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 .
DETAILED ACTION
Claims 1, 16, 20, 26-27, 32-33, 37-38, 41, 43-48, 50-52, 54, 62-65 and 75-78 are pending. Claims 62-63 and 65 are withdrawn.
Response to Amendment
The objection of claims 1 and 44 is withdrawn in view of the amendment.
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 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, 16, 20, 26-27, 32-33, 37-38, 41, 43, 45 and 50-52 remain rejected under 35 U.S.C. 103 as being unpatentable over Bilgicer (WO2014121291, published 08/07/2014, of record in Office Correspondence mailed on 07/15/2025) in view of Rodriguez (Journal of Controlled Release 133.1 (2009): 52-59, of record in Office Correspondence mailed on 07/15/2025).
Regarding claims 1 and 16, Bilgicer teaches a lipid composition containing a therapeutic agent such as nucleic acid (Abstract, page 1 line 33, page 14 line 6). Bilgicer teaches the composition comprises peptide-lipid conjugate (Figure 1). Bilgicer teaches peptide can include 10 to about 50 amino acids (page 4 line 9). Bilgicer teaches peptides YCDGFYACYMDV and YCDPC (page 26 line 38).
Bilgicer does not teach at least 25% of the amino acids in the peptide are proline.
However, Rodriguez teaches a lipid nanoparticle comprising a nucleic acid and a proline-rich peptide with sequence (VRLPPP)3 (9 prolines out of 18 amino acids, i.e., 50% of amino acids are proline) (Title, Abstract, the sentence bridging page 52 and page 53). Rodriguez teaches the peptide demonstrated good translocation properties and is non-cytotoxic (page 53 left column lines 1-2).
It would have been prima facie obvious to one of ordinary skill in the art before the effective filing date of the claimed invention to modify the composition taught by Bilgicer by adding (VRLPPP)3 peptide onto Bilgicer’s peptide-lipid conjugate as suggested by Rodriguez. One of ordinary skill in the art would be motivated to do so in order to improve the translocation of the composition into the cells. Since both Bilgicer and Rodriguez teach a desire to form a peptide lipid composition to deliver nucleic acid, there is a reasonable expectation of success.
Bilgicer teaches about 3 mol% of the molecules of the liposome are lipid conjugate (PEG350-lipids) (page 2 lines 9-11), which falls within the instant limitation of 0.1 mol % to 4 mol %.
Regarding claim 20, Bilgicer teaches peptides YCDGFYACYMDV and YCDPC which comprise 7 and 4 hydrophilic amino acids, respectively (i.e., 58% and 80% respectively).
Regarding claim 26, Bilgicer the peptide comprises hydrophilic amino acid aspartic acid (D).
Regarding claims 27 and 32, Bilgicer teaches peptide YCDPC with no glycine. Rodriguez teaches peptide (VRLPPP)3 with no glycine.
Regarding claim 33, Bilgicer teaches the composition is liposome or micelle (Abstract).
Regarding claim 37, Bilgicer teaches the composition comprises cholesterol (page 2 line 21). Applicant discloses that cholesterol is a helper lipid and a sterol (specification [00108]). Rodriguez teaches cationic lipids can be formulated as solid lipid nanoparticles (page 52 left column first para.). One of ordinary skill in the art would be motivated to add cationic lipids to form a lipid nanoparticle.
Regarding claim 38, Bilgicer teaches about 2 mol% of the molecules of the liposome are lipid conjugate (PEG350-lipids) (page 2 lines 9-11) . One of ordinary skill in the art would be motivated to optimize the concentration of the peptide-lipid conjugate in order to form stable lipid particles.
Regarding claim 41, Bilgicer teaches the composition comprises encapsulated drugs (Abstract) and teaches nucleic acid is a drug (page 14 lines 6-7).
Regarding claim 43, Bilgicer teaches peptide is conjugated to lipid via a linker PEG (Figure 1).
Regarding claim 45, Bilgicer teaches pegylated lipid DSPE (claim 4).
Regarding claim 50, Bilgicer teaches the composition comprises cholesterol (page 2 line 21). Applicant discloses that cholesterol is a helper lipid (specification [00108]).
Regarding claim 51, Bilgicer teaches a lipid composition containing a therapeutic agent such as nucleic acid (Abstract, page 1 line 33, page 14 line 6). Bilgicer teaches the composition comprises peptide-lipid conjugate (Figure 1). Bilgicer teaches peptide can include 10 to about 50 amino acids (page 4 line 9). Bilgicer teaches peptides YCDGFYACYMDV and YCDPC which comprise 7 and 4 hydrophilic amino acids, respectively (i.e., 58% and 80% respectively). Peptide YCDPC does not comprise any glycine. Peptide YCDGFYACYMDV comprises 8% glycine. Bilgicer teaches the composition comprises cholesterol (page 2 line 21). Applicant discloses that cholesterol is a helper lipid and a sterol (specification [00108]).
Regarding claim 52, Bilgicer teaches the nucleic acid is siRNA or DNA (page 14 line 7).
Claim 44 remains rejected under 35 U.S.C. 103 as being unpatentable over Bilgicer and Rodriguez as applied to claims 1 and 43 above, and further in view of Lee (US-20200385721 A1, published 12/10/2020)
Regarding claim 44, Bilgicer teaches linker is PEG but does not teach linker has a structure comprising succinyl (-(O)CCH2CH2C(O)-).
However, Lee teaches lipid particles comprising lipid conjugates and teaches PEG can be substituted by other linker such as amido (-C(O)NH-), amino (-NR-), carbonyl (-C(O)-), carbamate (-NHC(O)O-), urea (-NHC(O)NH-), disulphide (-S-S-), ether (-0-), succinyl (-(O)CCH2CH2C(O)-), succinamidyl (-NHC(O)CH2CH2C(O)NH-), and ether ([0237], [0242]).
It would have been prima facie obvious to one of ordinary skill in the art before the effective filing date of the claimed invention to further modify the composition taught by Bilgicer by substituting Lee’s linker comprising succinyl for Bilgicer’s PEG, as suggested by Lee. MPEP 2144.06 II states that it is obvious to substitute equivalents know for the same purpose. Lee teaches these linkers are equivalents and used for the same purpose.
Claims 46 and 47 remain rejected under 35 U.S.C. 103 as being unpatentable over Bilgicer and Rodriguez as applied to claim 1 above, and further in view of Boesen (US20190030115, of record in IDS, hereinafter “Boesen”).
Regarding claims 46 and 47, Bilgicer teaches the peptide can be conjugated at its N-terminus or C-terminus (page 21 lines 20-23, lines 26-30).
Bilgicer does not teach wherein the peptide is conjugated to the lipid of the peptide-lipid conjugate at its C-terminus and the amino group of the N-terminus of the peptide is substituted with one or two C1.6 alkyl groups or amido groups and wherein the peptide is conjugated to the lipid of the peptide-lipid conjugate at its N-terminus, and the amino acid at the C-terminus of the peptide is alkylated to form a C1.6 alkyl ester or is amidated.
However, Boesen teaches method of producing peptides ([0002]) and teaches amino-alkyl amino acid residue is covalently linked to the N-terminus of peptide or covalently linked to the C-terminus ([0031]). Boesen teaches such modification improves the peptide feature such as increasing its stability ([0011]).
It would have been prima facie obvious to one of ordinary skill in the art before the effective filing date of the claimed invention to further modify the composition taught by Bilgicer by modifying the non-conjugated terminus, C-terminus or N-terminus, with amino-alkyl amino acid residue in order to increase the stability of the peptide.
Claims 54 and 64 remain rejected under 35 U.S.C. 103 as being unpatentable over Bilgicer and Rodriguez as applied to claim 1 above, and further in view of Blair (Cancer Research 78.13_Supplement (2018): 724-724, of record in Office Correspondence mailed on 04/10/2024, hereinafter “Blair”)
Regarding claims 54 and 64, Bilgicer teaches the nucleic acid is an siRNA but does not teach the RNA is self-replicating RNA (srRNA).
However, Blair teaches srRNA formulated with a lipid nanoparticle (LNP), which facilitates efficient cellular uptake of the RNA and enhances antigen expression as well as the resulting immune response (page 1).
It would have been prima facie obvious to one of ordinary skill in the art before the effective filing date of the claimed invention to further modify the lipid composition taught by Bilgicer by using self-replicating mRNA as the nucleic acid as suggested by Blair, with a reasonable expectation of success. One of ordinary skill in the art would be motivated to do so in order to use the composition as a vaccine as suggested by Blair.
Claims 48, 75 and 77-78 remain rejected under 35 U.S.C. 103 as being unpatentable over Bilgicer and Rodriguez as applied to claims 1 and 26 above, and further in view of Galeotti (US 20120219578-A1, published 08/30/2012).
Regarding claim 48, Bilgicer does not teach liposome comprises cationic lipid DOTAP. However, Galeotti teaches liposome comprising cationic lipid DOTAP and teaches cationic liposomes have been shown to mediate intracellular delivery of plasmid DNA ([0155], [0156], [0157]).
It would have been prima facie obvious to one of ordinary skill in the art before the effective filing date of the claimed invention to further modify the composition taught by Bilgicer by adding cationic lipid DOTAP as suggested by Galeotti. One of ordinary skill in the art would be motivated to do so in order to form liposome capable of intracellular delivery of DNA. Since Bilgicer teaches a desire to form liposome to deliver drug such as DNA, there is a reasonable expectation of success.
Regarding claims 75 and 77-78, Bilgicer does not teach amino acids having a hydrophilic side chain are a combination of glutamic acid, serine, and threonine and does not teach a peptide that comprises at least one unit of a STEP tetrapeptide.
However, Galeotti teaches peptides SAAGSTEPLA (SerAlaAlaGlySerThrGluProLeuAla) (SEQ ID NO: 37018) and PSTQPSSTQP (ProSerThrGlnProSerSerThrGlnPro) (SEQ ID NO: 4993). Galeotti teaches these peptides are used as vaccines diagnostic reagents, immunogenic compositions and teaches liposomes are acceptable carriers (Abstract, [0114]).
It would have been prima facie obvious to one of ordinary skill in the art before the effective filing date of the claimed invention to further modify the composition taught by Bilgicer by adding peptides SAAGSTEPLA and PSTQPSSTQP as suggested by Galeotti. One of ordinary skill in the art would be motivated to do so in order to form a vaccine. Since Bilgicer teaches a desire to form a composition carrying peptides, there is reasonable expectation of success.
Claims 76-78 remain rejected under 35 U.S.C. 103 as being unpatentable over Bilgicer and Rodriguez as applied to claim 1 above, and further in view of Galeotti (US 20120219578-A1, published 08/30/2012) and Sagan (Current medicinal chemistry 11.21 (2004): 2799-2822, of record in Office Correspondence mailed on 04/10/2024, hereinafter “Sagan”).
The teachings of Galeotti are discussed above and applied herein.
Regarding claims 76-78, Bilgicer does not teach the combination of methyl serine, methyl threonine, and glutamine.
However, Sagan teaches methylation is used in peptide modifications to induce effects on the conformation of the peptide, on its stability towards enzymatic degradation and / or on its biological activity (page 2799 left column para. 3) and teaches serine and threonine can be methylated (page 2800 para. “Methylation of protected amino acids).
It would have been prima facie obvious to one of ordinary skill in the art before the effective filing date of the claimed invention to further modify the composition taught by Bilgicer by methylating amino acids such as serine and threonine as suggested by Sagan. One of ordinary skill in the art would be motivated to do so in order to induce effects on the conformation of the peptide, on its stability towards enzymatic degradation and/or on its biological activity as taught by Sagan.
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, 16, 20, 26-27, 32-33, 37-38, 41, 43-47, 50-52, 64 and 75-78 remain provisionally rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1, 16, 47, 48, 60, 67-69, 70, and 72-73 of copending Application No. 17/737862. Although the claims at issue are not identical, they are not patentably distinct from each other because the instant claims are obvious over the conflicting claims.
Regarding claims 1, 16, 20, 26-27, 32, 38, 43-45, 51, 75-78, copending claim 67 recites peptide STEP-STEP-STEP linked to a lipid DMG. Patent claim 72 peptide-lipid conjugate makes up 0.5 to 5 mol % of all lipids in the lipid composition. While the exact concentration is not recited in copending claims, it is generally noted that differences in concentration do not support the patentability of subject matter. One of ordinary skill in the art would be motivated to optimize the concentration of the peptide-lipid conjugate in order to form a stable composition
Regarding claim 33, copending claim 69 recites the lipid composition comprises liposomes or lipid nanoparticles.
Regarding claims 37 and 50, copending claim 73 recites the lipid composition further comprising a cationic lipid, a sterol, and a helper lipid.
Regarding claims 41, 52 and 64, copending claim 70 recites the liposomes or lipid nanoparticles encapsulate a nucleic acid selected from a messenger RNA, a siRNA, a transfer RNA, a microRNA, RNAi, or DNA.
Regarding claims 46-47, copending claim 1 recites the lipid is conjugated to the N-terminus, C-terminus, or an amino acid side chain of the peptide and the peptide of is optionally protected with a neutral group selected from an amide and a C1-6 alkyl ester at its C-terminus when conjugated at its N-terminus or an amino acid side chain.
This is a provisional nonstatutory double patenting rejection because the patentably indistinct claims have not in fact been patented.
Response to Arguments
Applicant's arguments filed 10/15/2025 have been fully considered but they are not persuasive.
Applicant argues that Rodriguez does not teach or suggest a peptide-lipid conjugate, wherein at least 25% of the amino acids in the peptide of the peptide-lipid conjugate are praline, as recited in the instant claims. Rather, Rodriguez teaches generation of a non-covalent Sweet Arrow Peptide (SAP)-DNA complex, and subsequent addition of the complex to a previously prepared solid lipid nanoparticle (SLN) to form a resultant SAP-DNA-SLN vector.
In response to the argument, the rationale for the maintained obviousness rejection is based on adding the peptide taught by Rodriguez to the composition taught by Bilgicer. Bilgicer teaches a lipid composition comprising nucleic acid and peptide-lipid conjugate (Abstract, Figure 1). Thus, Bilgicer teaches that a peptide can be conjugated to a lipid. Rodriguez teaches a lipid nanoparticle comprising a nucleic acid and a proline-rich peptide and teaches that the peptide demonstrated good translocation properties and is non-cytotoxic. (Title, Abstract, the sentence bridging page 52 and page 53, page 53 left column lines 1-2). Since Bilgicer teaches a desire to form a composition to deliver drug, and since Rodriguez teaches a non-cytotoxic peptide with good translocation properties, one of ordinary skill in the art would be motivated to add the peptide of Rodriguez to the composition of Bilgicer and have a reasonable expectation of success in order to improve the translocation of the composition into the cells. Conclusive proof of efficacy is not required to show a reasonable expectation of success, and obviousness does not require absolute predictability (See MPEP 2143.02(I) and MPEP 2143.02(II)). In addition, the claim recites a composition comprising a nucleic acid. The claim does not exclude the presence of peptide-DNA complex.
Applicant argues Bilgicer seeks to achieve a different technical objective than the present application. Applicant argues Bilgicer aims to achieve optimization of the length of PEG coating and peptide-EG-linker length for enhancing liposomal/micellar cellular uptake whereas the objective of the present application is to provide an alternative to use of PEG conjugates in lipid-based compositions.
In response to the argument, the claim recites a composition comprising a nucleic acid and a peptide-lipid conjugate. The claim does not exclude the presence of PEG.
Applicant requests that the double patenting rejection over co-pending application 17/737862 be held in abeyance (Remarks p. 16). A request to hold a rejection in abeyance is not a proper response to a rejection. Rather, a request to hold a matter in abeyance may only be made in response to an OBJECTION or REQUIREMENTS AS TO FORM (see 37 CFR 1.111(b) and MPEP §714.02). Thus, the double patenting rejections of record have been maintained as no response to these rejections has been filled by applicant at this time.
Conclusion
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 MARY A CRUM whose telephone number is (571)272-1661. The examiner can normally be reached M-F 8:00-5:00 CT with alternate Fridays off.
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/MARY A CRUM/Examiner, Art Unit 1657
/THANE UNDERDAHL/Primary Examiner, Art Unit 1699