9” (i.e., flavopiridol).
While Bernstein does not teach the administration of flavopiridol to patients suffering from Ewing Sarcoma, a person of ordinary skill in the art, at the effective time of filing, would have a reasonable expectation of success in substituting flavopiridol for the VACD component actinomycin D, for the following reasons:
Bernstein teaches that the VACD components can be substituted with other chemotherapy agents;
Blagosklonny teaches that flavopiridol and actinomycin D have similar biological effects despite distinct mechanisms of RNA Polymerase II inhibition and are thus functionally exchangeable as transcription inhibitors;
Li teaches that flavopiridol is effective in the suppression of Ewing’s family tumor (EFT) cells, particularly cells expressing the EWS-FLI1 fusion gene.
Bernstein teaches that the VACD components can be substituted with other chemotherapy agents, as the standard four-component treatment was combined with ifosfamide and etoposide to provide a VACD-IE six-component treatment, while a five component VDC-IE was also implemented (page 512). Bernstein’s Table 3 (bridging pages 511-512) details a list of clinical trials with variations in the Ewing Sarcoma treatment regime including any of the original VACD agents, replacements or additions with ifosfamide and/or etoposide, and even including cis-platinum.
Blagosklonny provides a review of the biological effects of flavopiridol as a CDK inhibitor and a transcription inhibitior, particularly in comparison to actinomycin D, describing flavopiridol as “not just a second actinomycin D” (Abstract, page 1537). Blagosklonny teaches that actinomycin D and flavopiridol both inhibit RNA transcription, while they each do so by distinct mechanisms, with flavopiridol inhibiting CDK9 and thus blocking the elongation phase of RNA Polymerase II transcription, and actinomycin D blocking transcription by RNA Polymerase II by intercalating with DNA (page 1538 and pages 1537-1538, bridging paragraph), and Blagosklonny further teaches that both actinomycin D and flavopiridol exhibit both cytotoxicity and transcription inhibition aspects of their biological effects (page 1538). Blagosklonny teaches that “Like Actinomycin D and DRB (other inhibitors of transcription), flavopiridol downregulates thousands of mRNAs that have a short half-life” (page 1538). Blagosklonny further teaches that flavopiridol causes cell cycle arrest by inhibiting transcription and “Similarly for many years, inhibitors of RNA synthesis (actinomycin D and DRB) were used to arrest cell cycle. Transcription is absolutely necessary for cell cycle progression” (page 1538). Additionally, Blagosklonny teaches that Actinomycin D and flavopiridol share the property of potentiating drugs that target Tumor Necrosis Factor (TNF), thus turning apoptosis-reluctant cells into apoptosis prone cells (page 1538). Finally, Blagosklonny also teaches that actinomycin D and flavopiridol share the property of upregulating the transcription factor E2F-1 (page 1539) and share the common side effect of neutropenia which may be a side effect associated to the transcription inhibition by both agents (page 1540).
Li teaches the use of flavopiridol in the treatment of Ewing’s family tumor (EFT) cells, particularly cells expressing the EWS-FLI1 fusion gene. Li reports that “flavopiridol efficiently suppressed the growth of EFT cells in vitro and in vivo” (p385). Li shows that cultured populations of EFT cells in 96-well plates were suppressed by treatment of flavopiridol, whereas the non-EFT human fibroblast cell line BJ-1 was significantly less affected (page 390, Figure 4A), and that xenograft tumors of human EFT cell line WE-68, grown in Balb/C mice were effectively suppressed by treating the mice with flavopiridol, showing a dose-dependent inhibition of tumor growth relative to control mice treated with saline (Figures 7A and 7B, page 392).
Applicant’s invention is unpatentable over the teaching of Bernstein in view of the teachings of Blagosklonny and Li, because a person of ordinary of ordinary skill in the art, at the effective time of filing, would have a reasonable expectation of success in treating patients suffering from Ewing Sarcoma, a cancer known to exhibit the EWS-FLI1 fusion oncogene, with a modified VACD treatment regime wherein actinomycin D is substituted with flavopiridol, because Bernstein teaches that the VACD regime can be modified by replacements and/or additional therapeutic agents, and Blagosklonny teaches that actinomycin D and flavopiridol are similar agents, each functioning as a transcription inhibitor showing similar biological effects to each other, and Li teaches that flavopiridol is an effective agent for the suppression of cells exhibiting the EWS-FLI1 fusion oncogene in both in vitro and in vivo experiments.
Thus, the invention was prima facie obvious at the time of filing.
Claims 2 and 4 further limit claim 1 with respect to the target cell population(s), of being either Ewing sarcoma/fibromyxoid liposarcoma, or having a specific FET-fused oncogene selected from a Markush group that includes EWS-FLI1, respectively, and are both met by the rejection above.
Claim 7 further limits claim 1 to wherein the DNA damaging agent, comprising a topoisomerase poison, further comprises an additional aspect selected from a Markush group that includes targeted radiation therapy. As discussed above, Bernstein teaches that the VACD regime includes radiation therapy.
Claim 8 further limits claim 7 to wherein the topoisomerase poison is selected from a Markush group that includes doxorubicin, and is met by the rejection above.
Claim 9 further limits claim 7 to wherein the additional DNA damaging therapy, if selected as a DNA crosslinker, must be cisplatin, carboplatin, or oxaliplatin, but does not require that the additional DNA damaging therapy is a DNA crosslinker. Therefore, claim 9 is met by the rejection above, wherein the additional DNA damaging therapy is radiation therapy.
Claim 10 further limits claim 7 to wherein the additional DNA damaging therapy, if selected as a DNA repair inhibitor, must be selected from a Markush group of known agents, but does not require that the additional DNA damaging therapy is a DNA repair inhibitor. Therefore, claim 10 is met by the rejection above, wherein the additional DNA damaging therapy is radiation therapy.
Claim 12 depends from claim 1 and requires that the RNA Pol II targeting inhibitor is selected from a Markush group that includes flavopiridol, and is met by the rejection above.
Claim 14 further limits the method of claim 1 to wherein the method is used for treating a tumor having a FET-fused oncogene, and is met by the rejection above.
Claim 15 further limits the method of claim 1 to wherein the method is used for treating a patient having a FET-fused oncogene, and is met by the rejection above.
Claim 16 further limits the method of claim 1 to wherein the presence of the FET fusion protein or expression of the FET fusion protein is confirmed by immunohistochemistry or an oligonucleotide-based technique. Claim 18 further limits the method of claim 16 to wherein the oligonucleotide-based technique is selected from a Markush group that includes RT-PCR (reverse transcriptase polymerase chain reaction) and FISH (fluorescence in situ hybridization). Bernstein teaches that, using molecular detection methods to monitor the EWS-FLI1 gene rearrangement, RT-PCR and FISH, the presence of the t(11;22)(q24;q12) EWS-FLI1 translocation in 85% of Ewing’s sarcoma has been confirmed (page 507).
Claim 19 is drawn to a method of treating a patient with a tumor having a FET-fused oncogene, said method comprising: administering to the patient an effective amount of a composition comprising both an RNA Pol II targeting inhibitor comprising a cyclin-dependent kinase inhibitor targeting CDK9 (i.e., flavopiridol, as discussed above), and a DNA damaging agent comprising a topoisomerase poison, wherein the composition inhibits growth of the tumor, inhibits replication of cells in the tumor, or induces cell death in cells of the tumor, and is met by the rejection above.
Claim 20 further limits claim 19 to wherein the tumor having a FET-fused oncogene is a Ewing's sarcoma tumor or a fibromyxoid liposarcoma tumor, and is met by the rejection above.
Claim 21 further limits claim 19 to wherein the FET-fused oncogene is selected from a Markush group that includes EWS-FLI1 and is met by the rejection above.
Claim 25 further limits claim 19 to wherein the DNA damaging agent, comprising a topoisomerase poison, further comprises another therapy selected from a Markush group that includes targeted radiation therapy, and is met by the rejection above.
Claim 33 further limits claim 19 to wherein the patient is human, and is met by the rejection above.
Applicant’s invention is unpatentable over the teaching of Bernstein in view of the teachings of Blagosklonny and Li, because a person of ordinary skill in the art, at the effective time of filing, would have a reasonable expectation of treating human patients suffering from Ewing sarcoma, a cancer that forms sarcomas (tumors) that are known (by oligonucleotide-based techniques) to exhibit the EWS-FLI1 fusion oncogene, by modifying the VACD treatment regime that includes radiation therapy along with the topoisomerase poison doxorubicin, to substitute actinomycin D for flavopiridol, because Bernstein teaches that the VACD treatment can be modified with substitutions and/or additions, and Blagosklonny teaches that actinomycin D and flavopiridol are both transcription inhibitors with similar biological effects despite distinct mechanisms of action, and Li teaches that flavopiridol is an effective agent for the suppression of EWS-FLI1-expressing cancer cells and tumors.
Thus, the invention was prima facie obvious at the time of filing.
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.
Any inquiry concerning this communication or earlier communications from the examiner should be directed to W. JUSTIN YOUNGBLOOD whose telephone number is (703)756-5979. The examiner can normally be reached on Monday-Thursday from 8am to 5pm. The examiner can also be reached on alternate Fridays.
If attempts to reach the examiner by telephone are unsuccessful, the examiner’s supervisor, Jeffrey S. Lundgren, can be reached at telephone number (571) 272-5541. The fax phone number for the organization where this application or proceeding is assigned is 571-273-8300.
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/W.J.Y./Examiner, Art Unit 1629
/JEFFREY S LUNDGREN/Supervisory Patent Examiner, Art Unit 1629
1 Emphasis added by Examiner.
2 Emphasis added by Examiner.
3 The Examiner notes that claim 1, while not prior listed under this rejection, is inherently rejected together with claim 12, because claim 12 depends from and includes all the limitations of claim 1.