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 .
Priority
Receipt is acknowledged of certified copies of papers required by 37 CFR 1.55.
Information Disclosure Statement
The information disclosure statement (IDS) was filed before the mailing date of the non-final first action on the merits. The submission is in compliance with the provisions of 37 CFR 1.97. Accordingly, the information disclosure statement is being considered by the examiner.
Specification
The disclosure is objected to because it contains an embedded hyperlink and/or other form of browser-executable code ( See page 29 line 8) . Applicant is required to delete the embedded hyperlink and/or other form of browser-executable code; references to websites should be limited to the top-level domain name without any prefix such as http:// or other browser-executable code. See MPEP § 608.01.
Claim Interpretation
It should be noted that the optional recitations in claims 1 and 25 are not given patentable weight as they are not required by the subject claim.
Claim Rejections - 35 USC § 102
The following is a quotation of the appropriate paragraphs of 35 U.S.C. 102 that form the basis for the rejections under this section made in this Office action:
A person shall be entitled to a patent unless –
(a)(1) the claimed invention was patented, described in a printed publication, or in public use, on sale, or otherwise available to the public before the effective filing date of the claimed invention.
(a)(2) the claimed invention was described in a patent issued under section 151, or in an application for patent published or deemed published under section 122(b), in which the patent or application, as the case may be, names another inventor and was effectively filed before the effective filing date of the claimed invention.
Claim 25 is rejected under 35 U.S.C. 102(a)(1) as being anticipated by McCarthy et al ( US 2015/0314011 A1) .
Regarding claim 25, McCarthy et al disclose an amphipathic peptide and methods of using the amphipathic peptide for delivering small molecule to a cell. According to McCarthy et al, the amphipathic cell penetrating peptide comprises less than approximately 50 amino acid residues with at least 6 arginine residues; at least 12 alanine Residues; at least 6 leucine residues; optionally at least one cysteine residue; and at least two but no greater than three glutamic acids; wherein the arginine residues are evenly distributed along the length of the peptide; and the peptide has a defined ratio of arginine to negatively charged amino acid residues from at least 6:2 to 9:2; and a defined ratio of hydrophilic amino acid residues to hydrophobic amino acid residues at pH 7 of at least 30:67 to 40:60. ( See abstract, and claim 1). McCarthy et al also teach an amphipathic cell penetrating peptide comprising SEQ ID NO.1 that is 100% identical to SEQ ID NO.1 of instant claim. McCarthy at al also teach a cell delivery system comprising the aforementioned amphipathic peptide complexed with a nucleic acid. ( See claim 18). Furthermore, McCarthy et al also teach a composition comprising the amphipathic peptide complexed with nucleic acid. (See paragraph [0101]). Therefore, McCarthy et al anticipate instant claim.
Claim Rejections - 35 USC § 103
The following is a quotation of 35 U.S.C. 103 which forms the basis for all obviousness rejections set forth in this Office action:
A patent for a claimed invention may not be obtained, notwithstanding that the claimed invention is not identically disclosed as set forth in section 102, if the differences between the claimed invention and the prior art are such that the claimed invention as a whole would have been obvious before the effective filing date of the claimed invention to a person having ordinary skill in the art to which the claimed invention pertains. Patentability shall not be negated by the manner in which the invention was made.
The text of those sections of Title 35, U.S. Code not included in this action can be found in a prior Office action.
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.
Claims 1-2, 4-13,14,16-17, 19-20, and 22-24 are rejected under 35 U.S.C. 103 as being unpatentable over Huang et al ( Journal of Virology Methods, 2013), in view of McCarthy et al ( US 2015/0314011 A1), and McCarthy et al (Journal of Controlled Release, 2014), Fischer et al ( Biomaterials, 2003), and Kafil et al ( BioImpacts, 2011), as evidenced by the teachings of MD Anderson Cancer Center.
Regarding claim 1, Huang et al teach a method for producing viral particles using the cationic polymer polyethylenimine (PEI) to deliver plasmid DNA into HEK293 cells, which are then cultured to produce viral particles. Specifically, the method involves co-transfecting HEK293 cell (i.e. producer cell) with three plasmids (i.e. 3 nucleic acids) required for AAV serotype 2 virus packaging, wherein the delivery of the plasmids is mediated by the transfection reagent 25 kDa linear polyethylenimine (PEI). According to Huang et al, PEI interacts strongly with the nucleic acids through electrostatic forces between its positively charged protonated amine groups and the negatively charged phosphate groups of DNA, forming condensed complexes (i.e.polyplexes) capable of penetrating the cell wall by endocytosis and then escaping from endosomes by the so-called "proton sponge" effect, releasing the DNA to the cytosol. ( See page 271, 1st column,2nd paragraph). Huang et al also state that “the use of PEI as a transfection reagent is a simple, more cost-effective, and stable means of high-throughput production of high-titer AAV serotype 2”. ( See abstract).
Huang et al do not teach using the amphipathic cell penetrating peptides of instant claim to produce viral vector.
Fischer et al provide a comparative in vitro cytotoxicity study with different transfection reagents, including PEI. Fischer et al demonstrate that the magnitude of the all-polymer’s cytotoxic effects varies with time- and concentration, with PEI having the highest cytotoxicity. (See abstract).
Kafil et al also provide a comparative in vitro cytotoxicity study with linear and branched PEI, demonstrating that both linear PEI ( LPEI) and branched PEI (BPEI) exhibit cytotoxicity in A431 cell lines upon transfection, which appears to be largely dependent on concentration and polymer structure (See Fig. 3).
McCarthy et al (2014), on the other hand, disclose an amphipathic cell penetrating peptide (known as RALA) that is capable of delivering a functional nucleic acid cargo into a cell. It should be noted that RALA comprises of “WEARLARALARALARHLARALARALRACEAM” which is 100% identical to SEQ ID NO 1 of the instant claim. Thus, RALA reads on the amphipathic cell penetrating peptide of the instant claim. McCarthy et al additionally demonstrate that RALA is highly effective DNA delivery platform with no evidence of aggregation. Specifically, McCarthy et al demonstrate that RALA efficiently delivers pEGFP-N1 with a transfection efficiency of 60% in NCTC-929 cells ( See Fig. 5A), 57% in ZR-75-1 cells and 27% in PC-3 cells (See Fig. 5B). McCarthy et al further demonstrate that the transfection efficacy achieved using RALA/pDNA nanoparticles in vitro was comparable to commercially available Lipofectamine, a well know transfection reagent, while exhibiting significantly lower cytotoxicity (See Fig. 5). It should be noted that Lipofectamine is a commonly used reagent for the production of viral particles as well, as evidenced by the MD Anderson Cancer Center protocol.
In addition, McCarthy et al (2015), as set forth above, disclose the same amphipathic cell penetrating peptide (termed RALA) of the instant claim that is capable of delivering a functional nucleic acid cargo into a cell. McCarthy et al also compare PEI, Lipofectamine, and RALA, demonstrating that RALA is less cytotoxic than Lipofectamine ( See Figs.34 and 36, and [0043]) and elicits a significantly lower initial TNFa response than the PEI (See paragraph [0218]), as well as teaching the advantages of RALA peptides (See paragraph [0238]), especially their lower immunogenicity and improved vector expression (See paragraph [0042]).
It should also be noted that it is well known in the art that a transfection reagent capable of delivering nucleic acid to a cell can also be used to produce viral vectors in a producer cell. For example, a transfection reagent such as PEI can be used to transduce a cell with a nucleic acid that encodes a protein, causing the transduced cells to produce high amounts of said protein, or it can be used to produce viral particles in a producer cells by acting as a vehicle to deliver the nucleic acids required for viral assembly, as taught by Huang et al.
Taken together, Huang et al teach a method producing viral vector using the transfection reagent PEI, whereas McCarthy 2014 and 2015 teach the advantages of using the amphipathic cell penetrating peptides as transfection reagents. It is noted that neither Huang et al nor McCarthy (2014 and 2015) teach or suggest using the amphipathic peptides recited in instant claim to produce viral vectors; however, claim 1 would have been obvious to one of ordinary skill in the art, as there was some teaching, suggestion, or motivation in the prior art that would have led one of ordinary skill to modify the prior art reference or to combine prior art reference teachings to arrive at the claimed invention. Huang et al teach a method for producing viral vector using PEI, a commonly used transfection reagent in the art for gene delivery and viral production. Fischer et al and Kafil et al demonstrate that PEI has a high cytotoxicity when used as a transfection reagent. McCarthy (2014) and (2015) teach an amphipathic cell penetrating peptide that can also be used as a transfection reagent, demonstrating that the peptides tend to be less immunogenic than PEI and less toxic than the commonly used transfection agent lipofectamine. Therefore, one with ordinary skill in the art who had reviewed Huang et al could have come across McCarthy(2014) and (2015), Fischer, and Kafil and immediately noticed the strong possibility of using the amphipathic peptide, taught by McCarthy (2014 and 2015), instead of PEI taught by Huang et al, to produce viral particle according to the method of Huang et al. There is a reasonable expectation of success, when producing viral vectors, that taking the McCarthy’s amphipathic peptide, and using it as a transfection reagents instead of PEI, that the viral vector of claim 1 could be successfully produced.
Regarding claim 2, following the discussion of claim 1 above, McCarthy (2014) and (2015) teach a peptide with a sequence identity that is 100% identical to SEQ ID NO.1 of instant claim.
Regarding claims 4-7,14,16-17, 20, and 22-23, following the discussion of claim 1 above, the method of Huang et al involves harvesting the viral vectors produced by the transfected producer cells (e.g. HEK293), this reads on claim 4. ( See section 2.5 “ Virus harvest” on page 271). The method of Huang et al also includes complexing the transfection reagent (i.e. PEI) with three plasmids (i.e. 3 nucleic acids) to form nanoparticles prior to transfection, this reads on claim 5. Furthermore, the method of Huang et al also involves pooling nucleic acids comprising of three plasmids: a plasmid comprising the RepCap genes, a helper plasmid, and a plasmid comprising a transgene before mixing them with PEI to form nanoparticles, this reads on step (b) of claim 6 and claims 7 and 16. (See section 2.4. “ Co-transfection of three plasmids” on page 271). Huang et al also teach using the transfection reagent PEI to produce AAV2, this reads on claims 12,14, and 23. ( See abstract). The method of Huang et al additionally involves PEI-mediated transfection of HEK293 in an adherent culturing system, this reads on claim 17. ( See section 2.3. “ Preparation of AAV-293 cells for transfection” on page 271). Huang et al also teach a step for purifying the produced viral vector, this reads on claim 20. ( See sections 2.6-2.7 on pages 271-272). The method of Huang et al does not include an anion exchange polishing step or ultrafiltration polishing step, this reads on claim 22.
Huang et al do not use the amphipathic peptide of instant claim to initiate nanoparticle formation and viral production.
McCarthy et al (2014 and 2015), as discussed above, demonstrate the use of the amphipathic peptide of the instant claim as a transfection reagent to deliver DNA into a cell, as well as the advantages of using the peptide over PEI and lipofectamine. Therefore, it would have been prima facie obvious to one with ordinary skill in the art at the time the invention was filed to substitute the transfection reagent of Huang et al and use the amphipathic peptide, taught by McCarthy (2014 and 2015), to produce viral vectors according to the method of Huang et al. One would have been motivated to switch to the amphipathic peptide over PEI, because of its high transfection efficiency, decreased cytotoxicity, and immunogenicity. Taken together, substitution of one known element for another known element, the elements having equivalent effect, is considered to be obvious, absent showing that the result of the substitution yields more than predictable results. See MPEP 2143(I)(B).
Regarding claims 8-9, following the discussion of claims 4-7, Huang et al in view of McCarthy (2014 and 2015) render obvious substituting PEI for the amphipathic peptide taught by McCarthy (2014 and 2015) . McCarthy et al demonstrated that transfection with RALA peptide derivative 2-6 showed transfection efficiencies of at least 40%. ( See paragraphs [0212], [0242], and Table 3). McCarthy et al also teach that the peptides are not strongly cytotoxic, causing only a 20% reduction in cell viability in transfected cell monolayers. ( See paragraph [0238]).
Regarding claims 10-11,19, the claims recite limitations that are directed to results that flow from performing the steps of the method, and do not particularly provide patentable weight when determining the patentability of the claimed methods. In this case. the teachings of Huang et al in view of McCarthy (2014 and 2015) render obvious the method of producing viral vectors using the amphipathic peptide of the invention, thus the results are expected to be the same.
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 1-2, 4-13,14,16-17, 19-20, and 22-25 are rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1-2,5-7,19, and 22 of U.S. Patent No. 10,500 ,287, hereafter ‘287, in view Huang et al ( Journal of Virology Methods, 2013), McCarthy et al ( US 2015/0314011 A1), McCarthy et al (Journal of Controlled Release, 2014), Fischer et al ( Biomaterials, 2003), and Kafil et al ( BioImpacts, 2011).
Regarding claims 1-2, 4-13,14,16-17, 19-20, and 22-25, claims 1-2,5-7,19, and 22 of US patent ‘287 teach amphipathic cell penetrating peptides with 100% sequence identity to the peptides with SEQ ID NO 1,2, and 5 of the instant claims. The claims of US patent ‘287 teach a nanoparticle comprising the aforementioned amphipathic cell penetrating peptides complexed with one or more nucleic acids. The claims also teach a method for the delivery of nucleic acid to a cell, which includes providing and administering the nanoparticle to said cell, as well as a composition comprising the same.
The claims of US ‘287 do not teach a method for using the nanoparticles to produce viral vectors.
The teachings of Huang et al, McCarthy et al (2014 and 2015), Fischer, and Kafil are set forth above.
Therefore, instant claims would have been obvious to one of ordinary skill in the art, as there was some teaching, suggestion, or motivation in the prior art that would have led one of ordinary skill to modify the prior art reference or to combine prior art reference teachings to arrive at the claimed invention. The claims of ‘287 teach a nanoparticle comprising amphipathic cell penetrating peptides complexed with one or more nucleic acids that can be used for the delivery of nucleic acid to a cell. Huang et al teach a method for producing viral vector using PEI, a commonly used transfection reagent in the art for gene delivery and viral production. Fischer et al and Kafil et al demonstrate that PEI has a high cytotoxicity when used as a transfection reagent. McCarthy (2014) and (2015) teach an amphipathic cell penetrating peptide that can also be used as a transfection reagent, and demonstrate that the peptides tend to be less immunogenic than PEI and less toxic than the commonly used transfection agent lipofectamine. Therefore, one with ordinary skill in the art who had reviewed ‘287 could have come across Huang et al, McCarthy(2014 and 2015), Fischer, and Kafil and immediately noticed the strong possibility of using the amphipathic peptide, taught by ‘287, instead of PEI taught by Huang et al, to produce viral particle according to the method of Huang et al. There is a reasonable expectation of success, when producing viral vectors, that taking the amphipathic peptide of the ‘287, and using it as a transfection reagents instead of PEI, that the viral vector of instant claims could be successfully produced.
Claims 1-2, 4-13,14,16-17, 19-20, and 22-25 are rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1-2,7-9,15-16 of U.S. Patent No. 9,744,244 hereafter ‘244, in view Huang et al ( Journal of Virology Methods, 2013), McCarthy et al ( US 2015/0314011 A1), McCarthy et al (Journal of Controlled Release, 2014), Fischer et al ( Biomaterials, 2003), and Kafil et al ( BioImpacts, 2011).
Regarding claims 1-2, 4-13,14,16-17, 19-20, and 22-25, claims 1-2,7-9,15-16 of US patent ‘244 teach amphipathic cell penetrating peptides with sequence identity that is 100% identical to the peptides with SEQ ID NO 1-7 of the instant claims. The claims of US patent ‘244 also teach a cell delivery system comprising of the aforementioned amphipathic cell penetrating peptides complexed with one or more nucleic acids that can be used as vehicle for the delivery of nucleic acid to a cell.
The claims of US ‘244 do not teach a method for using the cell delivery system to produce viral vectors.
The teachings of Huang et al, McCarthy et al (2014 and 2015), Fischer, and Kafil are set forth above.
Therefore, instant claims would have been obvious to one of ordinary skill in the art, as there was some teaching, suggestion, or motivation in the prior art that would have led one of ordinary skill to modify the prior art reference or to combine prior art reference teachings to arrive at the claimed invention. ‘244 teach a cell delivery system comprising amphipathic cell penetrating peptides complexed with one or more nucleic acids that can be used for the delivery of nucleic acid to a cell. Huang et al teach a method of producing viral vector using PEI, a commonly used transfection reagent in the art for gene delivery and viral production. Fischer et al and Kafil et al demonstrate that PEI has a high cytotoxicity when used as a transfection reagent. McCarthy (2014) and (2015) teach an amphipathic cell penetrating peptide that can also be used as a transfection reagent, and demonstrate that the peptides tend to be less immunogenic than PEI and less toxic than the commonly used transfection agent lipofectamine. Therefore, one with ordinary skill in the art who had reviewed ‘244 could have come across Huang et al, McCarthy(2014) and (2015), Fischer, and Kafil and immediately have noticed the strong possibility of using the amphipathic peptide, taught by ‘244 , instead of PEI taught by Huang et al, to produce viral particle according to the method of Huang et al. There is a reasonable expectation of success, when producing viral vectors, that taking the amphipathic peptide of the ‘244 , and using it as a transfection reagents instead of PEI, that the viral vector of instant claims could be successfully produced.
Claims 1-2, 4-13,14,16-17, 19-20, and 22-25 are rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1-3,7,10 of U.S. Patent No. 10,188,744, hereafter ‘744, in view Huang et al ( Journal of Virology Methods, 2013), McCarthy et al ( US 2015/0314011 A1), McCarthy et al (Journal of Controlled Release, 2014), Fischer et al ( Biomaterials, 2003), and Kafil et al ( BioImpacts, 2011).
Regarding claims 1-2, 4-13,14,16-17, 19-20, and 22-25, claims 1-3,7,and 10 of US patent ‘277 teach amphipathic cell penetrating peptides with sequence identity that is 100% identical to the peptides with SEQ ID NO 1, and 4 of the instant claims. The claims of US patent ‘277 also teach a cell delivery system comprising of the aforementioned amphipathic cell penetrating peptides complexed with one or more nucleic acids that can be used as a vehicle for the delivery of nucleic acid to a cell.
The claims of US ‘277 do not teach a method for using the cell delivery system to produce viral vectors.
The teachings of Huang et al, McCarthy et al (2014 and 2015), Fischer, and Kafil are set forth above.
Therefore, instant claims would have been obvious to one of ordinary skill in the art, as there was some teaching, suggestion, or motivation in the prior art that would have led one of ordinary skill to modify the prior art reference or to combine prior art reference teachings to arrive at the claimed invention. ‘277 teach a cell delivery system comprising amphipathic cell penetrating peptides complexed with one or more nucleic acids that can be used as a vehicle for the delivery of nucleic acid to a cell. Huang et al teach a method of producing viral vector using PEI, a commonly used transfection reagent in the art for gene delivery and viral production. Fischer et al and Kafil et al demonstrate that PEI has a high cytotoxicity when used as a transfection reagent. McCarthy (2014) and (2015) teach an amphipathic cell penetrating peptide that can also be used as a transfection reagent, and demonstrate that the peptides tend to be less immunogenic than PEI and less toxic than the commonly used transfection agent lipofectamine. Therefore, one with ordinary skill in the art who had reviewed ‘277 could have come across Huang et al, McCarthy(2014) and (2015), Fischer, and Kafil and immediately have noticed the strong possibility of using the amphipathic peptide, taught by ‘277, instead of PEI taught by Huang et al, to produce viral particle according to the method of Huang et al. There is a reasonable expectation of success, when producing viral vectors, that taking the amphipathic peptide of the ‘277, and using it as a transfection reagents instead of PEI, that the viral vector of claim instant claims could be successfully produced.
Conclusion
No claim is allowed.
Any inquiry concerning this communication or earlier communications from the examiner should be directed to FATIMAH KHALAF MATALKAH whose telephone number is (703)756-5652. The examiner can normally be reached Monday-Friday,7:30 am-4:30 pm EST.
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/FATIMAH KHALAF MATALKAH/Examiner, Art Unit 1638
/Tracy Vivlemore/Supervisory Primary Examiner, Art Unit 1638