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 .
Claims 1-20 are pending and claim 21 is cancelled.
Election/Restrictions
Applicant’s election of Group I, claims 11-15, 17, and 18 in the reply filed on 09/19/2025 is acknowledged. Because applicant did not distinctly and specifically point out any errors in the restriction requirement, the election has been treated as an election without traverse (MPEP § 818.01(a)).
Claims 1-10, 16, 19, and 20 are withdrawn from further consideration pursuant to 37 CFR 1.142(b) as being drawn to a nonelected invention, there being no allowable generic or linking claim. Election was made without traverse in the reply filed on 09/19/2025.
Claims 11-15, 17, and 18 are under current examination.
Claim Rejections - 35 USC § 112
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.
Claim 15 is rejected under 35 U.S.C. 112(a) or 35 U.S.C. 112 (pre-AIA ), first paragraph, because 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 the claim.
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 or use the invention commensurate in scope with claim 15.
Enablement is considered in view of the Wands factors (MPEP 2164.01 (A)).
These include:
(A) The breadth of the claims;
(B) The nature of the invention;
(C) The state of the prior art;
(D) The level of one of ordinary skill;
(E) The level of predictability in the art;
(F) The amount of direction provided by the inventor;
(G) The existence of working examples; and
(H) The quantity of experimentation needed to make or use the invention based
on the content of the disclosure
All of the Wands factors have been considered with regard to the instant claims
as discussed below:
(A)/(B) The breadth of the claims/The nature of the invention:
The claims are directed to a method of killing cancer stem cells (CSC) in a subject comprising administering a therapeutically effective amount of a nanoparticle of claim 7 to a subject in need thereof, wherein the nanoparticle of claim 7 is a nanoparticle for targeted siRNA delivery, comprising: an iron oxide core and a chitosan-polyethylene glycol-polyethylenimine copolymer coating surrounding the core; chlorotoxin covalently coupled to the coating; and an siRNA reversibly associated to the coating by non-covalent interaction, wherein the siRNA reduces the expression of O6-methylguanine-DNA methyltransferase in a subject. The claims place no limitation on the type of CSC and therefore the scope of the claimed cells being killed is astronomical. In order to practice the full scope of the invention, one having ordinary skill would need to know every subcategory of CSC that would be susceptible to siRNA inhibition of MGMT gene expression and either respond by dying or becoming more sensitive to treatment. In the latter case, one having ordinary skill would then need to identify a co-treatment that would kill the CSC. According to the National Cancer Institute, "cancer'' embraces over 100 types of related proliferation disorders. Cancers are broadly classified into carcinoma, sarcoma, leukemia, lymphoma, multiple myeloma, melanoma, brain and spinal cord tumors, germ cell tumors, neuroendocrine tumors, and carcinoid tumors. Of these, only leukemia does not include solid tumors. Cancer types are subdivided by tissue of origin and are often subcategorized within that classification by histological markers or other clinical and histopathological features. See What is Cancer website, pages 4-7. In summary, the term “cancer” embraces hundreds of different diseases having different molecular mechanisms driving pathology and different responsiveness to therapies. Thus, the claims embrace killing CSC derived from any of the over 100 different cancer types. The term “cancer stem cell” refers to a concept, albeit well-established, wherein quiescent and poorly differentiated cells within a tumor mass contribute to drug resistance, and under permissive conditions, are responsible for tumor recurrence and metastasis (Snyder: abstract). Therefore, the claims embrace killing a cell that has not been fully defined as of the filing date of the instant invention. The scope of the claims is colossal.
(C)/(D) The state of the prior art/The level of predictability in the art:
The necessary steps to make and use the invention, as claimed, are to identify every subcategory of CSC that would be susceptible to siRNA inhibition of MGMT gene expression and either respond by dying or becoming more sensitive to treatment. In the latter case, one having ordinary skill would then need to identify a co-treatment that would kill the CSC. The field of killing CSCs is in early stages of development and the level of predictability is very low. The term “cancer stem cell” refers to a concept, albeit well-established, wherein quiescent and poorly differentiated cells within a tumor mass contribute to drug resistance, and under permissive conditions, are responsible for tumor recurrence and metastasis (Snyder: abstract). Moreover, some cancers do not follow the cancer stem cell model (Chu: page 8, right col). There remains much controversy surrounding the scientific techniques employed to identify surface markers for CSCs (Snyder: page 2). At the time of the instant invention, accurately identifying a CSC was an area of active research, and it remains so today. Snyder’s table 1, spanning pages 2-3, summarizes some of the CSC markers that had been suggested by 2018 and Chu’s table 2, spanning pages 10-12, lists biomarkers that had been suggested by 2024. In view of the foregoing it is clear that there is not a unifying marker to unambiguously and reliably identify everything within the scope of “cancer stem cell” and discern these CSCs from other cancer cells. Once the artisan of ordinary skill had discovered a suitable collection of biomarker to identify CSCs from every type of cancer cell, they would need to isolate these cells and experimentally determine whether MGMT inhibition by siRNA alone or in combination with another therapeutic agent could be delivered to and kill the CSC. Therefore, simply finding the CSCs to evaluate for its tendency to die on exposure to siRNA that decreases MGMT expression would be a herculean task. There would have been no way for one of ordinary skill to intuit this, as would be the case in a well-established field; it would need to be determined empirically for each type of cancer.
The instant claims require a chlorotoxin (CTX) targeting agent covalently attached to the polymer that coats the nanoparticle core and directs the construct to a glioblastoma multiforme cell. Therefore the claims require an inherent step of targeting the nanoparticles to cells that bind CTX. Chlorotoxin has been recognized as a targeting agent for brain cancer; however, recent work indicates that it may also be useful to detect other malignancies (Ramsoomair: abstract). This means in addition to discovering which cancer stem cells respond to siRNA inhibition of MGMT expression, the artisan of ordinary skill would have to empirically distinguish those CSCs that may be targeted from those that cannot be effectively targeted by CTX.
Finally, inhibition of MGMT expression alone may not be sufficient to kill a cancer cell, but instead this treatment sensitizes the cell to DNA alkylating cytotoxic agents (Singh: abstract). MGMT expression is altered in multiple types of cancer (see Singh, table 2, which describes MGMT expression in various cancers). The link to prognosis and sensitivity to alkylating agents is not entirely predictable by MGMT status (e.g. see lung cancer). Cancer stem cells possess various traits that make them more resistant to treatment, including the ability to enter a quiescent state in which they are not sensitive to chemotherapy agents that rely on DNA damage that occurs during cell cycle progression as well as high expression of drug transporters that expel chemotherapy drugs from the interior of the CSC (Chu: page 9, left col). One having ordinary skill would have no means of knowing, a priori, which types of CSCs would possess additional means to circumvent treatment with alkylating agents, rendering them insensitive despite reduced expression of MGMT. Thus, one having ordinary skill would again need to empirically delineate in which CSC siRNA inhibition of MGMT would be sufficient to sensitize to alkylating agents, and which CSC might possess other mechanisms to circumvent treatment.
With regard to both practicing the invention for the full scope of killing cancer stem cells by administering a therapeutically effective amount of an iron oxide nanoparticle coated with a chitosan-PEG-PEI copolymer that is covalently attached to CTX and non-covalently associated with an siRNA that decreases expression of the MGMT gene, MPEP 2164.03 indicates that the physiological art in general is unpredictable. “A single embodiment may provide broad enablement in cases involving predictable factors, such as mechanical or electrical elements. In re Vickers, 141 F.2d 522, 526-27, 61 USPQ 122, 127 (CCPA 1944); In re Cook, 439 F.2d 730, 734, 169 USPQ 298, 301 (CCPA 1971). However, in applications directed to inventions in arts where the results are unpredictable, the disclosure of a single species usually does not provide an adequate basis to support generic claims. In re Soll, 97 F.2d 623, 624, 38 USPQ 189, 191 (CCPA 1938). In cases involving unpredictable factors, such as most chemical reactions and physiological activity, more may be required. In re Fisher, 427 F.2d 833, 839, 166 USPQ 18, 24 (CCPA 1970) (contrasting mechanical and electrical elements with chemical reactions and physiological activity). See also In re Wright, 999 F.2d 1557, 1562, 27 USPQ2d 1510, 1513 (Fed. Cir. 1993); In re Vaeck, 947 F.2d 488, 496, 20 USPQ2d 1438, 1445 (Fed. Cir. 1991). This is because it is not obvious from the disclosure of one species, what other species will work.” A similar statement appears at In re Application of Hozumi et al., 226 USPQ 353: "In spite of the vast expenditure of human and capital resources in recent years, no one drug has been found which is effective in treating all types of cancer. Cancer is not a simple disease, nor is it even a single disease, but a complex of a multitude of different entities, each behaving in a different way". There are compounds that treat a modest range of cancers, but no one has ever been able to figure out how to get a compound to be effective against cancer generally, or even a majority of cancers.
In summary, the field of killing cancer stem cells in nascent stages of development, the specific field was highly unpredictable, and the biological arts are unpredictable in general.
(D) The level of one of ordinary skill:
One having ordinary skill in the art would have an advanced degree in biomedical research and/or clinical practice such as a Ph.D. and/or an M.D., therefore the level of skill is high.
(F) The amount of direction provided by the inventor/(G) The existence of working examples:
The specification states that cancer stem cells are thought to be much harder to sensitize to TMZ likely because CSCs are more resistant to TMZ than non-stem cancer cells. An experiment shows suppression of MGMT activity in orthotopic glioblastoma multiforme (GBM) patient-derived xenografts displaying GBM Stem Cell (GSC) markers and Applicant concludes that the NP-PEI-siMGMT complex according to the invention can be loaded with and deliver a much greater amount of siRNAs than nanoparticle covalent formulations, and thus shows much higher effectiveness in sensitizing cancer stem cells and better therapeutic effect in cell killing. The specification does not provide further guidance on readily identifiable properties of a cell that link susceptibility to the claimed method of killing CSCs. Thus, given the unpredictability in the art, the amount of guidance in the specification regarding making/using the claimed nanoparticles to kill any CSC regardless of origin is not sufficient to enable one of ordinary skill to practice the full scope of the claimed invention.
(H) The quantity of experimentation needed to make or use the invention based on the content of the disclosure:
In view of the foregoing analysis, the quantity of experimentation to practice the full scope of the invention would be undue.
Claim Rejections - 35 USC § 112
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.
Claim 15 is 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.
Applicant is referred to the Guidelines on Written Description published at FR 66(4) 1099-1111 (January 5, 2001) (also available at www.uspto.gov). The following passage is particularly relevant:
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 structure and function, or by a combination of such identifying characteristics, sufficient to show the applicant was in possession of the claimed genus.
A "representative number of species" means that the species which are adequately described are representative of the entire genus. Thus, when there is substantial variation within a genus, one must describe a sufficient number of species to reflect the variation within the genus. What constitutes a "representative number" is an inverse function of the skill and knowledge in the art. Satisfactory disclosure of a "representative number" depends on whether one of skill in the art would recognize that applicant was in possession of the necessary common attributes or features of the elements possessed by the members of the genus in view of the species disclosed. In an unpredictable art, adequate written description of a genus which embraces widely variant species cannot be achieved by disclosing only one species within the genus.
For Example MPEP 2163 states, in part,
An adequate written description of a chemical invention also requires a precise definition, such as by structure, formula, chemical name, or physical properties, and not merely a wish or plan for obtaining the chemical invention claimed. See, e.g., Univ. of Rochester v. G.D. Searle & Co., 358 F.3d 916, 927, 69 USPQ2d 1886, 1894-95 (Fed. Cir. 2004) (The patent at issue claimed a method of selectively inhibiting PGHS-2 activity by administering a non-steroidal compound that selectively inhibits activity of the PGHS-2 gene product, however the patent did not disclose any compounds that can be used in the claimed methods. While there was a description of assays for screening compounds to identify those that inhibit the expression or activity of the PGHS-2 gene product, there was no disclosure of which peptides, polynucleotides, and small organic molecules selectively inhibit PGHS-2. The court held that “[w]ithout such disclosure, the claimed methods cannot be said to have been described.”).
The claims are directed to a method of killing cancer stem cells (CSC) in a subject comprising administering a therapeutically effective amount of a nanoparticle of claim 7 to a subject in need thereof, wherein the nanoparticle of claim 7 is a nanoparticle for targeted siRNA delivery, comprising: an iron oxide core and a chitosan-polyethylene glycol-polyethylenimine copolymer coating surrounding the core; chlorotoxin covalently coupled to the coating; and an siRNA reversibly associated to the coating by non-covalent interaction, wherein the siRNA reduces the expression of O6-methylguanine-DNA methyltransferase in a subject. The claims place no limitation on the type of CSC and therefore the scope of the claimed cells being killed is astronomical.
With respect to the genus embraced by the claims, the phrase “cancer stem cell” embraces an enormous genus encompassing any CSC derived from any type of cancer. According to the National Cancer Institute, "cancer'' embraces over 100 types of related proliferation disorders. Cancers are broadly classified into carcinoma, sarcoma, leukemia, lymphoma, multiple myeloma, melanoma, brain and spinal cord tumors, germ cell tumors, neuroendocrine tumors, and carcinoid tumors. Of these, only leukemia does not include solid tumors. Cancer types are subdivided by tissue of origin and are often subcategorized within that classification by histological markers or other clinical and histopathological features. See What is Cancer website, pages 4-7. In summary, the term “cancer” embraces hundreds of different diseases having different molecular mechanisms driving pathology and different responsiveness to therapies. Thus, the claims embrace killing CSC derived from any of the over 100 different cancer types. The term “cancer stem cell” refers to a concept, albeit well-established, wherein quiescent and poorly differentiated cells within a tumor mass contribute to drug resistance, and under permissive conditions, are responsible for tumor recurrence and metastasis (Snyder: abstract). Therefore, the claims embrace killing a cell that has not been fully defined as of the filing date of the instant invention. The scope of the claims is colossal.
With respect to disclosure of a representative number of species, the level of skill of an artisan in the field of biologically derived wound dressing as well as the level of knowledge in the prior art and the predictability of the prior art must be considered. The artisans of skill in the field of killing CSCs would be a collaborative team of materials scientists, physicians, and/or biologists possessing an advanced degree in biomedicine and/or a doctor of medicine degree, thus the level of skill is high. The level of unpredictability in the art of killing CSCs is also very high: The term “cancer stem cell” refers to a concept, albeit well-established, wherein quiescent and poorly differentiated cells within a tumor mass contribute to drug resistance, and under permissive conditions, are responsible for tumor recurrence and metastasis (Snyder: abstract). Moreover, some cancers do not follow the cancer stem cell model (Chu: page 8, right col). There remains much controversy surrounds the scientific techniques employed to identify surface markers (Snyder: page 2). At the time of the instant invention, accurately identifying a CSC was an area of active research, and it remains so today. Snyder’s table 1, spanning pages 2-3, summarizes some of the CSC markers that had been suggested by 2018 and Chu’s table 2, spanning pages 10-12, lists biomarkers that had been suggested by 2024. In view of the foregoing it is clear that there is not a unifying marker to unambiguously and reliably identify everything within the scope of “cancer stem cell” and discern these CSCs from other cancer cells. Once the artisan of ordinary skill had discovered a suitable collection of biomarker to identify CSC from every type of cancer, they would need to isolate these cells and experimentally determine whether MGMT inhibition by siRNA alone or in combination with another therapeutic agent could be delivered to and kill the CSC. Therefore, simply finding the CSCs to evaluate for its tendency to die on exposure to siRNA that decreases MGMT expression would be a herculean task. There would have been no way for one of ordinary skill to intuit this, as would be the case in a well-established field; it would need to be determined empirically for each type of cancer.
The instant claims require a chlorotoxin (CTX) targeting agent covalently attached to the polymer that coats the nanoparticle core that directs the construct to brain tumor cells. Therefore the claims require an inherent step of targeting the nanoparticles to cells that bind CTX. Chlorotoxin has been recognized as a targeting agent for brain cancer; however, recent work indicates that it may also be useful to detect other malignancies (Ramsoomair: abstract). This means in addition to discovering which cancer stem cells respond to siRNA inhibition of MGMT expression, the artisan of ordinary skill would have to empirically distinguish those CSCs that may be targeted from those that cannot be effectively targeted by CTX.
Finally, inhibition of MGMT expression alone may not be sufficient to kill a cancer cell, but instead this treatment sensitizes the cell to DNA alkylating cytotoxic agents (Singh: abstract). MGMT expression is altered in multiple types of cancer (see Singh, table 2, which describes MGMT expression in various cancers). The link to prognosis and sensitivity to alkylating agents is not entirely predictable by MGMT status (e.g. see lung cancer). Cancer stem cells possess various traits that make them more resistant to treatment, including the ability to enter a quiescent state in which they are not sensitive to chemotherapy agents that rely on DNA damage that occurs during cell cycle progression as well as high expression of drug transporters that expel chemotherapy drugs from the interior of the CSC (Chu: page 9, left col). One having ordinary skill would have no means of knowing, a priori, which types of CSCs would possess additional means to circumvent treatment with alkylating agents, rendering them insensitive despite reduced expression of MGMT. Thus, one having ordinary skill would again need to empirically delineate in which CSC siRNA inhibition of MGMT would be sufficient to sensitize to alkylating agents, and which CSC might possess other mechanisms to circumvent treatment. The state of the art fails to remedy the deficiencies under 35 USC 112(a) in terms of establishing applicant was in possession of the full scope of the claimed invention.
As noted above, in order to satisfy the written description requirement under 35 USC 112(a), the original disclosure may provide 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 structure and function, or by a combination of such identifying characteristics, sufficient to show the applicant was in possession of the claimed genus.
Regarding reduction to drawings, Figure 2A, drawing sheet 5 provides a general pictorial representation of the mechanism via which the nanoparticles deliver siRNA to cells and prevent MGMT expression. This figure does not describe a means to discern the CSCs that will be killed by administering the claimed nanoparticles from those that will not. Figure 8 describes the outcome of an experiment where it is concluded that “TMZ in combination with the nanoparticles of the invention having siRNA associated to the nanoparticle by non-covalent interaction are therapeutically efficacious in GBM cell killing, while the combination of TMZ with the nanoparticles having siRNA covalently coupled to the nanoparticle are not”. Figure 8 is a summary of data from the experiment described in the specification evaluating the effect of the claimed nanoparticles in combination with the alkylating agent TMZ, the only working example in the specification (pages 17 and 18). The experiment shows cytotoxicity when the nanoparticles are combined with TMZ in a cell line that possesses stem cell characteristics. Applicant also states “Similar results (i.e., negligible cell killings) of these covalent nanoparticle formulations were also demonstrated in the studies with other cancer stem cells including GBM8, GSC38b, GSC41b, and GBM6 tumors (not shown).” Therefore a functional example from one type of cancer, glioblastoma multiforme, is described in the specification.
The description of a single species of cancer stem cell type that responds to co-treatment with TMZ and the claimed nanoparticles as well as the low predictability regarding which CSC might respond to siRNA that reduces MGMT expression supports the conclusion that Applicant has not provided sufficient written description to reasonably convey to one skilled in the relevant art that the inventor, at the time the application was filed, had possession of the claimed invention. The intended outcome recited in instant claim 15 “killing cancer stem cells” appears to be merely a wish or plan for obtaining the invention as claimed, consistent with the patent at issue in University of Rochester vs. G.D. Searle & Co. In view of the foregoing the claims are rejected under 35 USC 112(a) as failing to satisfy the written description requirement.
Claim Rejections - 35 USC § 103
In the event the determination of the status of the application as subject to AIA 35 U.S.C. 102 and 103 (or as subject to pre-AIA 35 U.S.C. 102 and 103) is incorrect, any correction of the statutory basis (i.e., changing from AIA to pre-AIA ) for the rejection will not be considered a new ground of rejection if the prior art relied upon, and the rationale supporting the rejection, would be the same under either status.
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 11-15, 17, and 18 are rejected under 35 U.S.C. 103 as being unpatentable over Kievit et al. (ACS NANO 4(8):4587-4594; publication year: 2010) in view of Yan et al. (US 20110165227; publication date: 07/07/2011).
With regard to claims 11 and 12, Kievit discloses a chlorotoxin labeled nanovector for targeted gene delivery to glioma (title). The nanoparticle contains an iron oxide core coated with a copolymer of chitosan-PEG-PEI and the DNA is loaded via electrostatic interaction (i.e. it is associated to the particle by non-covalent interaction; Figure 1, page 4588). The loaded nanoparticles are administered to mice in a xenograft model of glioma via tail vein injection (i.e. intravenous administration; page 4589, left col) and gene expression is detected in the tumor, indicating successful delivery to the biological target (Figure 4, page 4590).
Thus, Kievit discloses a method of treating brain cancer in a subject comprising administering an amount of a nanoparticle comprising an iron oxide core and a chitosan-polyethylene glycol-polyethylenimine copolymer coating surrounding the core; chlorotoxin covalently coupled to the coating; and a DNA molecule reversibly associated to the coating by non-covalent interaction. Kievit does not disclose that the siRNA reduces expression of O6-methylguanine DNA methyltransferase (MGMT), as required by the instant claims and that the method is for suppressing the expression of MGMT in a subject.
Yan teaches an siRNA molecule targeting MGMT is effective to treat the brain cancer glioblastoma multiforme (GBM) and that GBM is frequently associated with elevated levels of O6-methylguanine-DNA-methlytransferase (AGT), a DNA repair enzyme that enhances neoplastic resistance to chemotherapeutics such as Temozolomide (TMZ; 0004).
It would have been prima facie obvious to deliver siRNA targeting MGMT using the nanoparticles disclosed by Kievit. The skilled artisan would have been motivated to do so and had reasonable expectation of success because the nanoparticles have been demonstrated to effectively deliver genetic material to brain tumor cells, and express the delivered gene and MGMT knockdown can re-sensitize brain cancer cells to the chemotherapy agent TMZ.
With regard to claims 13 and 14, Kievit discloses that the nanoparticle has been shown to knockdown expression of green fluorescence protein in glioma cells that have been modified to express this gene after tail vein delivery. Yan discloses that siRNA targeting MGMT is effective to sensitize glioblastoma cells to TMZ, as discussed above. One having ordinary skill would have been motivated and had expectation of success treating glioblastoma multiforme for the same reasons discussed above for other brain cancers.
With regard to claim 15, in view of the foregoing, one having ordinary skill would have been motivated to knock down expression of MGMT in TMZ resistant glioma tumors followed by treatment with TMZ, with the reasonable expectation that the cells would have been re-sensitized to this agent. Neither reference discloses cancer stem cells; however, the instant specification indicates that this method has the claimed outcome of killing cancer stem cells. Therefore, the examiner considers the intended outcome recited in instant claim 15 to be a natural consequence of following the teachings of the prior art. See MPEP 2112.
With regard to claim 17, as noted above, the nanoparticles can successfully deliver their payload by intravenous injection.
With regard to claim 18, Yan discloses treating human subjects (0091) and the objective of any preclinical work (e.g. the mouse model disclosed by Kievit) is eventual use in humans, therefore administering the siRNA-loaded nanoparticles to a human would have been prima facie obvious to one of ordinary skill.
Conclusion
No claims are allowed.
Any inquiry concerning this communication or earlier communications from the examiner should be directed to KATHERINE PEEBLES whose telephone number is (571)272-6247. The examiner can normally be reached Monday through Friday: 9 am to 3 pm.
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/KATHERINE PEEBLES/Primary Examiner, Art Unit 1617