DETAILED ACTION
A request for continued examination under 37 CFR 1.114, including the fee set forth in 37 CFR 1.17(e), was filed in this application after final rejection. Applicant’s Request for Continued Examination, Amendment and Arguments/Remarks received on 11 June 2026 have been entered.
Claims 1-4, 6, 8-10, 12-13, 22-23, 26, 35, 38-39, and 50-51 were previously pending in the application. Claims 22-23 have been cancelled, and new claim 52 has been added by Applicant. Claims 1-4, 6, 8-10, 12-13, 26, 35, 38-39, and 50-52 are currently pending and under examination in the application. Claims 1, 26, 35, 38, and 39 are independent claims. An action on the merits follows.
The present application, filed on or after March 16, 2013, is being examined under the first inventor to file provisions of the AIA . The text of those sections of Title 35, U.S. Code not included in this action can be found in a prior Office action.
Priority
The present application is a 35 U.S.C. 371 national stage filing of International Application No. PCT/US201950850, filed 12 September 2019, which claims priority to U.S. Provisional Application No. 62/730,387, filed 12 September 2018.
Thus, the earliest possible priority for the instant application is 12 September 2018.
Specification
The objection to the specification of the disclosure for containing an embedded hyperlink and/or other form of browser-executable code is withdrawn in view of the amendment to the specification. The amendment to the specification of the disclosure filed 11 June 2026 has been entered.
Claim Rejections - 35 USC § 112(b)
The rejection of Amended, previously presented, original, and cancelled claims 1-4, 6, 8-10, 12-13, 22-23, 26, 35, 38-39, and 50-51 under 35 U.S.C. 112(b) as failing to particularly point out and distinctly claim the subject matter which the inventor(s) regards as the invention for reciting “slow cycling” in claims 1, 26, and 35 is withdrawn in view of Applicant’s amendments to the claims such that slow cycling cells have been defined as tumor cells having a doubling time of at least 50 hours.
New claim 52 is newly 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.
New claim 52 recites, “the genes of claim 35”, which is indefinite because although amended claim 35 recites a list of gene, claim 35 is directed to a method of preparing a liposome composition and not directed to genes. As such, the metes and bounds of new claim 52 cannot be determined.
Claim Rejections - 35 USC § 112(d)
The rejection of cancelled claim 22 under 35 U.S.C. 112(d) as being of improper dependent form for failing to further limit the subject matter of the claims upon which it depends (claim 1) is withdrawn.
Claim Rejections - 35 USC § 103
The rejection of amended, previously presented, original, and cancelled claims 1-4, 6, 8-10, 12-13, 22-23, 26, 35, 38-39, and 50-51 under 35 U.S.C. 103 as being unpatentable over Sayour et al. [2017, Oncoimmunology, Vol. 6(1), e1256527, 1-14, published 03 January 2017, IDS, cited in a prior action]; in view of Vik-Mo et al. [2013, Cancer Immunology & Immunotherapy, Vol. 62, 1499-1509, cited in a prior action]; Moore et al. [2012, Stem Cells and Development, 21(10), 1822-1830, IDS]; Batlle & Clevers [2017, Nature Medicine, 23(10), 1124-1134]; Sen et al. [2018, Glioblastoma: Methods and Protocols, Methods in Molecular Biology, Vol. 1741, 151-170, published 2 February 2018, cited in a prior action]; Patel et al. [2014, Science, Vol. 344(6190), 1396-1401, IDS, cited in a prior action]; and Wang et al. [2018, Frontiers in Pharmacology, Vol. 9, 1-14, published 5 September 2018, cited in a prior action]; is withdrawn.
Amended, previously presented, original, and new claims 1-4, 6, 8-10, 12-13, 26, 35, 38-39, and 50-52 are newly rejected under 35 U.S.C. 103 as being unpatentable over Sayour et al. [2017, Oncoimmunology, Vol. 6(1), e1256527, 1-14, published 03 January 2017, IDS, cited in a prior action]; in view of Vik-Mo et al. [2013, Cancer Immunology & Immunotherapy, Vol. 62, 1499-1509, cited in a prior action]; Moore et al. [2012, Stem Cells and Development, 21(10), 1822-1830, IDS, cited in a prior action]; Batlle & Clevers [2017, Nature Medicine, 23(10), 1124-1134, cited in a prior action]; Richichi et al. [2013, Neoplasia, 15(7), 840-847]; Sen et al. [2018, Glioblastoma: Methods and Protocols, Methods in Molecular Biology, Vol. 1741, 151-170, published 2 February 2018, cited in a prior action]; Patel et al. [2014, Science, Vol. 344(6190), 1396-1401, IDS, cited in a prior action]; and Wang et al. [2018, Frontiers in Pharmacology, Vol. 9, 1-14, published 5 September 2018, cited in a prior action].
Regarding claim 1, Sayour teaches a composition comprising a liposome comprising a cationic lipid (e.g., DOTAP) and RNA consisting essentially of tumor-derived transcriptome RNAs (e.g., B16F0, B16F10, or KR158B-luc tumor cells) for use as a cancer vaccine which peripherally activates T cells against tumor antigens to target the destruction of tumor cells [column 1 ¶ 1, column 7 ¶ 1, column 9 ¶ 2- column 10 ¶ 1, Figure 3]. Sayour also teaches that total tumor RNA (TTRNA) is a rich source of antigenic material for induction of antitumor immunity [column 7 ¶ 2]. Sayour also teaches vaccination of mice with total tumor RNA nanoparticles (TTRNA-NP) derived from KR158B-luc cells had comparable expansion of tumor-specific T cells compared to mice receiving DC vaccines [column 6 ¶ 3- column 7 ¶ 1], and that treatment with TTRNA-NP elicited antitumor efficacy in an adoptive cellular therapy model in which mice were implanted with a radiation resistant and temozolomide resistant infiltrative murine astrocytoma of KR158B-luc cells, wherein the efficacy was similar to that elicited by total tumor RNA pulsed dendritic cells (TTRNA-pulsed DC) [column 7 ¶ 1]. Sayour also teaches that although the local and systemic milieu of invasive malignancies such as glioblastoma (GBM) is notoriously immunosuppressive, the immune modulating properties of RNA-NPs can be harnessed to re-program the quiescent immune environment toward an activated phenotype [column 9 ¶ 1].
Sayour does not teach that the RNA consists essentially of slow cycling cell (SCC) transcriptome RNA, wherein the SCC is a tumor cell having a doubling time of at least 50 hours, and wherein the RNA comprises RNA molecules encoded by all of the about 580 genes recited in claim 1.
Vik-Mo teaches a DC-based vaccine targeting cancer stem cells in glioblastoma in which cancer stem cell total mRNA was isolated from glioblastoma stem cells (GSCs) (which had been isolated and expanded as tumorspheres) and transfected into autologous DCs [abstract]. Vik-Mo also teaches that an immune response induced by vaccination was identified in all seven treated patients, without any autoimmune events or other side effects, and that progression-free survival was 2.9 times longer in vaccinated patients compared to matched controls, such that vaccination against glioblastoma stem cells is safe, well-tolerated, and may prolong progression-free survival [abstract]. Vik-Mo further teaches that cancer stem cells drive tumor growth and are resistant to current therapy, and that cancer stem cells likely must be eradicated to cure the cancer [column 1 ¶ 3- column 2 ¶ 1]. Vik-Mo also teaches that the immune response induced by the autologous DCs transfected with autologous glioblastoma stem cells (GSCs) mRNA is targeted against the patient’s own GSCs and further that the matured DCs which have been loaded with the GSC mRNA express glioblastoma stem cell antigens [column 2 ¶ 3, Figure 1]. Vik-Mo additionally teaches that glioblastomas are highly heterogenous both within tumors and between individual patients, and that the use of autologous GSC antigens may stimulate immunity against antigens unique to the patient, such that use of an individualized therapeutic approach may be very important when targeting GSC, as tumors may be derived from a range of different progenitor cells [column 13 ¶ 2]. Vik-Mo also teaches that the use of mRNA to load the DCs has several advantages over other DC-based approaches, including the ability to amplify mRNA in vitro which allows for a low amount of starting cell materials to be used, that mRNA is safter than DNA due to the short half-lives and lack of genomic integration, that RNA outperforms DNA in DCs T-cell induction, and that loading with tumor RNA is superior to loading with lysate or fusion of tumor cells with DCs [column 15 ¶ 2]. Further, Vik-Mo teaches that targeting the cancer stem cell population may be therapeutically rewarding. Therefore, an ordinarily skilled artisan at the time of filing the instant application would have been motivated to formulate a cancer vaccine with total mRNA derived from an isolated cancer stem cell population, such as GSCs, for the treatment of cancer, such as glioblastoma, to extend progression free survival.
Moore teaches the isolation and identification of a population of slow-cycling, label/dye-retaining tumor cells in both in vitro sphere cultures and in vivo xenograft models which have a multifold increase in ability to survive traditional forms of chemotherapy and reenter the cell cycle [abstract]. Moore also teaches that slow-cycling cells are activated after chemotherapy withdrawal to repropagate the tumor [column 12 ¶ 4]. Moore further teaches that isolation and characterization of the chemoresistant cell population will allow development of more targeted therapies [column 12 ¶ 7].
Batlle teaches that the ability of cancer stem cells to adopt a quiescent state is an important driver of drug resistance [column 8 ¶ 4]. Batlle further teaches that slow cycling cancer stem cells in mouse models of glioblastoma resist temozolamide treatment and that genetic ablation of that slow cycling cell population renders glioblastomas susceptible to chemotherapy [column 9 ¶ 1]. Batlle also teaches that in models of human glioblastoma, cancer stem cells evade anti-proliferative therapy by adopting a slow proliferative state, which depends on Notch signaling and requires epigenetic remodeling [column 9 ¶ 2], thus supporting the notion that resident quiescent cancer stem cells cause relapse after initially successful chemotherapeutic treatment [column 9 ¶ 3].
Richichi teaches that dye-retaining, slow-dividing glioblastoma (GBM) cells feature a population made up of homogenous stem cells that sustain tumor growth and therefore represent a viable target for GBM therapy development [abstract, pg 841 col 2 ¶ 3-4, ], wherein the slow-dividing cells sorted from four different patient-derived samples have doubling times ranging from about 80 hours to about 200 hours [Figure W1]. As such, Richichi is teaching both the motivation to target slow cycling glioblastoma stem cells and that such cells inherently have a doubling time of at least 80 hours.
Therefore, given the teachings of Moore and Batlle that slow cycling tumor stem cells contribute to chemoresistance and tumor relapse; the teaching of Batlle that ablation of the slow cycling cells renders glioblastomas susceptible to chemotherapy; and the teachings of Richichi that dye-retaining, slow-cycling stem cells in glioblastoma have doubling times of about 80 hours to 200 hours, an ordinarily skilled artisan would have been motivated to specifically target a slow cycling cell population of cancer stem cells for the treatment of cancers such as glioblastoma, wherein the SCCs are tumor cells having a doubling time of at least 50 hours.
Sen teaches that a slow-cycling cell population within a patient-derived glioblastoma cell culture contains cells with stem-like properties and differential gene expression between the slow-cycling and --fast-cycling cells, including the expression of FST and RNF150 in the FACS-isolated dye-retaining slow cycling cells [page 154 ¶ 3, page 165 ¶ 5, Figure 2-3].
Additionally, Patel teaches that glioblastomas contain a primitive subpopulation of stemlike cells (GSCs) which exhibit a stemlike phenotype, divide at lower overall rates, have low expression of cell cycle signature genes, and express stemness genes, including the expression of GRIA2 in the glioblastoma stem cells [column 11 ¶ 2-column 13 ¶ 2, Figure 3].
Note that claim 1 recites a list of genes which encode mRNAs that are a part of the slow cycling cell transcriptome, wherein the SCC is a tumor cell having a doubling time of at least 50 hours. The expression of genes by a cell is an inherent property of the cell. As such, any cell which meets all of the other limitations of the recited “slow cycling cell (SCC)” as set forth in claim 1 is presumed, absent evidence to the contrary, to express the same genes. Reliance upon inherency is not improper even though rejection is based on Section 103 instead of Section 102. In re Skoner, et al. 186 USPQ 80 (CCPA). As stated in MPEP 2112, The express, implicit, and inherent disclosures of a prior art reference may be relied upon in the rejection of claims under 35 U.S.C. 102 or 103."The inherent teaching of a prior art reference, a question of fact, arises both in the context of anticipation and obviousness." In re Napier, 55 F.3d 610, 613, 34 USPQ2d 1782, 1784 (Fed. Cir. 1995). See also In re Grasselli, 713 F.2d 731,739, 218 USPQ 769, 775 (Fed. Cir. 1983). Note that the claim as written only limits the SCCs to being any tumor cells having a doubling time of at least 50 hours and expressing the recited genes.
Accordingly, in generating a cancer vaccine comprising the total RNA of slow cycling tumor stem cells having a doubling time of at least 50 hours, as taught by Vik-Mo, Moore, Batlle, Richichi, Sen, and Patel, and given the inherency of gene expression as discussed above, an ordinarily skilled artisan would inherently be generating a composition comprising RNA molecules encoded by all of the genes recited in claim 1, absent evidence to the contrary.
Given the teachings of Vik-Mo to specifically target cancer stem cells with a cancer vaccine in which DC cells are transfected with total transcriptome RNA from isolated glioblastoma stem cells to express tumor-specific antigens; the teachings of Vik-Mo of the superiority of total mRNA for providing tumor-specific antigens in cancer vaccines due to easier preparations, increased safety, and improved efficacy; the motivation taught by Vik-Mo to formulate a cancer vaccine with total mRNA derived from a cancer stem cell population, such as GSCs, for the treatment of cancer, such as glioblastoma, to extend progression free survival; the teachings of Moore of the isolation of a population of slow-cycling, label-retaining tumor cells in both in vitro sphere cultures and in vivo xenograft models which have a multifold increase in ability to survive traditional forms of chemotherapy and reenter the cell cycle which may be targeted for more targeted therapeutic approaches; the teachings of Batlle that genetic ablation of that slow cycling cell population renders glioblastomas susceptible to chemotherapy; the motivation taught by Moore and Batlle to specifically target a slow cycling cell population of cancer stem cells for the treatment of cancers such as glioblastoma; the teachings of Richichi that slow-cycling glioblastoma stem cells have doubling times of about 80 hours to about 100 hours; and the teachings of Sen and Patel that isolated slow cycling cells have a transcriptome which is distinct from fast cycling cells isolated from the same mixed tumor population; it would have been prima facie obvious to an ordinarily skilled artisan at the time of filing the instant application to modify the method of Sayour to specifically target a slow cycling cell population of cancer stem cells by formulating a liposome comprising a cationic lipid and RNA such that the RNA consists essentially of slow cycling cell (SCC) transcriptome RNA, wherein the RNA inherently comprises RNA molecules encoded by all of the about 580 genes recited in claim 1, and wherein the SCC have a double time of at least 50 hours (i.e., about 80-200 hours), to therapeutically target slow cycling tumor cells with a reasonable expectation of success.
Regarding claim 2, Sayour teaches that the cationic lipid is DOTAP [abstract].
Regarding claims 3 and 51, Sayour teaches that the TTRNA-NP liposomes comprising a cationic lipid (DOTAP) and mRNA extracted from isolated tumor cells have an average zeta potential of about 30 mV (e.g., 27.28 mV) [column 4 ¶ 1]. Wang further supplements Sayour by teaching liposome compositions with zeta potentials of 50 mV and liposome-mRNA compositions with zeta potentials of 40 mV [column 13 ¶ 1, Figure 3], and that high zeta potential of about 35 mV can better target human and murine dendritic cells to induce significant antitumor responses and that cationic liposomes comprising nucleic acids with zeta potentials of greater than 30 mV exert excellent in vitro targeted genome editing and in vivo antitumor effects [column 23 ¶ 1]. Therefore, an ordinarily skilled artisan at the time of filing the instant application would have been motivated to generate liposomes comprising a cationic lipid and nucleic acids wherein the liposome has a zeta potential of about 30 mV to at least about 50 mV or of about 40 mV to about 50 mV.
Regarding claims 4 and 50, Sayour teaches that the nanoliposome DOTAP can encapsulate RNA into about 70-200 nm particles protecting nucleic acids from degradation while simultaneously delivering them to antigen presenting cells (APCs) in lymphoid organs where peripheral T cells can be activated against intracranial malignancies [column 7 ¶ 2].
Regarding claims 6 and 8-9, Sayour teaches that the RNA molecules complexed with the cationic lipid DOTAP at an RNA: cationic lipid ratio of about 1:10 to about 1:20 (e.g., 1 ug of RNA to 10-20 ug of DOTAP) achieved peak transfection efficiencies, with the selection of a ratio of 1:15 specifically used in their cationic nanoliposome formulations [column 3 ¶ 2].
Regarding claim 10, Sayour teaches that the TTRNA-NP liposomes comprise a cationic lipid (DOTAP) and mRNA extracted from isolated tumor cells [column 4 ¶ 1].
Regarding claims 12-13, Sayour teaches isolating transcriptome RNA from a KR158 cell line which was originally isolated from a spontaneously arising astrocytoma in an NF1:Trp53 mutant mouse with a C57Bl/6 background, thereby teaching that the transcriptome RNA was isolated from tumor cells which were isolated from a mixed tumor cell population obtained from a subject with a tumor. Additionally, Vik-Mo teaches isolation of GSC transcriptome RNA from GSCs that are isolated from a mixed tumor cell population obtained from a subject with a glioblastoma tumor (e.g., from tumor biopsies) [column 4 ¶ 2]. As discussed above, Vik-Mo also teaches that the immune response induced by the autologous DCs transfected with autologous glioblastoma stem cells (GSCs) mRNA is targeted against the patient’s own GSCs and further that the matured DCs which have been loaded with the GSC mRNA express glioblastoma stem cell antigens [column 2 ¶ 3, Figure 1]. Vik-Mo additionally teaches that glioblastomas are highly heterogenous both within tumors and between individual patients, and that the use of autologous GSC antigens may stimulate immunity against antigens unique to the patient, such that use of an individualized therapeutic approach may be very important when targeting GSC, as tumors may be derived from a range of different progenitor cells [column 13 ¶ 2]. As such, an ordinarily skilled artisan at the time of filing the instant application would have been motivated to isolate transcriptome RNA from a target cell type (e.g., slow cycling glioblastoma stem cells as described above) which has been isolated from a mixed tumor cell population obtained from a subject with a tumor (e.g., glioblastoma) to generate a cancer cell vaccine for the treatment of the tumor.
Regarding claim 26 and 38, Sayour teaches a method of preparing a liposome composition comprising a cationic lipid (e.g., DOTAP) and RNA consisting essentially of tumor-derived transcriptome RNAs, wherein the method comprises isolating tumor cells from a tumor (e.g., mixed tumor cell population) to produce a cell population consisting of KR158 cells, extracting nucleic acid molecules from isolated tumor cells (e.g., B16F0, B16F10, or KR158B-luc tumor cells) and mixing the nucleic acid molecules extracted from the isolated tumor cells with a cationic lipid (e.g., DOTAP) to make a liposome composition (e.g., RNA-NPs) [column 7 ¶ 1, column 9 ¶ 2- column 10 ¶ 1]. Additionally, Vik-Mo teaches isolation of GSC transcriptome RNA from GSCs that are isolated from a mixed tumor cell population obtained from a subject with a glioblastoma tumor (e.g., from tumor biopsies) [column 4 ¶ 2]. Further, as discussed above, Vik-Mo, Moore, Batlle, Richichi, Sen, and Patel provide the teachings and motivation to substitute isolated slow cycling tumor stem cells having doubling times of 80-200 hours for the total tumor cells taught by Sayour to produce a cancer vaccine targeting slow cycling cancer stem cells. Further, by teaching the preparation of the liposome composition, Sayour, Vik-Mo, Moore, Batlle, Richichi, Sen, and Patel also teach the liposome composition itself, as recited in claim 38.
Regarding amended claim 35 and new claim 52, as described above, Sayour teaches a method of preparing a liposome composition comprising mixing a cationic lipid (e.g., DOTAP) and RNA molecules consisting essentially of tumor-derived transcriptome RNA [column 7 ¶ 1, column 9 ¶ 2- column 10 ¶ 1]. Also, as discussed above, Vik-Mo, Moore, Batlle, Richichi, Sen, and Patel provide the teachings and motivation to substitute isolated slow cycling tumor stem cells for the total tumor cells taught by Sayour to produce a cancer vaccine targeting slow cycling cells having a doubling time of about 80-200 hours. Given the inherency of gene expression, as further discussed above, absent evidence to the contrary, in producing the liposome composition from the slow cycling tumor stem cells, an ordinarily skilled artisan would inherently be generating a composition comprising RNA molecules encoded by at least 10 or at least 11 of the about 580 genes recited in claim 35.
Regarding claim 39, Sayour further teaches a method of treating gliomas comprising administering the total tumor RNA-NPs to a subject with malignant gliomas induced by intracranial implantation of KR158B-luc cells [column 7 ¶ 1, column 9 ¶ 4- column 10 ¶ 6, column 11 ¶ 5- column 13 ¶ 2]. Sayour also teaches that total tumor RNA (TTRNA) is a rich source of antigenic material for induction of antitumor immunity [column 7 ¶ 2], and that the nanoliposome DOTAP can protect nucleic acids from degradation while simultaneously delivering them to antigen presenting cells (APCs) in lymphoid organs where peripheral T cells can be activated against intracranial malignancies [column 7 ¶ 2]. Sayour additionally teaches that the antitumor efficacy of the TTRNA-NP against the KR158B-luc implanted tumor was not significantly different than the efficacy elicited by TTRNA-pulsed DCs [column 7 ¶ 1]. Further, Sayour teaches that the promise of RNA-pulsed DC vaccines was demonstrated in a randomized clinical trial design demonstrating a significantly prolonged survival benefit in patients with glioblastoma (GBM) receiving an optimized DC platform, but that the advancement of cellular therapeutics through the commercialization pipeline has been fraught with challenges in the development, manufacturing, and marketing of successful cancer immunotherapies, along with the problem of significant delays due to prolonged production times of autologous DC manufacturing and testing which can preclude candidates with rapid disease progression [column 1 ¶ 1, column 7 ¶ 2]. Sayour goes on to teach that RNA-NPs circumvent the challenges associated with DC vaccines by leveraging the use of commercially available and clinically translatable nanoparticles (NPs) that can be combined with tumor-derived RNA to peripherally activate T cells against tumor antigens, can be generated in a few days after tumor tissue procurement, and abrogate the need for complex cellular processing [column 1 ¶ 1, column 7 ¶ 2]. Sayour also teaches that although the local and systemic milieu of invasive malignancies such as GBM is notoriously immunosuppressive, the immune modulating properties of RNA-NPs can be harnessed to re-program the quiescent immune environment toward an activated phenotype [column 9 ¶ 1]. As such, Sayour teaches to administer the liposome composition to a subject with not only glioma generally, but glioblastoma specifically. Further, as discussed above for claim 22, Vik-Mo, Moore, Batlle, Sen, and Patel provide the teachings and motivations to generating a cancer vaccine comprising the total RNA of slow cycling tumor stem cells, which are indistinguishable from “slow cycling cells” as claimed. Also, given the inherency of gene expression, as further discussed above, in generating a cancer vaccine comprising the total RNA of slow cycling tumor stem cells, an ordinarily skilled artisan would inherently be generating a composition comprising RNA molecules encoded by all of the about 580 genes recited in claim 1.
Therefore, given the teachings and motivations discussed above for claim 1 to specifically target a slow cycling cell population of cancer stem cells having a doubling time of at least 50 hours (e.g., of at least 80-200 hours as taught by Richichi) by formulating a liposome comprising a cationic lipid and RNA such that the RNA consists essentially of slow cycling cell (SCC) transcriptome RNA, wherein the RNA inherently comprises RNA molecules encoded by at least 10, at least 11, and up to all of the about 580 genes recited in claims 1 and 35, to target slow cycling stem cells in a tumor; the motivation taught by Wang to generate liposomes comprising a cationic lipid and nucleic acids wherein the liposome has a zeta potential of about 30 mV to at least about 50 mV or of about 40 mV to about 50 mV; the motivation taught by Vik-Mo to isolate transcriptome RNA from a target cell type (e.g., slow cycling glioblastoma stem cells) which has been isolated from a mixed tumor cell population obtained from a subject with a tumor (e.g., glioblastoma) to generate a cancer cell vaccine for the treatment of the tumor; and the teaching of Vik-Mo to isolate GSC transcriptome RNA from GSCs that are isolated from a mixed tumor cell population obtained from a subject with a glioblastoma tumor (e.g., from tumor biopsies); it would have been prima facie obvious to an ordinarily skilled artisan at the time of filing the instant application to modify the method of Sayour as described for claim 1 above and further such that the liposomes have zeta potentials of about 40 mV to about 50 mV and to isolate the slow cycling cells from a mixed tumor cell population to produce a cell population consisting essentially of SCCs, from which total transcriptome RNA is isolated which consists essentially of SCC transcriptome RNA and comprises RNA molecules encoded by at least 10, at least 11, and up to all of the about 580 genes recited in claims 1 and 35 with a reasonable expectation of success.
Insofar as Applicant’s arguments apply to this new grounds of rejection, Applicant argues that:
the Office failed to establish that any of the cited references alone or in combination discloses each and every element of amended claims 1, 26, and 35, in that the cells disclosed by Vik-Mo, Sen, and Patel are distinct from those of the instant claims in that Vik-Mo, Sen, and Patel do not teach wherein the slow cycling cells are tumor cells having a doubling time of at least 50 hours; wherein:
Vik-Mo does not identify, isolate, or characterize any cell population based on doubling time;
Sen does not report doubling time of the cells nor establish that the dye-retaining cells have a doubling time of at least 50 hours;
Patel does not identify or characterize any cell population as having a doubling time of at least 50 hours nor isolate cells based on proliferation rate; and
None of Moore, Batlle, and Wang disclose slow cycling cells that are tumor cells that have a doubling time of at least 50 hours;
the Office has not provided an objective reason as to why one skilled in the art would modify the teachings of the cited references to allegedly arrive at the claimed invention; and
there is nothing in the record that allegedly establishes that the cell populations of the cited references would inherently have the features recited in the claims in that gene expression profiles are highly variable across different cell populations and Examiner has not provided evidence or a technical reasoning to support that the complete set of approximately 600 gene recited in amended claims 1 and 35 would necessarily be expressed in any slow cycling cell population not having a doubling time of at least 50 hours.
However, this is not agreed.
In response to Applicant’s arguments against the references individually, it is noted that the test for obviousness is not whether the features of a secondary reference may be bodily incorporated into the structure of the primary reference; nor is it that the claimed invention must be expressly suggested in any one or all of the references. Rather, the test is what the combined teachings of the references would have suggested to those of ordinary skill in the art. See In re Keller, 642 F.2d 413, 208 USPQ 871 (CCPA 1981). One cannot show nonobviousness by attacking references individually where the rejections are based on combinations of references. See In re Keller, 642 F.2d 413, 208 USPQ 871 (CCPA 1981); In re Merck & Co., 800 F.2d 1091, 231 USPQ 375 (Fed. Cir. 1986). Further, the Examiner recognizes that obviousness may be established by combining or modifying the teachings of the prior art to produce the claimed invention where there is some teaching, suggestion, or motivation to do so found either in the references themselves or in the knowledge generally available to one of ordinary skill in the art. See In re Fine, 837 F.2d 1071, 5 USPQ2d 1596 (Fed. Cir. 1988), In re Jones, 958 F.2d 347, 21 USPQ2d 1941 (Fed. Cir. 1992), and KSR International Co. v. Teleflex, Inc., 550 U.S. 398, 82 USPQ2d 1385 (2007). In addition, 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).
Specifically, regarding Applicant’s argument 1), note that none of Sayour, Vik-Mo, Sen, Patel, Moore, Batlle, nor Wang were relied on for teaching that the slow cycling tumor cells have a doubling time of at least 50 hours. As discussed above, Richichi is cited for teaching that the slow cycling, dye-retaining stem cells isolated from glioblastoma tumors have a doubling time of about 80 hours to about 200 hours. Note further, that Moore additionally teaches that a population of slow cycling, dye-retaining melanoma cells are tumor cells which have a doubling time of 4 weeks [pg 1 col 1 ¶ 2]. Together, Richichi and Moore indicate that slow cycling tumor cells having doubling times of at least 50 hours are not uniquely identified by the instant inventors nor unknown prior to the instant filing.
Additionally, by teaching identification and isolation of the slow cycling cells by sorting dye-retaining glioblastoma cells which comprise a homogenous stem cell population [pg 841 col 2 ¶ 3-4], Richichi is teaching both a cell population which is encompassed by the instant claims and a cell population which is consistent with the slow cycling tumor cells / stem cells taught by Vik-Mo, Moore, Sen, and Patel. As such, the cited references disclose the particular cell subpopulation required by the instant claims.
Regarding Applicant’s argument 2), as discussed in detail above, Vik-Mo was cited for teaching the motivation to formulate a cancer vaccine with total mRNA derived from a cancer stem cell population, such as GSCs, for the treatment of cancer, such as glioblastoma, to extend progression free survival. Additionally, Moore, Battle, and Richichi were cited for teaching the motivation to specifically target a slow cycling cell population of cancer stem cells for the treatment of cancers such as glioblastoma, wherein the slow cycling cell population has a doubling time of at least 80 hours. Accordingly, the cited references provide the teachings and motivation to substitute the cell population used by Sayour with a cell population consisting of slow cycling cells which are tumor cells having a doubling time of at least 50 hours.
Regarding Applicant’s argument 3), as discussed above, the cited references disclose the particular cell subpopulation required by the instant claims. Accordingly, given that the cited references disclose the particular cell subpopulation required by the instant claims, then it necessarily follows that the cells taught by the cited references also inherently express the genes recited by the instant claims. Note that Richichi was cited for teaching that dye-retaining, slow cycling cells isolated from glioblastoma tumors have doubling times of greater than 50 hours. As such, the cells of the cited references are slow cycling cells which are tumor cells having a doubling time of at least 50 hours and are not “any slow cycling cell population not having a doubling time of at least 50 hours” and suggested by Applicant.
Therefore, Applicant’s arguments do not overcome a finding of obviousness under 35 U.S.C. 103 over Sayour, Vik-Mo, Moore, Batlle, Richichi, Sen, Patel, and Wang.
Conclusion
No claim is allowed.
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DR. KATIE L. PENNINGTON
Examiner
Art Unit 1634
/KATIE L PENNINGTON/Examiner, Art Unit 1634
Dr. A.M.S. Wehbé
/ANNE MARIE S WEHBE/Primary Examiner, Art Unit 1634
Prosecution Insights