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 .
Response to Amendment/Status of Claims
Receipt of Arguments/Remarks filed on 12/03/2025 is acknowledged. Claims 3 and 20 were amended. Claims 1-20 are pending and under examination.
Response to Arguments
Applicant’s arguments and amendments, see page 5, filed 12/03/2025, with respect to the 35 U.S.C. 112(b) rejection of claims 3 and 20 have been fully considered and are persuasive due to the amendments to claims 3 and 20 to recite the proper claim dependency which corrects the antecedent basis issues. The 35 U.S.C. 112(b) rejection of claims 3 and 20 has been withdrawn.
The rejections below have been reiterated, and a response to arguments is provided below each of the rejections.
Priority
This application is a CON of PCT/US2021/049108 filed 09/03/2021 and claims benefit of 63/076,294, filed 09/09/2020 as reflected by the most recent filing receipt.
Claim Rejections - 35 USC § 103
The text of those sections of Title 35, U.S. Code not included in this action can be found in a prior Office action.
Claims 1-3 and 8-20 are rejected under 35 U.S.C. 103 as being unpatentable over Gradalis (WO 2011/079077, Published 30 June 2011) in view of Abdelaziz et al. (Journal of Controlled Release, 24 Nov 2017, vol. 269, pp. 374-392), both cited on an IDS.
Regarding claims 1-3, Gradalis teach a method of treating non-small cell lung cancer (NSCLC) in a patient comprising administering an expression vector plasmid comprising a bishRNA furin/GMCSF expression vector plasmid comprising a first nucleic acid insert encoding GM-CSF cDNA and a second nucleic acid insert encoding one or more short hairpin RNAs capable of hybridizing to a region of an mRNA transcript encoding furin, thereby inhibiting furin expression via RNA interference (page 5, lines 26-32 and page 6, lines 1-4). Gradalis teach the shRNA may be bifunctional, i.e., it may simultaneously incorporate siRNA (cleavage dependent RISC formatted), and either miRNA or miRNA-like (cleavage independent RIC formatted) motifs and inhibit furin in both a cleavage dependent RIC formatted and cleavage independent RISC formatted manner (page 7, lines 17-20).
Regarding claim 8, Gradalis teach the expression vector is a plasmid (page 5, lines 26-32).
Regarding claim 13, Gradalis recites a method of treating cancer by administering a therapeutically effective dose of the genetically modified cells (transfected with the expression vector comprising the first insert encoding GM-CSF and a second nucleic acid insert operably linked to the promoter, the second insert encoding one or more shRNA capable of hybridizing to a region of a mRNA transcript encoding furin thereby inhibiting furin expression via RNA interference), to the subject in an amount sufficient to treat or ameliorating the symptoms of the cancer, with claim 50 reciting the cancer may be non-small-cell lung cancer.
Regarding claim 15, Gradalis teach the GM-CSF is a human GM-CSF (page 3, line 14 and page 4, line 10).
Regarding claim 16, Gradalis teach the expression vector comprises a promoter, as it teaches the first nucleic acid insert is operably linked to a promoter, and the second nucleic acid insert operably linked to a promoter, and teaches the construct has a single mammalian promoter (CMV) that drives the entire cassette (page 5, lines 16-18; page 27, line 28).
Gradalis does not teach administering an inhalable dosage form comprising the expression vector, and does not teach a stabilizing excipient, and does not teach delivering the expression vector to the respiratory tract of a subject by aerosolizing a dry powder formulation and administering the aerosolized particles to the subject.
However, before the effective filing date, Abdelaziz et al. teach that there is a progressive evolution in the use of inhalable drug delivery systems for lung cancer therapy, and that the inhalation route offers many advantages, being non-invasive and localized delivery of anti-cancer drugs to tumor tissue (Abstract). Abdelaziz et al. teach lung cancer is highly fatal, and became the major cause of an all cancer-associated deaths all over the world by the end of the twentieth century, and that histologically, two types of lung cancer could be distinguished, small cell lung carcinoma and non-small cell lung carcinoma, and that NSCLC is usually diagnosed at a late stage with poor prognosis (Introduction, first paragraph). Abdelaziz et al. teach surgery, chemotherapy, radiotherapy and targeted therapies are the main treatment modalities depending on the treatment stage, but usually surgery is ineligible due to the patient’s advanced stage, and therefore chemotherapy is usually the major treatment of lung cancer.
However, Abdelaziz et al. teach benefits of inhalation treatment compared to systemic chemotherapy, as inhalation treatment locally delivers the chemotherapeutic agent to tumor tissues enhancing its efficacy and lowering systemic side effects, and increases patient comfort (Page 375, left column).
Abdelaziz et al. teach dry powder inhalers as a solid-based delivery system can overcome problems encountered by nebulization, offering several benefits including being propellant free, easy to handle, easy to operate, and improved long term stability (page 382, Section 3.2). Abdelaziz et al. teach to ensure sufficient delivery of inhaled particles deeply into the lungs, particles should possess an aerodynamic diameter of 1-5 micrometers (page 382, Section 3.2). Abdelaziz et al. teach preparing an inhalable dry powder of siRNA and chitosan in the presence of mannitol using supercritical carbon dioxide and biodistribution studies showed the inhalable powder could provide extended exposure and higher concentrations of siRNA/chitosan complex on lung surface (page 385, left column).
Abdelaziz et al. also teach dry powder inhaler formulations developed by lyophilization of liposomes in the presence of trehalose (stabilizing excipient), and formulations displayed suitable aerodynamic properties for deep lung deposition and no change was detected in supercoiled DNA of the lipoplexes during aerosolization, reflecting pure and stable pDNA with powerful transfection (page 385, right column).
Therefore, Abdelaziz et al. teach the remaining limitations regarding the inhalable dosage form and stabilizing excipient of claims 1,9 and 10, and that the inhalable dosage form has particles as in claim 9 as well as the particle size encompassed by claims 11-12, dry powder inhaler formulations that are lyophilized for claims 14,17-19, and that dry powder inhaler formulations were aerosolized for claim 20.
Therefore, it would have been obvious to one of ordinary skill in the art before the effective filing date, to have combined the lung tumor treatment method of Gradalis using the bishRNA furin/GMCSF expression vector plasmid with the teachings of Abdelaziz et al. regarding the benefits of inhalable drug delivery systems for lung cancer treatment to have arrived at the instant claims with a reasonable expectation of success. There would be a reasonable expectation of success as both Gradalis and Abdelaziz et al. pertain to treating lung cancer, and amount to applying a known technique of inhalable particulate drug delivery for lung cancer therapy to a known method of treating cancer using the plasmid vector of Gradalis ready for improvement to yield predictable results. One of ordinary skill in the art would have been motivated to administer the expression vector of Gradalis in an inhalable dosage form and wherein the dosage form contains a stabilizing excipient, because Abdelaziz et al. teach the benefits of inhalation treatment compared to systemic chemotherapy for treating lung cancer, as inhalation treatment locally delivers the chemotherapeutic agent to tumor tissues enhancing its efficacy and lowering systemic side effects, and increases patient comfort (Page 375, left column) and that dry powder inhaler formulations developed by lyophilization of liposomes in the presence of trehalose (stabilizing excipient) displayed suitable aerodynamic properties for deep lung deposition and no change was detected in supercoiled DNA of the lipoplexes during aerosolization, reflecting pure and stable pDNA with powerful transfection (page 385, right column).
Accordingly, the limitations of claims 1-3,8-10 and 14-20 would have been prima facie obvious to one of ordinary skill in the art.
It would have been obvious to one of ordinary skill in the art before the effective filing date, to have combined the lung tumor treatment method of Gradalis using the bishRNA furin/GMCSF expression vector plasmid with the teachings of Abdelaziz et al. regarding the benefits of inhalable drug delivery systems for lung cancer treatment to have arrived at the instant claims with a reasonable expectation of success. There would be a reasonable expectation of success as both Gradalis and Abdelaziz et al. pertain to treating lung cancer, and amount to applying a known technique of inhalable particulate drug delivery for lung cancer therapy to a known method of treating cancer using the plasmid vector of Gradalis ready for improvement to yield predictable results. One of ordinary skill in the art would have been motivated to administer the expression vector of Gradalis in an inhalable dosage form comprising particles having diameter from about 0.5-10 micrometers or 1-3 micrometers, because Abdelaziz et al. teach dry powder inhalers as a solid-based delivery system can overcome problems encountered by nebulization, offering several benefits including being propellant free, easy to handle, easy to operate, and improved long term stability (page 382, Section 3.2) and to ensure sufficient delivery of inhaled particles deeply into the lungs, particles should possess an aerodynamic diameter of 1-5 micrometers (page 382, Section 3.2), and therefore falls within the recited particle diameter. Abdelaziz et al. teach preparing an inhalable dry powder of siRNA and chitosan in the presence of mannitol using supercritical carbon dioxide and biodistribution studies showed the inhalable powder could provide extended exposure and higher concentrations of siRNA/chitosan complex on lung surface (page 385, left column).
Accordingly, the limitations of claims 11-12 would have been prima facie obvious to one of ordinary skill in the art.
It would have been obvious to one of ordinary skill in the art, to have arrived at the limitations of claim 13 reciting the expression vector is present from about 1-10% by weight based on the teachings of Gradalis with a reasonable expectation of success as Gradalis teach administering a therapeutically effective dose in an amount sufficient to treat or ameliorate the symptoms of the cancer, which may be non-small-cell lung cancer. The amount of a specific ingredient in a composition is clearly a result effective parameter that a person of ordinary skill in the art would routinely optimize. Optimization of parameters is a routine practice that would be obvious for a person of ordinary skill in the art to employ and reasonably would expect success. It would have been customary for an artisan of ordinary skill to determine the optimal amount of each ingredient to add in order to best achieve the desired results, such as to provide the optimal therapeutic level of the expression vector upon administration to treat lung cancer. The amount of an active ingredient is a parameter that a person of ordinary skill in the art would routinely optimize based on the condition being treated, severity or stage of the condition, desired dosing frequency, weight and age of the subject, among other factors. It would have been obvious to one of ordinary skill in the art at the time of the invention to engage in routine experimentation to determine optimal or workable ranges that produce expected results. Where the general conditions of a claim are disclosed in the prior art, it is not inventive to discover the optimum or workable ranges by routine experimentation. In re Aller, 220 F. 2d 454, 105 USPQ 233 (CCPA 1955). NOTE: MPEP 2144.05.
In addition, while the exact precent by weight of the vector is not disclosed by Gradalis, it is generally noted that differences in percent by weight of an active ingredient do not support the patentability of subject matter encompassed by the prior art unless there is evidence indicating such percent by weight is critical. "[W]here the general conditions of a claim are disclosed in the prior art, it is not inventive to discoverthe optimum or workable ranges by routine experimentation." In re Aller, 220 F.2d 454,456, 105 USPQ 233, 235 (CCPA 1955). Given that applicant did not point out the criticality of the percent by weight of the vector of the invention, it is concluded that the normal desire of scientists or artisans to improve upon what is already generally known would provide the motivation to determine wherein a disclosed set of ranges is the optimum percent by weight. NOTE: MPEP 2144.05.
Accordingly, the limitations of claim 13 would have been prima facie obvious to one of ordinary skill in the art.
Response to Arguments
Applicant's arguments filed 12/03/2025 have been fully considered but they are not persuasive.
Applicant argues on page 6 that Gradalis does not teach or suggest an inhalable, dry powder formulation, and is focused on ex vivo cell vaccines, not direct pulmonary delivery of a plasmid or expression vector formulated as a dry powder for inhalation, and there is no teaching of suggestion of formulating the expression vector with a stabilizing excipient, nor of pulmonary, inhaled, or deep-lung delivery. Applicant argues the Abdelaziz provides a broad review of inhalable drug delivery systems for lung cancer therapy and general statements about dry powder inhalers, particle size and use of excipients such as trehalose, but does not disclose, suggest or enable the combination of a bishRNA furin/GM-CSF expression vector in a dry powder inhalable form with specific stabilizing excipients for treatment of lung tumors. Abdelaziz does not teach or suggest the use of the specific expression vector in the claims or the context of the precise particle size ranges, excipient identities and functional attributes recited.
This is not found persuasive. Regarding Applicant’s argument that Gradalis does not teach or suggest an inhalable dry powder formulation and that Gradalis provides a broad review of inhalable drug delivery systems for lung cancer therapy, and is focused on ex vivo cell vaccines, one cannot show nonobviousness by attacking references individually where the rejections are based on combinations of references. In re Keller, 642 F.2d 413, 208 USPQ 871 (CCPA 1981); In re Merck & Co., Inc., 800 F.2d 1091, 231 USPQ 375 (Fed. Cir. 1986). Where a rejection of a claim is based on two or more references, a reply that is limited to what a subset of the applied references teaches or fails to teach, or that fails to address the combined teaching of the applied references may be considered to be an argument that attacks the reference(s) individually. Where an applicant’s reply establishes that each of the applied references fails to teach a limitation and addresses the combined teachings and/or suggestions of the applied prior art, the reply as a whole does not attack the references individually as the phrase is used in Keller and reliance on Keller would not be appropriate. This is because "[T]he test for obviousness is what the combined teachings of the references would have suggested to [a PHOSITA]." In re Mouttet, 686 F.3d 1322, 1333, 103 USPQ2d 1219, 1226 (Fed. Cir. 2012). The examiner provided reasons in the rejection for combining the references regarding the teachings of Abdelaziz et al. teaching benefits of inhalable drug delivery systems for lung cancer, and that both Gradalis and Abdelaziz et al. pertain to treatment of lung cancer. Abdelaziz et al. taught dry powder formulations developed by lyophilization of liposomes in the presence of trehalose, and formulations displayed suitable aerodynamic properties for deep lung deposition and no change in the supercoiled DNA of the lipoplexes during aerosolization, reflecting pure and stable pDNA with powerful transfection (office action page 7). Therefore, the office action cited support in Abdelaziz et al. regarding dry powder inhaler formulations containing pDNA (plasmid DNA) being stable and having powerful transfection. Since Abdelaziz et al. taught that plasmid DNA can be stable and delivered in the form of a dry powder inhaler formulation, there would be a reasonable expectation of success that the composition comprising the bishRNA and GMCSF expression vector plasmid of Gradalis would have a reasonable expectation of success as being delivered as an inhalable dosage form and dry powder formulation. In addition, the part of Gradalis that the examiner cited in the original rejection was page 5, lines 26-32 to page 6, lines 1-4 of Gradalis, which does not even mention ex vivo cells, and recites administering the FANG vaccine comprising a bishRNA/GMCSF expression vector plasmid, wherein the vector plasmid comprises a first nucleic acid insert operably linked to a promoter, wherein the first insert encodes GM-CSF cDNA, a second nucleic acid insert operably linked to the promoter, wherein the second insert encodes one or more short hairpin RNAs (shRNA) capable of hybridizing to a region of a mRNA transcript encoding furin. To provide further support regarding a reasonable expectation of success that a expression vector plasmid can be formulated for inhalation including a dry powder formulation, before the effective filing date, Chow et al. (Advanced Drug Delivery Reviews 168 (2021) 217-228, available online 5 June 2020) taught the feasibility of nebulising pDNA into inhalable aerosols was demonstrated over two decades ago, as Schwarz et al., Eastman et al. and other groups reported aerosolization of pDNA conjugated to cationic lipids using jet nebulisers with bioactivity retained both in vitro and in vivo (page 220, Section 4.1.1). Table 1 also shows delivery vectors and nebulisers used in studies for nebulization of plasmid DNAs and mRNAs (page 222). Chow et al. also teaches the first reported respirable formulation of pDNAs could be dated back to 2002, when Seville et al. proposed the feasibility of utilising SD to manufacture respirable powders of pDNA conjugated with a nonviral lipid-polycation delivery vector, and that during the same period, Okamoto et al. in Japan began their investigation on employing SCF drying to prepare inhalable dry powder of pDNA and later confirmed their improved pDNA stability during manufacturing and storage for up to 4 weeks (page 222, Section 4.2.1). Table 2 also shows delivery vectors, excipients used in powder formulations of plasmid DNA and mRNAs which are relevant for pulmonary delivery (page 224). Therefore, based on what was known in the art before the effective filing date as shown by Chow et al., there would be a reasonable expectation of success in combining Gradalis and Abdelaziz et al. Obviousness does not require absolute predictability, however, at least some degree of predictability is required. Evidence showing there was no reasonable expectation of success may support a conclusion of nonobviousness. NOTE: MPEP 2143.02. The examiner maintains that there would be a reasonable expectation of success that the composition of Gradalis can be modified and delivered as an inhalable dosage form including as a dry powder inhalation formulation.
Regarding Applicant’s arguments that Abdelaziz provides a broad review of inhalable drug delivery systems for lung cancer therapy and general statements about dry powder inhalers, particle size and use of excipients such as trehalose, but does not disclose, suggest or enable the combination of a bishRNA furin/GM-CSF expression vector in a dry powder inhalable form with specific stabilizing excipients for treatment of lung tumors, the rejection is made under 103 and does not need to exemplify all embodiments, only suggest. “Disclosed examples and preferred embodiments do not constitute a teaching away from the broader disclosure or non-preferred embodiment.” In re Susi, 440 F.2d 442, 169 USPQ 423 (CCPA 1971). MPEP 2123. Therefore, applicant’s arguments that Abdelaziz provides a broad review and general statements about dry powder inhalers, particle size and use of excipients is not found persuasive as broad disclosure is still art. As stated above, Abdelaziz et al. taught dry powder formulations developed by lyophilization of liposomes in the presence of trehalose, and formulations displayed suitable aerodynamic properties for deep lung deposition and no change in the supercoiled DNA of the lipoplexes during aerosolization, reflecting pure and stable pDNA with powerful transfection (office action page 7).
Applicant argues unexpected results on page 6 based on data from Examples 2 and 3 demonstrating the claimed inhalable formulation preserves plasmid integrity and function after lyophilization and aerosolization, with successful transfection and GM-CSF expression in target cells, which results are not predictable based on the cited art given challenges of formulating nucleic acids for inhalation and maintaining biological activity after aerosolization and lung delivery.
This is not found persuasive. The examples cited by Applicant do not show that the results are unexpected or surprising and do not show any comparisons to show there is an unexpected effect in any cell line, and only show the effect of the claimed composition in different cell lines. While there might be differences in cell lines, any differences between the claimed invention and the prior art may be expected to result in some differences in properties. The issue is whether the properties differ to such an extent that the difference is really unexpected. An unexpected property or result must actually be unexpected and of statistical and practical significance. The burden is on the applicant to establish the results are in fact unexpected, unobvious and of statistical and practical significance. See MPEP 716.02.
In addition to not seeing unexpected results, it is also noted that the examples cited by applicant are not commensurate in scope with the claims. Whether the unexpected results are the result of unexpectedly improved results or a property not taught by the prior art, the "objective evidence of nonobviousness must be commensurate in scope with the claims which the evidence is offered to support." In other words, the showing of unexpected results must be reviewed to see if the results occur over the entire claimed range. In re Clemens, 622 F.2d 1029, 1036, 206 USPQ 289, 296 (CCPA 1980). See also In re Peterson, 315 F.3d 1325, 1329-31, 65 USPQ2d 1379, 1382-85 (Fed. Cir. 2003). Note: MPEP 716.02(d).
In this case, Examples 2 and 3 are not commensurate in scope with the claims, because these examples pertain to transfection efficiencies of the lyophilized particles in cell lines which are human colorectal carcinoma cell lines and human bone Ewing’s sarcoma cell line (paragraphs 0114,0119) and a human lung cancer cell line (paragraph 0119) and which are transfected by electroporation (paragraph 0115). Example 3, paragraph 0122 discloses that raw furin expression is 2x higher in the Calu-3 cells compared to CCL-247 and RD-ES cells, and furin knockdown occurred in all 3 cell lines, but 2x less in Calu-3 (the human lung cancer cell line). Example 3 paragraph 0123 also shows GM-CSF expression was lower in Calu-3 and A-549 cell lines (human non-small cell lung cancer cell line). The claims recite a method for treating a tumor in a subject and administering to the subject an inhalable dosage form, while the unexpected results argued by applicant occur in cell lines including cell lines that are not lung cancer cell lines and are not in vivo in a subject, and are delivered to the cells by electroporation, not by an inhalable dosage form. In addition, it is noted that Example 2 paragraph 0117 states Lipo 3000 and “Lyo DNA” with 5% trehalose yielded the best GM-CSF expression. Example 3, paragraph 0210 shows using mannitol as the excipient. This also shows the that results are not commensurate in scope with the claims, as claims 1-8,13,15-20 do not recite a specific stabilizing excipient, and claims 9,11-12,14 lists multiple stabilizing excipients and claim 10 recites the stabilizing excipient is trehalose. Therefore, even applicant’s examples show higher knockdown in some cell lines and less knockdown in other cells lines, and better results using specific excipients.
Applicant argues on page 7 that the Examiner’s rationale for combining references is based on general statements about the desirability of pulmonary delivery for lung cancer, but there is no teaching, suggestion or motivation in the prior art to combine the specific Gradalis vector technology with the dry powder inhalation formulation approaches of Abdelaziz. Applicant argues the unpredictable nature of nucleic acid stability, transfection efficiency and in vivo lung delivery against any reasonable expectation of success. Applicant cites MPEP 2143 and DyStar Textilfarben GmbH & Co. Deutschland KG v. C.H. Patrick Co., 464 F.3d 1356, 1360,80 USPQ2d 1641,1645 (Fed. Cir. 2006). Applicant argues that the nucleic acid delivery systems described in Abdelaziz are not gene therapy in the sense of the Gradalis construct (no large plasmid vectors; mostly siRNA or short oligos, not complex, regulated expression constructs), and no examples in Abdelaziz involving inhalation of large plasmid nucleic acid vectors intended for gene transfer or gene therapy, nor any ex vivo cell-based therapeutic paradigm. Applicant argues the different properties of plasmid vs siRNA/oligonucleotides, and that formulation, stability and delivery challenges for plasmid nucleic acid are fundamentally different than for small oligonucleotides or small-molecule drugs. Applicant argues on page 8 that Gradalis is focused on an ex vivo approach, not in vivo delivery, and emphasizes the importance of ex vivo manipulation of autologous cells, and the “vaccine” is not a product intended for directly inhalation. Applicant argues Abdeliziz’s discussion of inhalable nucleic acid delivery is limited to siRNA/oligonucleotides, not plasmid DNA or gene therapy constructs.
Regarding Applicant’s argument that the Examiner’s rationale for combining references is based on general statements about the desirability of pulmonary delivery for lung cancer, this is not found persuasive. MPEP 2143 G. states, “The courts have made clear that the teaching, suggestion, or motivation test is flexible and an explicit suggestion to combine the prior art is not necessary. The motivation to combine may be implicit and may be found in the knowledge of one of ordinary skill in the art, or, in some cases, from the nature of the problem to be solved. Id. at 1366, 80 USPQ2d at 1649. "[A]n implicit motivation to combine exists not only when a suggestion may be gleaned from the prior art as a whole, but when the ‘improvement’ is technology-independent and the combination of references results in a product or process that is more desirable, for example because it is stronger, cheaper, cleaner, faster, lighter, smaller, more durable, or more efficient. Because the desire to enhance commercial opportunities by improving a product or process is universal—and even common-sensical—we have held that there exists in these situations a motivation to combine prior art references even absent any hint of suggestion in the references themselves. In such situations, the proper question is whether the ordinary artisan possesses knowledge and skills rendering him capable of combining the prior art references." Id. at 1368, 80 USPQ2d at 1651”. The examiner stated in the rejection that Abdelaziz et al. teach the benefits of inhalation treatment as delivering the therapeutic agent to tumor tissues enhancing its efficacy and lowering systemic side effects and increasing patient comfort, and how dry powder inhalers can overcome problems encountered by nebulization, offering benefits of being propellant free, easy to handle, and improved long term stability, and taught an inhalable dry powder of siRNA and chitosan and mannitol could provide extended exposure and higher concentrations on the lung surface (office action, page 6).
Regarding Applicant’s argument pertaining to the small nucleic acids taught by Abdelaziz are not gene therapy in the sense of the Gradalis construct, and the different properties of plasmid vs siRNA/oligonucleotides, and that formulation, stability and delivery challenges for plasmid nucleic acid are fundamentally different than for small oligonucleotides or small-molecule drugs, this is not found persuasive. Abdelaziz et al. taught dry powder formulations developed by lyophilization of liposomes in the presence of trehalose, and formulations displayed suitable aerodynamic properties for deep lung deposition and no change in the supercoiled DNA of the lipoplexes during aerosolization, reflecting pure and stable pDNA with powerful transfection (office action page 7). Therefore, the office action cited support in Abdelaziz et al. regarding dry powder inhaler formulations containing pDNA (plasmid DNA) being stable and having powerful transfection.
To provide further support, before the effective filing date, Chow et al. (Advanced Drug Delivery Reviews 168 (2021) 217-228, available online 5 June 2020) taught the feasibility of nebulising pDNA into inhalable aerosols was demonstrated over two decades ago, as Schwarz et al., Eastman et al. and other groups reported aerosolization of pDNA conjugated to cationic lipids using jet nebulisers with bioactivity retained both in vitro and in vivo (page 220, Section 4.1.1). Table 1 also shows delivery vectors and nebulisers used in studies for nebulization of plasmid DNAs and mRNAs (page 222). Chow et al. also teaches the first reported respirable formulation of pDNAs could be dated back to 2002, when Seville et al. proposed the feasibility of utilising SD to manufacture respirable powders of pDNA conjugated with a nonviral lipid-polycation delivery vector, and that during the same period, Okamoto et al. in Japan began their investigation on employing SCF drying to prepare inhalable dry powder of pDNA and later confirmed their improved pDNA stability during manufacturing and storage for up to 4 weeks (page 222, Section 4.2.1). Table 2 also shows delivery vectors, excipients used in powder formulations of plasmid DNA and mRNAs which are relevant for pulmonary delivery (page 224). Therefore, based on what was known in the art before the effective filing date as shown by Chow et al., there would be a reasonable expectation of success in combining Gradalis and Abdelaziz et al. Obviousness does not require absolute predictability, however, at least some degree of predictability is required. Evidence showing there was no reasonable expectation of success may support a conclusion of nonobviousness. NOTE: MPEP 2143.02.
For the reasons above, the 35 U.S.C. 103 rejection of claims 1-3 and 8-20 as unpatentable over Gradalis in view of Abdelaziz et al. is maintained.
Claims 4-6 are rejected under 35 U.S.C. 103 as being unpatentable over Gradalis and Abdelaziz et al. as applied to claims 1-3,8-12 and 14-20 above, and further in view of Herold et al. (Eur. Radiol. 6, 596-606 (1996)).
The teachings of Gradalis and Abdelaziz et al. as applicable to claims 1-3,8-12 and 14-20 are described above.
Gradalis and Abdelaziz et al. do not teach wherein the tumor in the lung is caused by a metastatic event from a cancer in a different part of the subject’s body.
However, before the effective filing date, Herold et al. teach metastases are the most common malignant tumors found in the lung and the lungs are the organs that acquire the most metastases of any system in the entire body, because the lungs receive the entire cardiac output every minute, have the densest capillary bed in the body and are the first capillary plexus that most of the lymphatic drainage meets after entering the venous system (Page 597, left column). In addition, the lung consists of a meshwork of delicate membranes that easily entrap tumor cells which can readily draw on nearby oxygenated air for sustenance, and it is easily understood that metastases show a distinct tendency to develop in the lungs (Page 597, left column). Herold et al. teach virtually any malignancy may spread to the lungs, but the most common metastases stem from malignancies that arise in the male and female genital tracts, breast, colon, stomach, pancreas, kidney, skin, prostate, liver, thyroid and adrenal glands, and malignancies may spread to the lungs by different routes (page 597, left column). Herold et al. teach in general, metastases to the lung are found during the staging and follow-up of patients with known malignant disorders (page 596, Intro.).
Therefore, it would have been obvious to one of ordinary skill in the art before the effective filing date, that the combined teachings of Gradalis and Abdelaziz et al. be applied to treat a tumor in the lungs that is caused by a metastatic event from a cancer from a different part of the subject’s body, including from the breast, pancreas, kidney, skin, stomach, liver, male and female genital tracts, and thyroid, based on the teachings of Herold et al., with a reasonable expectation of success. There would be a reasonable expectation of success, because both Gradalis and Abdelaziz pertain to treating lung cancer, and it would be obvious to apply the combined teachings of Gradalis and Abdelaziz et al. to treat a lung tumor caused by a metastatic event from a different part of the subject’s body using known methods to yield predictable results. One of ordinary skill in the art would be motivated to apply the combined teachings of Gradalis and Abdelaziz et al. to treat a tumor in the lungs that is caused by a metastatic event from a cancer from a different part of the subject’s body, including from the breast, pancreas, kidney, skin, stomach, liver, male and female genital tracts, and thyroid, because Herold et al. teach metastases are the most common malignant tumors found in the lung and the lungs are the organs that acquire the most metastases of any system in the entire body, and Herold et al. teach that the most common metastases stem from malignancies that arise in the male and female genital tracts, breast, colon, stomach, pancreas, kidney, skin, prostate, liver, thyroid and adrenal glands, and malignancies may spread to the lungs by different routes (page 597, left column). Therefore, Herold et al. teach the obviousness of lung tumors being caused from cancer metastases from other parts of the body and would be obvious to use the combined methods of Gradalis and Abdelaziz et al. to apply the treatment to these lung tumors.
Accordingly the limitations of claims 4-6 would have been prima facie obvious to one of ordinary skill in the art before the effective filing date.
Response to Arguments
Applicant's arguments filed 12/03/2025 have been fully considered but they are not persuasive.
Applicant argues on page 8 that Herold et al. does not teach or suggest the claimed methods, vectors or formulations and the prior art does not provide motivation or reasonable expectation of success in treating metastatic lung tumors with the claimed inhalable bishRNA furin/GMCSF vector formulation. Applicant refers to the previous arguments and rationale set forth above, and that the mere recognition that metastatic tumors can occur in the lung does not render the presently claimed, highly specific inhalable gene therapy formulation obvious, and there is no suggestion in the cited art that the claimed method would be effective or feasible for treating metastatic lung tumors with the specific inhalable gene therapy product described herein.
This is not found persuasive. As the examiner argued above, one cannot show nonobviousness by attacking references individually where the rejections are based on combinations of references. In re Keller, 642 F.2d 413, 208 USPQ 871 (CCPA 1981); In re Merck & Co., Inc., 800 F.2d 1091, 231 USPQ 375 (Fed. Cir. 1986). The examiner provided support from Herold et al. regarding metastases being the most common malignant tumors found in the lung and that the lungs acquire the most metastases of any system in the body (office action page 11). Therefore, it is reasonable to conclude that the teachings of Gradalis and Abdelaziz et al. could be applied to treating a tumor in the lung caused by metastatic cancer from another part of the body.
Applicant argues on pages 8-9 that the pending claim address the challenge of delivering a functional gene therapy vector directly to the lung in a form that is stable, efficiently delivered and therapeutically effective, overcoming specific obstacles not addressed in Gradalis or Abdelaziz, and the use of specific stabilizing excipients (e.g., trehalose), precise particle size ranges, and lyophilization procedures not taught or suggested in the context of gene therapy for lung tumors.
This is not found persuasive because Abdelaziz et al. taught that the size of particles should have a diameter of 1-5 micrometers, and discussed dry powder formulations of siRNA and mannitol, as well as using trehalose in preparing dry powder inhaler formulations which displayed suitable aerodynamic properties for deep lung deposition and no change in the supercoiled DNA of the lipoplexes during aerosolization, reflecting pure and stable pDNA with powerful transfection (office action page 7).
Double Patenting
The nonstatutory double patenting rejection is based on a judicially created doctrine grounded in public policy (a policy reflected in the statute) so as to prevent the unjustified or improper timewise extension of the “right to exclude” granted by a patent and to prevent possible harassment by multiple assignees. A nonstatutory double patenting rejection is appropriate where the conflicting claims are not identical, but at least one examined application claim is not patentably distinct from the reference claim(s) because the examined application claim is either anticipated by, or would have been obvious over, the reference claim(s). See, e.g., In re Berg, 140 F.3d 1428, 46 USPQ2d 1226 (Fed. Cir. 1998); In re Goodman, 11 F.3d 1046, 29 USPQ2d 2010 (Fed. Cir. 1993); In re Longi, 759 F.2d 887, 225 USPQ 645 (Fed. Cir. 1985); In re Van Ornum, 686 F.2d 937, 214 USPQ 761 (CCPA 1982); In re Vogel, 422 F.2d 438, 164 USPQ 619 (CCPA 1970); In re Thorington, 418 F.2d 528, 163 USPQ 644 (CCPA 1969).
A timely filed terminal disclaimer in compliance with 37 CFR 1.321(c) or 1.321(d) may be used to overcome an actual or provisional rejection based on nonstatutory double patenting provided the reference application or patent either is shown to be commonly owned with the examined application, or claims an invention made as a result of activities undertaken within the scope of a joint research agreement. See MPEP § 717.02 for applications subject to examination under the first inventor to file provisions of the AIA as explained in MPEP § 2159. See MPEP § 2146 et seq. for applications not subject to examination under the first inventor to file provisions of the AIA . A terminal disclaimer must be signed in compliance with 37 CFR 1.321(b).
The filing of a terminal disclaimer by itself is not a complete reply to a nonstatutory double patenting (NSDP) rejection. A complete reply requires that the terminal disclaimer be accompanied by a reply requesting reconsideration of the prior Office action. Even where the NSDP rejection is provisional the reply must be complete. See MPEP § 804, subsection I.B.1. For a reply to a non-final Office action, see 37 CFR 1.111(a). For a reply to final Office action, see 37 CFR 1.113(c). A request for reconsideration while not provided for in 37 CFR 1.113(c) may be filed after final for consideration. See MPEP §§ 706.07(e) and 714.13.
The USPTO Internet website contains terminal disclaimer forms which may be used. Please visit www.uspto.gov/patent/patents-forms. The actual filing date of the application in which the form is filed determines what form (e.g., PTO/SB/25, PTO/SB/26, PTO/AIA /25, or PTO/AIA /26) should be used. A web-based eTerminal Disclaimer may be filled out completely online using web-screens. An eTerminal Disclaimer that meets all requirements is auto-processed and approved immediately upon submission. For more information about eTerminal Disclaimers, refer to www.uspto.gov/patents/apply/applying-online/eterminal-disclaimer.
Claims 1-20 are provisionally rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1-3,5,9 and 11-13 of copending Application No. 18/709,783 (‘783) in view of Abdelaziz et al. (Journal of Controlled Release, 24 Nov 2017, vol. 269, pp. 374-392), cited on an IDS.
Instant claims 1-20 recite a method for treating a tumor in the lung of a subject, the method comprising: administering to the subject an inhalable dosage form, comprising: a. an expression vector comprising i. a first insert comprising a nucleic acid sequence encoding a Granulocyte Macrophage Colony Stimulating Factor (GM-CSF) sequence; and ii. a second insert comprising a nucleic acid sequence encoding at least one bi- functional short hairpin RNA (bi-shRNA) capable of hybridizing to a region of a mRNA transcript encoding furin, thereby inhibiting furin expression via RNA interference wherein the bi-shRNA incorporates cleavage dependent siRNA and cleavage independent miRNA motifs; and b. at least one stabilizing excipient, to thereby treat the tumor. Instant claim 7 recites the expression vector comprises a nucleic acid sequence of SEQ ID NO: 2 or 9, and claims 9,14,17-19 recite more details about the inhalable dosage forming comprising particles, lyophilized particles, and being formulated for pulmonary delivery with an inhaler or nebulizer.
Claims 1-3,5,9 and 11-13 of ‘783 recite a method of treating an individual having cancer comprising: administering to the individual a therapy comprising an expression vector having (i) a first insert comprising a nucleic acid sequence encoding a Granulocyte Macrophage Colony Stimulating Factor (GM-CSF) sequence; and (ii) a second insert, wherein the second insert encodes one or more bifunctional short hairpin RNAs (shRNA) capable of hybridizing to one of more regions of a mRNA transcript encoding furin, wherein at least one of the regions is selected from base sequences 300-318, 731-740, 1967- 1991, 2425-2444, 2827-2851 or 2834-2852 of SEQ ID NO:1, thereby inhibiting furin expression via RNA interference, wherein each bifunctional short hairpin RNA comprises a first stem-loop structure that comprises an siRNA component and a second stem-loop structure that comprises a miRNA component and wherein the shRNA incorporates siRNA (cleavage dependent) and miRNA (cleavage-independent) motifs, wherein the therapy improves the treatment response in the individual with the elevated expression level compared to a patient with a tumor having a low expression level of the gene. Therefore, the expression vector of ‘783 is a species of the expression vector of the instant claims because it recites specific nucleotide sequences within SEQ ID NO:1 that the shRNA hybridizes to, and therefore the instant claims anticipate the expression vector of ‘783.
Claim 3 of ‘783 recites the second insert comprises a sequence having at least 90% identity to the sequence of SEQ ID NO: 2. SEQ ID NO: 2 of ‘783 is a 100% identical to instant SEQ ID NOs: 2 and 9 recited in instant claim 7.
Claim 9 of ‘783 recites the cancer is selected from the group consisting of ovarian cancer, breast cancer, melanoma and lung cancer, and therefore teaches treating lung cancer with an expression vector encompassed by the instant claims.
‘783 does not recite administering an inhalable dosage form comprising the expression vector and a stabilizing excipient.
However, before the effective filing date, Abdelaziz et al. teach that there is a progressive evolution in the use of inhalable drug delivery systems for lung cancer therapy, and that the inhalation route offers many advantages, being non-invasive and localized delivery of anti-cancer drugs to tumor tissue (Abstract). Abdelaziz et al. teach lung cancer is highly fatal, and became the major cause of an all cancer-associated deaths all over the world by the end of the twentieth century, and that histologically, two types of lung cancer could be distinguished, small cell lung carcinoma and non-small cell lung carcinoma, and that NSCLC is usually diagnosed at a late stage with poor prognosis (Introduction, first paragraph). Abdelaziz et al. teach surgery, chemotherapy, radiotherapy and targeted therapies are the main treatment modalities depending on the treatment stage, but usually surgery is ineligible due to the patient’s advanced stage, and therefore chemotherapy is usually the major treatment of lung cancer.
However, Abdelaziz et al. teach benefits of inhalation treatment compared to systemic chemotherapy, as inhalation treatment locally delivers the chemotherapeutic agent to tumor tissues enhancing its efficacy and lowering systemic side effects, and increases patient comfort (Page 375, left column).
Abdelaziz et al. teach dry powder inhalers as a solid-based delivery system can overcome problems encountered by nebulization, offering several benefits including being propellant free, easy to handle, easy to operate, and improved long term stability (page 382, Section 3.2). Abdelaziz et al. teach to ensure sufficient delivery of inhaled particles deeply into the lungs, particles should possess an aerodynamic diameter of 1-5 micrometers (page 382, Section 3.2). Abdelaziz et al. teach preparing an inhalable dry powder of siRNA and chitosan in the presence of mannitol using supercritical carbon dioxide and biodistribution studies showed the inhalable powder could provide extended exposure and higher concentrations of siRNA/chitosan complex on lung surface (page 385, left column).
Abdelaziz et al. teach dry powder inhaler formulations developed by lyophilization of liposomes in the presence of trehalose (stabilizing excipient), and formulations displayed suitable aerodynamic properties for deep lung deposition and no change was detected in supercoiled DNA of the lipoplexes during aerosolization, reflecting pure and stable pDNA with powerful transfection (page 385, right column).
Therefore, it would have been obvious to one of ordinary skill in the art before the effective filing date, to have combined the lung cancer treatment method of ‘783 using the bishRNA furin/GMCSF expression vector plasmid with the teachings of Abdelaziz et al. regarding the benefits of inhalable drug delivery systems for lung cancer treatment to have arrived at the instant claims with a reasonable expectation of success. There would be a reasonable expectation of success as both ‘783 and Abdelaziz et al. pertain to treating lung cancer, and amount to applying a known technique of inhalable particulate drug delivery for lung cancer therapy to a known method of treating cancer using the plasmid vector of ‘783 ready for improvement to yield predictable results. One of ordinary skill in the art would have been motivated to administer the expression vector of ‘783 in an inhalable dosage form and wherein the dosage form contains a stabilizing excipient, because Abdelaziz et al. teach the benefits of inhalation treatment compared to systemic chemotherapy for treating lung cancer, as inhalation treatment locally delivers the chemotherapeutic agent to tumor tissues enhancing its efficacy and lowering systemic side effects, and increases patient comfort (Page 375, left column) and that dry powder inhaler formulations developed by lyophilization of liposomes in the presence of trehalose (stabilizing excipient) displayed suitable aerodynamic properties for deep lung deposition and no change was detected in supercoiled DNA of the lipoplexes during aerosolization, reflecting pure and stable pDNA with powerful transfection (page 385, right column). One of ordinary skill in the art would have been motivated to administer the expression vector of ‘783 in an inhalable dosage form comprising particles having diameter from about 0.5-10 micrometers or 1-3 micrometers, because Abdelaziz et al. teach dry powder inhalers as a solid-based delivery system can overcome problems encountered by nebulization, offering several benefits including being propellant free, easy to handle, easy to operate, and improved long term stability (page 382, Section 3.2) and to ensure sufficient delivery of inhaled particles deeply into the lungs, particles should possess an aerodynamic diameter of 1-5 micrometers (page 382, Section 3.2), and therefore falls within the recited particle diameter. Abdelaziz et al. teach preparing an inhalable dry powder of siRNA and chitosan in the presence of mannitol using supercritical carbon dioxide and biodistribution studies showed the inhalable powder could provide extended exposure and higher concentrations of siRNA/chitosan complex on lung surface (page 385, left column).
This is a provisional nonstatutory double patenting rejection.
Response to Arguments
Applicant's arguments filed 12/03/2025 have been fully considered but they are not persuasive.
Applicant argues on page 9 that per MPEP 804 if a provisional nonstatutory double patenting rejection is the only rejection remaining in an application having the earlier patent term filing date, the examiner should withdraw the rejection in the application having the earlier patent term filing date, and that the present application has the earlier filing date.
This is not found persuasive because this is not the only rejection remaining in the application as the examiner has maintained the 35 U.S.C. 103 rejection above. See the response to the arguments above in the 103 rejections. Therefore, the examiner is maintaining this rejection.
Claims 1-20 are provisionally rejected on the ground of nonstatutory double patenting as being unpatentable over claims 11-13 and 15-18 of copending Application No. 18/285,214 (‘214) in view of Gradalis (WO 2011/079077) and Abdelaziz et al., cited above.
Instant claims 1-20 recite a method for treating a tumor in the lung of a subject, the method comprising: administering to the subject an inhalable dosage form, comprising: a. an expression vector comprising i. a first insert comprising a nucleic acid sequence encoding a Granulocyte Macrophage Colony Stimulating Factor (GM-CSF) sequence; and ii. a second insert comprising a nucleic acid sequence encoding at least one bi- functional short hairpin RNA (bi-shRNA) capable of hybridizing to a region of a mRNA transcript encoding furin, thereby inhibiting furin expression via RNA interference wherein the bi-shRNA incorporates cleavage dependent siRNA and cleavage independent miRNA motifs; and b. at least one stabilizing excipient, to thereby treat the tumor, with claim 7 reciting the expression vector comprises a nucleic acid sequence of SEQ ID NO: 2 or 9, and claims 9,14,17-19 reciting more details about the inhalable dosage forming comprising particles, lyophilized particles, and being formulated for pulmonary delivery with an inhaler or nebulizer.
Claims 11-13 and 15-18 of ‘214 recite a method of treating cancer in a cancer patient in need thereof, comprising administering to the cancer patient an expression vector comprising: a first insert comprising a nucleic acid sequence encoding a Granulocyte Macrophage Colony Stimulating Factor (GM-CSF) sequence; and b) a second insert comprising a sequence according to SEQ ID NO:2. SEQ ID NO: 2 of ‘214 is 100% identical to instant SEQ ID NO: 9 recited in instant claim 7. Claim 33 of ‘214 recites the cancer is lung cancer, however this claim does not pertain to the method of treatment but the method of claim 1 for predicting responsiveness of a cancer in a cancer patient to cancer treatment with the recited expression vector.
While claim 33 of ‘214 refers to lung cancer, ‘214 does not recite treating lung cancer and administering an inhalable dosage form comprising the expression vector and a stabilizing excipient.
However, Gradalis teach a method of treating non-small cell lung cancer (NSCLC) in a patient comprising administering an expression vector plasmid comprising a bishRNA furin/GMCSF expression vector plasmid comprising a first nucleic acid insert encoding GM-CSF cDNA and a second nucleic acid insert encoding one or more short hairpin RNAs capable of hybridizing to a region of an mRNA transcript encoding furin, thereby inhibiting furin expression via RNA interference (page 5, lines 26-32 and page 6, lines 1-4). Gradalis teach the shRNA may be bifunctional, i.e., it may simultaneously incorporate siRNA (cleavage dependent RISC formatted), and either miRNA or miRNA-like (cleavage independent RIC formatted) motifs and inhibit furin in both a cleavage dependent RIC formatted and cleavage independent RISC formatted manner (page 7, lines 17-20).
The teachings of Abdelaziz et al. have been described above.
Therefore, it would have been obvious to one of ordinary skill in the art before the effective filing date, to have combined the cancer treatment method of ‘214 using the bishRNA furin/GMCSF expression vector plasmid with the teachings of Gradalis regarding using the same bishRNA furin/GMCSF expression vector plasmid to treat lung cancer and teachings of Abdelaziz et al. regarding the benefits of inhalable drug delivery systems for lung cancer treatment to have arrived at the instant claims with a reasonable expectation of success. There would be a reasonable expectation of success as the same expression vector is recited in ‘214 and Gradalis and are used for treating cancer, and Gradalis and Abdelaziz et al. pertain to treating lung cancer, and amount to applying a known technique of inhalable particulate drug delivery for lung cancer therapy to a known method of treating cancer using the plasmid vector of ‘214 ready for improvement to yield predictable results. One of ordinary skill in the art would have been motivated to administer the expression vector of ‘214 in an inhalable dosage form and wherein the dosage form contains a stabilizing excipient, because Abdelaziz et al. teach the benefits of inhalation treatment compared to systemic chemotherapy for treating lung cancer, as inhalation treatment locally delivers the chemotherapeutic agent to tumor tissues enhancing its efficacy and lowering systemic side effects, and increases patient comfort (Page 375, left column) and that dry powder inhaler formulations developed by lyophilization of liposomes in the presence of trehalose (stabilizing excipient) displayed suitable aerodynamic properties for deep lung deposition and no change was detected in supercoiled DNA of the lipoplexes during aerosolization, reflecting pure and stable pDNA with powerful transfection (page 385, right column). One of ordinary skill in the art would have been motivated to administer the expression vector of ‘214 in an inhalable dosage form comprising particles having diameter from about 0.5-10 micrometers or 1-3 micrometers, because Abdelaziz et al. teach dry powder inhalers as a solid-based delivery system can overcome problems encountered by nebulization, offering several benefits including being propellant free, easy to handle, easy to operate, and improved long term stability (page 382, Section 3.2) and to ensure sufficient delivery of inhaled particles deeply into the lungs, particles should possess an aerodynamic diameter of 1-5 micrometers (page 382, Section 3.2), and therefore falls within the recited particle diameter. Abdelaziz et al. teach preparing an inhalable dry powder of siRNA and chitosan in the presence of mannitol using supercritical carbon dioxide and biodistribution studies showed the inhalable powder could provide extended exposure and higher concentrations of siRNA/chitosan complex on lung surface (page 385, left column).
This is a provisional nonstatutory double patenting rejection.
Response to Arguments
Applicant's arguments filed 12/03/2025 have been fully considered but they are not persuasive.
Applicant argues on page 9 that per MPEP 804 if a provisional nonstatutory double patenting rejection is the only rejection remaining in an application having the earlier patent term filing date, the examiner should withdraw the rejection in the application having the earlier patent term filing date, and that the present application has the earlier filing date.
This is not found persuasive because this is not the only rejection remaining in the application as the examiner has maintained the 35 U.S.C. 103 rejection above. See the response to the arguments above in the 103 rejections. Therefore, the examiner is maintaining this rejection.
Claims 1-20 are provisionally rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1-20 of copending Application No. 17/977,979 (‘979) in view of Gradalis (cited above).
Instant claims 1-20 recite a method for treating a tumor in the lung of a subject, the method comprising: administering to the subject an inhalable dosage form, comprising: a. an expression vector comprising i. a first insert comprising a nucleic acid sequence encoding a Granulocyte Macrophage Colony Stimulating Factor (GM-CSF) sequence; and ii. a second insert comprising a nucleic acid sequence encoding at least one bi- functional short hairpin RNA (bi-shRNA) capable of hybridizing to a region of a mRNA transcript encoding furin, thereby inhibiting furin expression via RNA interference wherein the bi-shRNA incorporates cleavage dependent siRNA and cleavage independent miRNA motifs; and b. at least one stabilizing excipient, to thereby treat the tumor, with claim 7 reciting the expression vector comprises a nucleic acid sequence of SEQ ID NO: 2 or 9, and claims 9,14,17-19 reciting more details about the inhalable dosage forming comprising particles, lyophilized particles, and being formulated for pulmonary delivery with an inhaler or nebulizer.
Claims 1-20 of ‘979 recite a method of treating a respiratory condition caused by a virus in an individual in need thereof, the method comprising administering to the individual an expression vector comprising: a. a first insert comprising a nucleic acid sequence encoding a Granulocyte Macrophage Colony Stimulating Factor (GM-CSF) sequence; and b. a second insert comprising a nucleic acid sequence encoding at least one bi-functional short hairpin RNA (bi-shRNA) capable of hybridizing to a region of a mRNA transcript encoding furin, thereby inhibiting furin expression via RNA interference wherein the bi-shRNA incorporates cleavage dependent siRNA and cleavage independent miRNA motifs, wherein the virus uses a furin produced by the individual to enable infection of a cell of the individual by the virus, and wherein the administering of the expression vector treats the respiratory condition. Claims 3-4 of ‘979 recite the second insert comprises a nucleic acid sequence according to SEQ ID NO: 3, which is 100% identical to instant SEQ ID NOs 2 and 9 in instant claim 7. Claim 7 of ‘979 recites the expression vector is lyophilized with a stabilizing excipient, with claim 8 reciting trehalose as the stabilizing excipient, and claims 9-10 reciting lyophilized particle diameters of less than 5 micrometers and 1-3 micrometers in diameter, as does instant claim 12. Claims 12-13 recite pulmonary delivery of the vector and using an inhaler or nebulizer as do instant claims 17-19. Claim 19 of ‘979 recites an inhalable dosage form of the same expression vector and stabilizing excipient and claim 20 recites a method of generating a lyophilized composition.
‘979 does not recite a method of treating lung cancer.
The teachings of Gradalis have been described above.
Therefore, it would have been obvious to one of ordinary skill in the art before the effective filing date, to have used the expression vector and the lyophilized and inhalable dosage forms recited in ‘979 for treating lung cancer in a subject according to Gradalis with a reasonable expectation of success. There would be a reasonable expectation of success, as the same expression vector containing same components (first and second insert, first insert comprising a nucleic acid encoding GM-CSF sequence and second insert encoding a bi-functional shRNA capable of hybridizing to a region of a mRNA transcript encoding furin…) are recited in ‘979 and Gradalis. One of ordinary skill in the art would have been motivated to use the expression vector and the lyophilized and inhalable dosage forms recited in ‘979 for treating lung cancer because Gradalis teach a method of treating non-small cell lung cancer (NSCLC) in a patient comprising administering an expression vector plasmid comprising a bishRNA furin/GMCSF expression vector plasmid comprising a first nucleic acid insert encoding GM-CSF cDNA and a second nucleic acid insert encoding one or more short hairpin RNAs capable of hybridizing to a region of an mRNA transcript encoding furin, thereby inhibiting furin expression via RNA interference (page 5, lines 26-32 and page 6, lines 1-4) and that the shRNA may be bifunctional, i.e., it may simultaneously incorporate siRNA (cleavage dependent RISC formatted), and either miRNA or miRNA-like (cleavage independent RIC formatted) motifs and inhibit furin in both a cleavage dependent RIC formatted and cleavage independent RISC formatted manner (page 7, lines 17-20).
This is a provisional nonstatutory double patenting rejection.
Response to Arguments
Applicant's arguments filed 12/03/2025 have been fully considered but they are not persuasive.
Applicant argues on page 10 that Application 17/977,979 has been expressly abandoned.
This is not found persuasive, as the abandonment is not appearing in the file wrapper yet. When/if the application does become abandoned, then the NSDP rejection over copending Application 17,977,979 will be withdrawn.
Claims 1-20 are rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1-18 of U.S. Patent No. 11,400,170 (‘170) in view of Abdelaziz et al., cited above.
Instant claims 1-20 recite a method for treating a tumor in the lung of a subject, the method comprising: administering to the subject an inhalable dosage form, comprising: a. an expression vector comprising i. a first insert comprising a nucleic acid sequence encoding a Granulocyte Macrophage Colony Stimulating Factor (GM-CSF) sequence; and ii. a second insert comprising a nucleic acid sequence encoding at least one bi- functional short hairpin RNA (bi-shRNA) capable of hybridizing to a region of a mRNA transcript encoding furin, thereby inhibiting furin expression via RNA interference wherein the bi-shRNA incorporates cleavage dependent siRNA and cleavage independent miRNA motifs; and b. at least one stabilizing excipient, to thereby treat the tumor, with claim 7 reciting the expression vector comprises a nucleic acid sequence of SEQ ID NO: 2 or 9, and claims 9,14,17-19 reciting more details about the inhalable dosage forming comprising particles, lyophilized particles, and being formulated for pulmonary delivery with an inhaler or nebulizer.
Claims 1 and 4-7 of ‘170 recites a method of treating cancer in an individual in need thereof, the method comprising administering an expression vector comprising: (a) a first insert comprising a nucleic acid sequence encoding a GM-CSF sequence and a second insert comprising a sequence of SEQ ID NO: 4. SEQ ID NO: 4 of ‘170 is a 100% identical to instant SEQ ID NOs: 2 and 9 recited in instant claim 7.
Claims 2 and 3 of ‘170 recite the cancer is selected from lung cancer.
Claims 8-18 recite treating BRCA1/2 wild type ovarian cancer in an individual by administering an expression vector comprising the same vector as recited in claim 1.
‘170 does not recite administering an inhalable dosage form comprising the expression vector and a stabilizing excipient.
The teachings of Abdelaziz et al. have been described above.
Therefore, it would have been obvious to one of ordinary skill in the art before the effective filing date, to have combined the cancer treatment and lung cancer treatment method of ‘170 using the bishRNA furin/GMCSF expression vector plasmid with the teachings of Abdelaziz et al. regarding the benefits of inhalable drug delivery systems for lung cancer treatment to have arrived at the instant claims with a reasonable expectation of success. There would be a reasonable expectation of success as both ‘170 and Abdelaziz et al. pertain to treating lung cancer, and amount to applying a known technique of inhalable particulate drug delivery for lung cancer therapy to a known method of treating cancer using the plasmid vector of ‘170 ready for improvement to yield predictable results. One of ordinary skill in the art would have been motivated to administer the expression vector of ‘170in an inhalable dosage form and wherein the dosage form contains a stabilizing excipient, because Abdelaziz et al. teach the benefits of inhalation treatment compared to systemic chemotherapy for treating lung cancer, as inhalation treatment locally delivers the chemotherapeutic agent to tumor tissues enhancing its efficacy and lowering systemic side effects, and increases patient comfort (Page 375, left column) and that dry powder inhaler formulations developed by lyophilization of liposomes in the presence of trehalose (stabilizing excipient) displayed suitable aerodynamic properties for deep lung deposition and no change was detected in supercoiled DNA of the lipoplexes during aerosolization, reflecting pure and stable pDNA with powerful transfection (page 385, right column). One of ordinary skill in the art would have been motivated to administer the expression vector of ‘170 in an inhalable dosage form comprising particles having diameter from about 0.5-10 micrometers or 1-3 micrometers, because Abdelaziz et al. teach dry powder inhalers as a solid-based delivery system can overcome problems encountered by nebulization, offering several benefits including being propellant free, easy to handle, easy to operate, and improved long term stability (page 382, Section 3.2) and to ensure sufficient delivery of inhaled particles deeply into the lungs, particles should possess an aerodynamic diameter of 1-5 micrometers (page 382, Section 3.2), and therefore falls within the recited particle diameter. Abdelaziz et al. teach preparing an inhalable dry powder of siRNA and chitosan in the presence of mannitol using supercritical carbon dioxide and biodistribution studies showed the inhalable powder could provide extended exposure and higher concentrations of siRNA/chitosan complex on lung surface (page 385, left column).
Response to Arguments
Applicant's arguments filed 12/03/2025 have been fully considered but they are not persuasive.
Applicant argues on page 10 that there is no teaching or suggestion of an inhalable, dry powder formulation in ‘170 which is focused on ex vivo cell vaccines, not directly pulmonary delivery of a plasmid or expression vector formulated as a dry powder for inhalation and no teaching or suggestion of formulating the expression vector with a stabilizing excipient, nor of pulmonary, inhaled or deep-lung delivery. Applicant provides the same arguments on pages 10-11 of the response regarding Abdelaziz et al. as discussed above in the arguments to the 35 U.S.C. 103 rejections.
This is not found persuasive. See the response to the arguments above in the 103 rejections. The rejection is maintained.
Claims 1-20 are rejected on the ground of nonstatutory double patenting as being unpatentable over claims 6-16 of U.S. Patent No. 9,695,422 (‘422) in view of Gradalis and Abdelaziz et al. (cited above).
Instant claims 1-20 recite a method for treating a tumor in the lung of a subject, the method comprising: administering to the subject an inhalable dosage form, comprising: a. an expression vector comprising i. a first insert comprising a nucleic acid sequence encoding a Granulocyte Macrophage Colony Stimulating Factor (GM-CSF) sequence; and ii. a second insert comprising a nucleic acid sequence encoding at least one bi- functional short hairpin RNA (bi-shRNA) capable of hybridizing to a region of a mRNA transcript encoding furin, thereby inhibiting furin expression via RNA interference wherein the bi-shRNA incorporates cleavage dependent siRNA and cleavage independent miRNA motifs; and b. at least one stabilizing excipient, to thereby treat the tumor, with claim 7 reciting the expression vector comprises a nucleic acid sequence of SEQ ID NO: 2 or 9, and claims 9,14,17-19 reciting more details about the inhalable dosage forming comprising particles, lyophilized particles, and being formulated for pulmonary delivery with an inhaler or nebulizer.
Claims 6-16 of ‘422 recite a method of enhancing an immune response in an individual in need thereof, the method comprising administering a therapeutically effective amount of cells transfected with the expression vector of claim 1 (an expression vector comprising: a first insert comprising a nucleic acid sequence encoding a GM-CSF sequence and a second insert encodes a bifunctional short hairpin RNA, and recites a species of the instant second insert.
‘422 does not recite a method of treating lung cancer and does not recite administering an inhalable dosage form comprising the expression vector and a stabilizing excipient.
The teachings of Gradalis and Abdelaziz et al. have been described above.
Therefore, it would have been obvious to one of ordinary skill in the art before the effective filing date, to have used the method of ‘422 to treat lung cancer as taught by Gradalis and to modify the dosage form based on the teachings of Abdelaziz et al. regarding the benefits of inhalable drug delivery systems for lung cancer treatment to have arrived at the instant claims with a reasonable expectation of success. There would be a reasonable expectation of success as both ‘422 and Gradalis use the same expression vector, Gradalis and Abdelaziz et al. both pertain to treating lung cancer, and amounts to applying a known technique of inhalable particulate drug delivery for lung cancer therapy to a known method of treating cancer using the plasmid vector of ‘422 ready for improvement to yield predictable results. One of ordinary skill in the art would have been motivated to administer the expression vector of ‘422 in an inhalable dosage form and wherein the dosage form contains a stabilizing excipient, because Abdelaziz et al. teach the benefits of inhalation treatment compared to systemic chemotherapy for treating lung cancer, as inhalation treatment locally delivers the chemotherapeutic agent to tumor tissues enhancing its efficacy and lowering systemic side effects, and increases patient comfort (Page 375, left column) and that dry powder inhaler formulations developed by lyophilization of liposomes in the presence of trehalose (stabilizing excipient) displayed suitable aerodynamic properties for deep lung deposition and no change was detected in supercoiled DNA of the lipoplexes during aerosolization, reflecting pure and stable pDNA with powerful transfection (page 385, right column). One of ordinary skill in the art would have been motivated to administer the expression vector of ‘422 in an inhalable dosage form comprising particles having diameter from about 0.5-10 micrometers or 1-3 micrometers, because Abdelaziz et al. teach dry powder inhalers as a solid-based delivery system can overcome problems encountered by nebulization, offering several benefits including being propellant free, easy to handle, easy to operate, and improved long term stability (page 382, Section 3.2) and to ensure sufficient delivery of inhaled particles deeply into the lungs, particles should possess an aerodynamic diameter of 1-5 micrometers (page 382, Section 3.2), and therefore falls within the recited particle diameter. Abdelaziz et al. teach preparing an inhalable dry powder of siRNA and chitosan in the presence of mannitol using supercritical carbon dioxide and biodistribution studies showed the inhalable powder could provide extended exposure and higher concentrations of siRNA/chitosan complex on lung surface (page 385, left column).
Response to Arguments
Applicant's arguments filed 12/03/2025 have been fully considered but they are not persuasive.
Applicant argues on page 11 that there is no teaching or suggestion in ‘422 of treating lung cancer or administering inhalable dosage forms. Applicant provides the same arguments on pages 11-12 of the response regarding Gradalis and Abdelaziz et al. as discussed above in the arguments to the 35 U.S.C. 103 rejections.
This is not found persuasive. See the response to the arguments above in the 103 rejections. The rejection is maintained.
Conclusion
Claims 1-20 are rejected.
THIS ACTION IS MADE FINAL. 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 STEPHANIE L SULLIVAN whose telephone number is (703)756-4671. The examiner can normally be reached Monday-Friday, 7:30-3:30 EST.
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/STEPHANIE L SULLIVAN/Examiner, Art Unit 1635
/ABIGAIL VANHORN/Primary Examiner, Art Unit 1636