DETAILED ACTION
Status of the Claims
Claims 1, 7-12, 19, 20 and 21 are pending in the instant application. Claims 1 and 7 have been withdrawn based upon Restriction/Election. Claims 8-12, 19, 20 and 21 are being examined on the merits in the instant application.
Advisory Notice
The present application, filed on or after March 16, 2013, is being examined under the first inventor to file provisions of the AIA .
All rejections and/or objections not explicitly maintained in the instant office action have been withdrawn per Applicants’ claim amendments and/or persuasive arguments.
Priority
The U.S. effective filing date has been determined to be 09/22/2021, the filing date of the U.S. Provisional Application No. 63/247,294.
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 8-10 remain rejected and claims 19-21 are newly rejected under 35 U.S.C. 103 as being unpatentable over XU (US 2020/0392507; published December, 2020) in view of DOHMEN (US 2018/0236090; published August, 2018); STANTON (US 2013/0178541; published July, 2013); Sajid et al. (“Overcoming the Barriers for siRNA Therapeutics: From Bench to Bedside,” 2020; MDPI; Pharmaceuticals, Vol. 13, No. 294, pp. 1-25).
Applicants Claims
Applicant claims a method of preparing a pharmaceutical nanoparticle composition, comprising mixing a nucleic acid solution having a pH of between about 4.0 and 6.9, and a solution of a branched histidine-lysine copolymer having a pH of between 5.5 and 6.0 wherein the ratio of histidine-lysine copolymer to nucleic acid is between about 2.5:1 to about 3:1 (w/w)(instant claim 8).
Determination of the scope
and content of the prior art (MPEP 2141.01)
Sajid et al. teaches overcoming barriers for siRNA Therapeutics (title, see whole document) and particularly that: “siRNAs, being negatively charged, are membrane-impermeable and highly unstable in the systemic circulation.” (abstract). Sajid et al. further teaches that: “As discussed earlier, naked siRNA cannot cross the plasma membrane because of its negative charge. Despite its small size, the negative charge and high hydrophilicity prevent siRNA from passing through the biological membrane. Hence, efficient delivery of siRNA needs modification to overcome this barrier. In this context, carriers that enable efficient siRNA delivery are required. Complexation of siRNA with cationic polymers or lipids can mask the net negative charge of siRNA. Furthermore, these nanoparticles with positive charge interact with the negatively charged biological membrane, thus causing internalization.” (p. 11, §10, 1st paragraph). And that: “Due to the hydrophilicity and negative charge of the siRNA, various carriers are used, including cationic polymers and peptides. Peptides, in particular, have received specific attention because they show great promise as siRNA carriers, based on the diversity of their physiochemical properties and functions.” (p. 11, §10, 2nd paragraph).
XU teaches “a method of activating fibroblast and myofibroblast apoptosis in a tissue of a mammal, comprising administering to the tissue a therapeutically\ effective amount of a composition comprising an siRNA molecule that binds to an mRNA that codes for TGFBl protein in a mammalian cell, an siRNA molecule that binds to an mRNA that codes for COX-2 protein in a mammalian cell, and a pharmaceutically acceptable carrier comprising a pharmaceutically acceptable histidine-lysine polymer.” (abstract, see whole document). And that: “We have developed a process to formulate Histidine Lysine co-Polymer (HKP) with selected siRNA duplexes targeting both TGF-β1 and COX-2 into an aqueous nanoparticle formulation. Delivery of this HKP/siRNA nanoparticle formulation through intra-dermal injection, revealed a synergistic effect of size reduction of excessive scars. This dual-targeted siRNA therapeutic approach exhibits potent anti-fibrotic activity through a newly discovered mechanism of action.” ([0005]).
XU teaches that: “When HKP and siRNA are mixed in aqueous solution with an optimized N/P ratio (4/1), the self-assembly of nanoparticles occurs through an electrostatic binding.” ([0054])(instant claims 19 & 21). The examiner notes that the electrostatic binding described by XU is clearly consistent with the peptide siRNA complexes described by Sajid et al. as necessary for delivery of siRNA in vivo for overcoming biological membranes (instant claim 8, mixing a nucleic acid solution and a solution of a branched histidine-lysine copolymer).
Regarding Applicants elected species, XU teaches that: “In one aspect of this embodiment, the histidine-lysine co-polymer comprises the histidine-lysine co-polymer species H3K4b or the histidine-lysine co-polymer species PT73. In another aspect of this embodiment, the histidine-lysine co-polymer has the formula (R)K(R)-K(R)-(R)K(X), where R=KHHHKHHHKHHHKHHHK, X=C(O)NH2, K=lysine, H=histidine, and N=asperagine. In still another aspect of this embodiment, the histidine-lysine co-polymer has the formula (R)K(R)-K(R)-(R)K(X), where R=KHHHKHHHKHHHKHHHK, or R=KHHHKHHHKHHHHKHHHK, X=C(O)NH2, K=lysine, H=histidine.” [emphases added](0046)(instant claims 10 & 20, HKP(+H) (SEQ ID NO:9)).
Ascertainment of the difference between
the prior art and the claims (MPEP 2141.02)
The difference between the rejected claims and the teachings of XU is that XU does not expressly teach the pH of the HKP solution or the pH of the nucleic acid solution on mixing; the ratio of the HKP copolymer to the nucleic acid is between about 2:2-1 to 3:1 (w/w).
DOHMEN teaches compositions for introducing nucleic acid into cells (title, see whole document) and particularly: “polymers comprising a characteristic combination of alkylene amine moieties which are useful as vehicles for transfecting a cell with a nucleic acid.” (abstract).
DOHMEN teaches that: “The polyplexes from the polymers with an even number of repeating aminoethylene units (PA-Es) achieved an order of magnitude higher transfection efficiency, without marked cytotoxicity, than those of the polymers with an odd number of repeating aminoethylene units (PA-Os). This odd-even effect agreed well with the buffering capacity of these polymers as well as their capability to disrupt membrane integrity selectively at endosomal pH, leading to highly effective endosomal escape of the PA-E polyplexes.” ([0006]).
DOHMEN teaches that: “In the compositions of the present invention, the copolymer and nucleic acid, in particular RNA, preferably single-stranded RNA such as mRNA, are typically contained, e.g., in a ratio weight copolymer/weight nucleic acid (w/w) of 0.25/1-50/1, preferably of 0.5/1-30/1, more preferably of 1/1-20/1.” ([0072])(instant claim 8, ratio of copolymer to nucleic acid)( MPEP 2144.05 - In the case where the claimed ranges "overlap or lie inside ranges disclosed by the prior art" a prima facie case of obviousness exists.).
DOHMEN teaches that: “It is well known to those skilled in the art that there is a large degree of flexibility with respect to the amount of substance of each component comprised in the composition according to the present invention. For example, so-called monomolecular binary polyplexes have been described for plasmid DNA where the composition consists of nanoparticles formed upon mixing of the polycation and the plasmid DNA which comprise exactly a single plasmid DNA molecule and as many polycation molecules which are required for charge neutralization or charge overcompensation (positive over negative). […] Summarizing, the compositions of the current invention are characterized by the input ratios of their components before self-assembly.” ([0083]).
DOHMEN teaches that: “The composition of the invention can be produced as described below. Typically, the nucleic acid, in particular RNA, preferably single-stranded RNA such as mRNA with a negative charge and the copolymers of the present invention preferably in a cationic form can self-assemble when brought in contact especially in a suitable solvent.” ([0085]). And that: “Copolymers in accordance with the present invention can be produced and purified as described herein. The copolymers can be stored in aqueous solution or in dried form, such as a dried powder, in which case they can be redissolved in aqueous medium, preferably water, before producing the composition. The pH of the solution is adjusted to neutral or slightly acidic (down to pH 4.5) with an acid, preferably with hydrochloric or citric acid, if required. In the case of RNA, preferably single-stranded RNA such as mRNA, being the nucleic acid comprised in the composition it is preferred that the pH is adjusted to about 4.5 to 5.5, preferably to about 4.9 to 5.1, more preferably to about 5.0.” ([0086])(instant claims 9-8, pH of copolymer solution and pH of nucleic acid solution).
STANTON teaches cationic lipids for oligonucleotide delivery (title, see whole document), and particularly that: “The present invention employs low molecular weight cationic lipids with one short lipid chain to enhance the efficiency and tolerability of in vivo delivery of siRNA.” (abstract).
STANTON teaches the process for LPN (lipid nanoparticle) production: “The Lipid Nano-Particles (LNP) are prepared by an impinging jet process. The particles are formed by mixing lipids dissolved in alcohol with siRNA dissolved in a citrate buffer. The mixing ratio of lipids to siRNA are targeted at 45-55% lipid and 65-45% siRNA. The lipid solution contains a novel cationic lipid of the instant invention, a helper lipid (cholesterol), PEG (e.g. PEG-C-DMA, PEG-DMG) lipid, and DSPC at a concentration of 5-15 mg/mL with a target of 9-12 mg/mL in an alcohol (for example ethanol). […]The siRNA solution contains one or more siRNA sequences at a concentration range from 0.3 to 1.0 mg/mL with a target of 0.3-0.9 mg/mL in a sodium citrate buffered salt solution with pH in the range of 3.5-5.” ([0183])(instant claim 8, the pH of the nucleic acid (siRNA) solution on mixing).
Finding of prima facie obviousness
Rationale and Motivation (MPEP 2142-2143)
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 produce a composition for delivery of a nucleic acid, particularly siRNA including a histidine-lysine copolymer (HKP) by preparing separate solutions and mixing them together, as suggested by XU, and to adjust the pH of each of the HKP-solution and the siRNA solution in the range of 4-5.5, as suggested by DOHMEN and STANTON, the mixing ratio being in the range of 1:1 to 1:20 (w/w), as suggested by DOHMEN in order to effectively delivery the siRNA to cells in vivo. The examiner further notes that Midoux et al.1 clearly teaches that: “Due to its protonation at pH 6.0, the imidazole ring of histidine is also a weak base, suitable to design cationic polymers exhibiting the capacity to condense DNA and to favour the [escape] of pDNA from endosomes (Figure 1).” therefore the pH of the HKP copolymer solution would have been adjusted to the acidic range to for a cation for self-assembly with the negatively charged nucleic acid as per the prior art discussed above and the ordinary level of knowledge in the art pertaining to HKP copolymers.
From the teachings of the references, it is apparent that one of ordinary skill in the art would have had a reasonable expectation of success in producing the claimed invention because it would have required no more than an ordinary level of skill in the art to adjust the pH of the HKP and siRNA solutions, and mixing ratio of the same, as per XU, producing the instantly claimed invention. Therefore, the invention as a whole would have been prima facie obvious to one of ordinary skill in the art before the effective filing date of the claimed invention, as evidenced by the references, especially in the absence of evidence to the contrary.
In light of the forgoing discussion, the Examiner concludes that the subject matter defined by the instant claims would have been obvious within the meaning of 35 USC 103(a).
Claims 11 and 12 remain rejected under 35 U.S.C. 103 as being unpatentable over XU in view of DOHMEN STANTON and Sajid et al., as applied to claims 8-10 and 19-21 above, and further in view of MALONEY (US 2014/0255400; published September, 2014) and BAKER (US 2012/0064136; published March, 2012).
Applicants Claims
Applicant claims a method of preparing a pharmaceutical nanoparticle composition, comprising mixing a nucleic acid solution having a pH of between about 4.0 and 6.9, and a solution of a branched histidine-lysine copolymer having a pH of between 5.5 and 6.0 wherein the ratio of histidine-lysine copolymer to nucleic acid is between about 2.5:1 to about 3:1 (w/w)(instant claim 8). Applicant further claims the method according to claim 8, wherein said histidine-lysine solution comprises ammonium acetate (claim 11) and sodium phosphate (claim 12).
Determination of the scope
and content of the prior art (MPEP 2141.01)
Sajid et al. teaches overcoming barriers for siRNA Therapeutics, as discussed above and incorporated herein by reference.
XU teaches Histidine Lysine co-Polymer (HKP) with selected siRNA duplexes targeting both TGF-β1 and COX-2 into an aqueous nanoparticle formulation, as discussed above and incorporated herein by reference.
DOHMEN teaches compositions for introducing nucleic acid into cells, as discussed above and incorporated herein by reference.
STANTON teaches cationic lipids for oligonucleotide delivery, as discussed above and incorporated herein by reference.
Ascertainment of the difference between
the prior art and the claims (MPEP 2141.02)
The difference between the rejected claims and the teachings of XU et al. is that XU et al. do not expressly teach the inclusion of ammonium acetate in the HKP solution or sodium phosphate in the nucleic acid solution.
MALONEY teaches polypeptide preparations including a buffer in a concentration of about 1 mM to about 15 mM that can include sodium phosphate and/or ammonium acetate, among others ([0003], [0012], [0045], claims 8-10)(instant claims 11-12). Regrading the amount of sodium phosphate: “In the case where the claimed ranges "overlap or lie inside ranges disclosed by the prior art" a prima facie case of obviousness exists.” (MPEP 2144.05-I).
BAKER teaches anti-aging nanoemulsion compositions (title, abstract) including pH adjuster such as sodium phosphate (claim 22, item b) and a buffer that includes ammonium acetate (claim 22, item c).
Regarding the amount of ammonium acetate “Generally, differences in concentration or temperature will not support the patentability of subject matter encompassed by the prior art unless there is evidence indicating such concentration or temperature is critical.” (MPEP §2144.05-II).
Finding of prima facie obviousness
Rationale and Motivation (MPEP 2142-2143)
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 produce a composition for delivery of a nucleic acid, particularly siRNA including a histidine-lysine copolymer (HKP) by preparing separate solutions and mixing them together, as suggested by XU, and to adjust the pH of each of the HKP-solution and the siRNA solution in the range of 4-5.5, as suggested by DOHMEN and STANTON, as discussed above, and further to utilize a known pH adjuster/buffer composition including sodium phosphate and/or ammonium acetate, as suggested by MALONEY and BAKER (MPEP §2144.07).
From the teachings of the references, it is apparent that one of ordinary skill in the art would have had a reasonable expectation of success in producing the claimed invention because it would have required no more than an ordinary level of skill in the art to adjust the pH of the HKP and siRNA solutions, and mixing ratio of the same, as per XU, producing the instantly claimed invention. Therefore, the invention as a whole would have been prima facie obvious to one of ordinary skill in the art before the effective filing date of the claimed invention, as evidenced by the references, especially in the absence of evidence to the contrary.
In light of the forgoing discussion, the Examiner concludes that the subject matter defined by the instant claims would have been obvious within the meaning of 35 USC 103(a).
Response to Arguments:
Applicant's arguments filed 12/03/2025 have been fully considered but they are not persuasive.
Applicant argues that: “Nothing in the cited references teaches or suggests that controlling either the nanoparticle size or size distribution (PDI) is desirable, let alone possible, and, accordingly, one skilled in the art would not even have been motivated to seek the surprising solution provided by the claimed methods. Accordingly, no prima facie case of obviousness exists and the rejection should be withdrawn.” (p. 6, 1st paragraph).
In response to applicant's argument that the references fail to show certain features of the invention, it is noted that the features upon which applicant relies (i.e., nanoparticle size and size distribution (PDI)) are not recited in the rejected claim(s). Although the claims are interpreted in light of the specification, limitations from the specification are not read into the claims. See In re Van Geuns, 988 F.2d 1181, 26 USPQ2d 1057 (Fed. Cir. 1993).
Applicant argues that: “The instant claims recite a very narrow range of ratios (from about 2.5:1 to about 3:1) of a specific type of polymer (HKP) to siRNA. By contrast, Dohmen is cited as teaching the use of a completely different polymer carrier where the narrowest range of ratios of polymer to siRNA is 1 : 1 to 20: 1. Nothing in Dohmen, or any of the other references, teaches or suggests using the narrow range of ratios recites in the instant claims, nor does Dohmen teach or suggest that restricting the ratio to the specific range recited in the claims would be desirable for any purpose, let alone that it could produce the surprising results with respect to particle size and PDI achieved by the claimed methods. Indeed, nothing in Dohmen teaches or suggests that, say, a ratio of 0.5: 1 would produce a result that is better or worse than a ratio of 50: 1.” (p. 6, 3rd paragraph). And further that: “The instant claims also recite use of an aqueous solution of a specific type of peptide polymer (HKP) that, at the pH ranges recited in the claims, has a particular charge distribution throughout the molecule, where that charge distribution is responsible for the mode of electrostatic binding to the nucleic acid. HKP is not a cationic lipid, nor does it structurally resemble a cationic lipid. As described above, the ratio of HKP to siRNA recited in the claimed methods is from about 2. 5: 1 to about 3: 1. By contrast, Stanton describes use of a non-aqueous ethanol solution of non-peptide cationic lipids, which are mixed with siRNA at a ratio of 45-55% lipid and 55-45% siRNA. This ratio range is significantly different than that recited in the instant claims. Moreover, the range of pH of the siRNA used by Stanton is significantly narrower than that recited in the instant claims, which presumably reflects the fact that Stanton used a completely different type of carrier molecule, with a completely different charge distribution in the carrier. Nothing in Stanton addresses the use of HKP as a carrier, nor does anything in Stanton teach or suggest replacing the cationic lipid with HKP. As such, nothing in Stanton would have suggested to one of ordinary skill in the art to mix an HKP solution at the pH range recited in the instant claims, let alone that doing so could produce the surprising results with respect to particle size and PDI achieved by the claimed methods.” (paragraph bridging pp. 6-7).
In response the examiner argues that it is Applicants opinion that the range is “very narrow” and MPEP §2144.05 makes clear that “In the case where the claimed ranges "overlap or lie inside ranges disclosed by the prior art" a prima facie case of obviousness exists” and DOHMEN teaches that: “In the compositions of the present invention, the copolymer and nucleic acid, in particular RNA, preferably single-stranded RNA such as mRNA, are typically contained, e.g., in a ratio weight copolymer/weight nucleic acid (w/w) of 0.25/1-50/1, preferably of 0.5/1-30/1, more preferably of 1/1-20/1.” ([0072]). Therefore, the range is considered prima facie obvious, and not a basis for patentability of the instantly rejected claims. The particle size and PDI are not limited by the claims. Regarding the pH of STANTON which is directed at cationic lipids for delivery of oligonucleotides, and teaches the pH of a their siRNA solution which is not different from the instantly rejected claims “a nucleic acid solution having a pH of between 4.0 and 6.9” (instant claim 8, line 2). STANTON teaching - “The siRNA solution contains one or more siRNA sequences at a concentration range from 0.3 to 1.0 mg/mL with a target of 0.3-0.9 mg/mL in a sodium citrate buffered salt solution with pH in the range of 3.5-5.” ([0183]). And furthermore, the instantly rejected claims are open to any additional components such as a cationic lipid disclosed (instant Specification, p. 12, [0063]; p. 22, [0103] through p. 23, [0106]).
Applicant further argues that: “For the reasons described above, nothing in the cited references teaches or suggests the specific pH ranges and HKP:nucleic acid ratios recited in the instant claims. Moreover, even if the combination of references were somehow to suggest the individual limitations of the instant claims (which they do not), nothing in the references or the art in general would have motivated the skilled artisan to make the combination. The rejection here relies purely on hindsight reasoning to identify individual purported aspects of the instant claims in four different references and fails to provide a proper rationale for combining the references. The rationale set forth in the office action relies on circular reasoning, asserting that it would have been obvious to vary the various parameters described in the cited art to arrive at the claimed invention, while omitting any explanation as to why the skilled artisan would even wish to vary those parameters. Moreover, none of the cited references, nor the combination of references, teaches or suggests anything about either particle size or PDI of the particle solution, let alone that controlling either parameter is either possible or desirable. Nothing in the combination of references would have suggested that the instantly claimed methods could have produced the surprising results with respect to particle size and PDI achieved by the instant claims.” (p. 7, 2nd paragraph).
In response the examiner maintains that: “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 produce a composition for delivery of a nucleic acid, particularly siRNA including a histidine-lysine copolymer (HKP) by preparing separate solutions and mixing them together, as suggested by XU, and to adjust the pH of each of the HKP-solution and the siRNA solution in the range of 4-5.5, as suggested by DOHMEN and STANTON, the mixing ratio being in the range of 1:1 to 1:20 (w/w), as suggested by DOHMEN in order to effectively delivery the siRNA to cells in vivo. The examiner further notes that Midoux et al.2 clearly teaches that: “Due to its protonation at pH 6.0, the imidazole ring of histidine is also a weak base, suitable to design cationic polymers exhibiting the capacity to condense DNA and to favour the [escape] of pDNA from endosomes (Figure 1).” therefore the pH of the HKP copolymer solution would have been adjusted to the acidic range to for a cation for self-assembly with the negatively charged nucleic acid as per the prior art discussed above and the ordinary level of knowledge in the art pertaining to HKP copolymers.”
In response to applicant's argument that the examiner's conclusion of obviousness is based upon improper hindsight reasoning, it must be recognized that any judgment on obviousness is in a sense necessarily a reconstruction based upon hindsight reasoning. But so long as it takes into account only knowledge which was within the level of ordinary skill at the time the claimed invention was made, and does not include knowledge gleaned only from the applicant's disclosure, such a reconstruction is proper. See In re McLaughlin, 443 F.2d 1392, 170 USPQ 209 (CCPA 1971).
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 §§ 706.02(l)(1) - 706.02(l)(3) 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 USPTO Internet website contains terminal disclaimer forms which may be used. Please visit www.uspto.gov/patent/patents-forms. The 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/process/file/efs/guidance/eTD-info-I.jsp.
Claims 8-12 and 19-21 are provisionally rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1-15 of copending Application No. 17/935,014 (hereafter ‘014) in view of XU (US 2020/0392507; published December, 2020) in view of DOHMEN (US 2018/0236090; published August, 2018); STANTON (US 2013/0178541; published July, 2013); Sajid et al. (“Overcoming the Barriers for siRNA Therapeutics: From Bench to Bedside,” 2020; MDPI); and MALONEY (US 2014/0255400; published September, 2014) and BAKER (US 2012/0064136; published March, 2012).
Instant claim is discussed above.
Copending ‘014 claim 1 recites a method of preparing a pharmaceutical composition, comprising mixing a nucleic acid solution and a histidine-lysine copolymer solution, wherein the histidine-lysine copolymer solution is mixed with the nucleic acid solution comprising one or more siRNA, miRNA and/or mRNA molecules, wherein the copolymer to nucleic acid ratio is between about 4.5:1 and about 2.0:1 (w/w). ‘014 claim 2 recites the method according to claim 1 wherein the nucleic acid solution has a pH between about 4.0 and 6.9, prior to mixing the histidine-lysine copolymer solution. ‘014 claim 4 recites the histidine-lysine copolymer is selected from HKP, HKP(+H), among others. ‘014 claim 6 recites acetate is added to the histidine-lysine copolymer solution in an amount of 11 to 20 percent. ‘014 claim 11 recites the phosphate anion is added to the copolymer in an amount between about 1 to about 2 mM.
The difference between the instantly rejected claims and the claims of copending ‘014 is that the claim of copending ‘014 do not expressly claim the pH of the histidine-lysine copolymer solution, or the species of acetate (ammonium acetate) or phosphate (sodium phosphate).
Sajid et al. teaches the motivation for encapsulation of siRNA in peptides for delivery to cells, as discussed above and incorporated herein by reference.
XU teaches histidine-lysine copolymers for delivery of siRNA including mixing the two in solutions to form an electrostatic bound complex for the same, as discussed above and incorporated herein by reference.
DOHMEN teaches compositions for introducing nucleic acid into cells, and particularly the pH of the nucleic acid solution and the polymer solution in the acidic range, as discussed above and incorporated herein by reference.
STANTON teaches cationic lipids for oligonucleotide delivery, and the process for LPN (lipid nanoparticle) production prepared by an impinging jet process, wherein the siRNA solution is in a buffered salt solution with pH in the range of 3.5-5, as discussed above and incorporated herein by reference.
It would have been prima facie obvious before the effective filing date of the claimed invention that the instantly rejected claims are an obvious variant of the claims of copending ‘014 because the claims are directed to substantially identical process of making HPK-siRNA nanoparticle compositions. The skilled artisan would have been motivated to modify the claims of copending ‘014 and produce the instantly rejected claim because the specific pH and the chemicals used would more particularly claim the scope of the method. Furthermore, the skilled artisan would have had a reasonable expectation of success in producing the invention of the instantly rejected claims because it would have required no more than an ordinary level of skill to produce the HPK-siRNA nanoparticle compositions using known method steps including adjusting the pH as needed.
This is a provisional obviousness-type double patenting rejection.
Response to Arguments:
Applicant's arguments filed 12/03/2025 have been fully considered but they are not persuasive.
The examiner acknowledges applicant's wish to hold the foregoing provisional obvious-type double patenting rejection in abeyance until allowable subject matter is indicated. Applicant is advised that the Patent Office does not hold either objections or rejections in abeyance, therefore the rejection is maintained.
Conclusion
Claims 8-12 and 19-21 are pending and have been examined on the merits. Claims 8-12 and 19-21 are rejected under 35 U.S.C. 103; and claims are provisionally rejected on the ground of nonstatutory double patenting as being unpatentable over claims of copending Application No. 17/935,014. No claims allowed at this time.
Applicant's amendment necessitated the new ground(s) of rejection presented in this Office action. Accordingly, THIS ACTION IS MADE FINAL. See MPEP § 706.07(a). 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 IVAN A GREENE whose telephone number is (571)270-5868. The examiner can normally be reached M-F, 8-5 PM PST.
Examiner interviews are available via telephone, in-person, and video conferencing using a USPTO supplied web-based collaboration tool. To schedule an interview, applicant is encouraged to use the USPTO Automated Interview Request (AIR) at http://www.uspto.gov/interviewpractice.
If attempts to reach the examiner by telephone are unsuccessful, the examiner’s supervisor, David Blanchard can be reached on (571) 272-0827. The fax phone number for the organization where this application or proceeding is assigned is 571-273-8300.
Information regarding the status of published or unpublished applications may be obtained from Patent Center. Unpublished application information in Patent Center is available to registered users. To file and manage patent submissions in Patent Center, visit: https://patentcenter.uspto.gov. Visit https://www.uspto.gov/patents/apply/patent-center for more information about Patent Center and https://www.uspto.gov/patents/docx for information about filing in DOCX format. For additional questions, contact the Electronic Business Center (EBC) at 866-217-9197 (toll-free). If you would like assistance from a USPTO Customer Service Representative, call 800-786-9199 (IN USA OR CANADA) or 571-272-1000.
/IVAN A GREENE/Examiner, Art Unit 1619
/GENEVIEVE S ALLEY/Primary Examiner, Art Unit 1617
1 “Chemical vectors for gene delivery: a current review on polymers, peptides and lipids containing histidine or imidazole as nucleic acids carriers,” British Journal of Pharmacology (2009), 157, 166–178; NPL Citation No. 5 on Applicant’s IDS dated 05/09/2023; and cited on the international search report for PCT/US2022/076886 which is the parent of the instant Application. See Midoux et al. at p. 168, col. 2, §Histidylated polylysine, lines 1-4.
2 “Chemical vectors for gene delivery: a current review on polymers, peptides and lipids containing histidine or imidazole as nucleic acids carriers,” British Journal of Pharmacology (2009), 157, 166–178; NPL Citation No. 5 on Applicant’s IDS dated 05/09/2023; and cited on the international search report for PCT/US2022/076886 which is the parent of the instant Application. See Midoux et al. at p. 168, col. 2, §Histidylated polylysine, lines 1-4.