DETAILED ACTION
Receipt of Arguments/Remarks filed on August 20 2026 is acknowledged. Claims 2-6, 8, 10-12, 14-16, 18, 20-23, 25-28, 31, 34-50, 53-57, 59, 61-62, 64-72, 74-85, 87-88, 90-92, 94 and 96-109 were/stand cancelled. Claims 1and 9 were amended. Claims 1, 7, 9, 13, 17, 19, 24, 29-30, 32-33, 51-52, 58, 60, 63, 73, 86, 89, 93 and 95 are pending and examined herein. Election was made without traverse in the reply filed on March 2 2026.
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 .
Withdrawn Rejections
The amendment filed August 20 2026 is sufficient to overcome the rejection of claim 9 under 35 USC 112(b). The claim clarifies the nucleotide sequence has from about 10 to about 30 nucleotides in length.
The arguments filed August 20 2026 are sufficient to overcome the rejection of claim 29. While applicants point to paragraph 0202 of the specification as filed, the examiner believes Applicants mean paragraph 0203 (page 52-53) which recites D-amino acids as well as unnatural basic amino acids which fall within the scope.
The terminal disclaimer filed on August 20 2026 disclaiming the terminal portion of any patent granted on this application which would extend beyond the expiration date of any patent granted on US Application No. 18259622 has been reviewed and is accepted. The terminal disclaimer has been recorded.
Therefore, in light of the filing of the terminal disclaimer the rejection of claims 1, 7, 13, 17, 19, 24, 29-30, 32-33, 51-52, 58, 60, 63, 73, 86, 89 and 95 on the ground of nonstatutory double patenting as being unpatentable over claims 1, 10, 15, 36, 40, 42, 47, 52-53, 55-56, 74-75, 79, 82, 85, 95, 118, 121, 124 and 127 of copending Application No. 18259622 (USPGPUB NO. 20240091151) is withdrawn.
Claim Rejections - 35 USC § 112
The following is a quotation of 35 U.S.C. 112(b):
(b) CONCLUSION.—The specification shall conclude with one or more claims particularly pointing out and distinctly claiming the subject matter which the inventor or a joint inventor regards as the invention.
The following is a quotation of 35 U.S.C. 112 (pre-AIA ), second paragraph:
The specification shall conclude with one or more claims particularly pointing out and distinctly claiming the subject matter which the applicant regards as his invention.
Claims 1, 7, 9, 13, 17, 19, 24. 29-30, 32-33, 51-52, 58, 60, 63, 73, 86, 89, 93 and 95 are rejected under 35 U.S.C. 112(b) or 35 U.S.C. 112 (pre-AIA ), second paragraph, as being indefinite for failing to particularly point out and distinctly claim the subject matter which the inventor or a joint inventor (or for applications subject to pre-AIA 35 U.S.C. 112, the applicant), regards as the invention.
Claim 1 recites a cationic carrier unit comprising various schemes. Each scheme contains a HM which stands for hydrophobic moiety. There is no limiting definition for this term in the instant specification. Therefore the BRI of HM is its normal art recognized definition which, as evidenced by Moore (HZO, November 14 2012) referring to the Meriam-Webster dictionary, is resistant to or avoiding wetting which is practically the opposite of hydrophilic which is defined as of, relating to, or having a strong affinity for water. Dependent claim 51 recites the hydrophobic moiety is one or more amino acids linked to a vitamin wherein the vitamin is selected from a particular list. Claim 52 recites the vitamin is vitamin B3. Specific amino acid-vitamin B3 claimed (and elected) is lysine-vitamin B3. However, neither lysine nor vitamin B3 is hydrophobic. As evidenced by the Nutrition Source, Niacin aka vitamin B3 is a water-soluble (aka hydrophilic) B vitamin. As evidenced by ECHEMI lysine is highly hydrophilic. Therefore, the elected species of the hydrophobic moiety is made up of two hydrophilic groups (e.g. lysine and vitamin B3). This creates uncertainty to the scope of hydrophobic moiety because the specifically claimed species for hydrophobic moiety are hydrophilic. While the recitation lysine-vitamin B3 is not indefinite, it is not clear from the specification or the claims if something must be connected to this moiety in order to make it hydrophobic. The specific examples of “hydrophobic” moiety creates uncertainty to the scope of this moiety because the specific species are not hydrophobic but hydrophilic. While there are amino acids which the art recognizes as hydrophobic, for example valine, and while there are vitamins which are hydrophobic, for example vitamin D, the full scope of the amino acids and vitamins as expressly claimed include hydrophilic species creating confusion of the scope.
Claims 7, 9, 13, 19, 24, 29-30, 32-33, 63, 73, 86, 89, 93 and 95 are included in the rejection as they depend on a rejected base claim and they do not clarify the issues.
Response to Arguments
Applicants’ arguments filed August 20 2026 have been fully considered but they are not persuasive.
Applicants argue that paragraph 0213 of the specification provides a definition for the term hydrophobic moiety. A person of ordinary skill in the art having read paragraph 0213 would reasonably understand that moieties such as lysine and vitamin B3 would fall within the definition of hydrophobic moiety.
MPEP 2173.05(a) is clear that terms used contrary to their ordinary meaning must be clearly redefined in the written description. The paragraph pointed to by Applicants does not provide a limiting definition. This paragraph states that the term hydrophobic moiety, as used herein, refers to a molecular entity that can, e.g…. The use of the e.g. means “for example”, this is not a limiting definition. This paragraph provides examples of what hydrophobic moiety could mean but does not clearly define the term such that one skilled in the art would be apprised of the scope. While lysine may be considered as falling within the scope of (vi) contribute positively charged groups to the cationic carried moiety, it is not clear what definition vitamin B3 would fall under. Furthermore, none of these i-vi provide structure (other than positive charge) and applicants appear to be trying to include as “definitions” functions opposed to actual structural requirements. Therefore, the recitation “hydrophobic moiety” is still deemed indefinite as Applicants intend to define the term contrary to its customary meaning and the specification fails to clearly redefine the term as required.
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 of this title, 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 set forth in Graham v. John Deere Co., 383 U.S. 1, 148 USPQ 459 (1966), that are applied for establishing a background for determining obviousness under 35 U.S.C. 103 are summarized as follows:
1. Determining the scope and contents of the prior art.
2. Ascertaining the differences between the prior art and the claims at issue.
3. Resolving the level of ordinary skill in the pertinent art.
4. Considering objective evidence present in the application indicating obviousness or nonobviousness.
This application currently names joint inventors. In considering patentability of the claims the examiner presumes that the subject matter of the various claims was commonly owned as of the effective filing date of the claimed invention(s) absent any evidence to the contrary. Applicant is advised of the obligation under 37 CFR 1.56 to point out the inventor and effective filing dates of each claim that was not commonly owned as of the effective filing date of the later invention in order for the examiner to consider the applicability of 35 U.S.C. 102(b)(2)(C) for any potential 35 U.S.C. 102(a)(2) prior art against the later invention.
Claims 1, 13, 17, 19, 24, 29-30, 32-33, 51-52, 58, 60, 63, 73, 86 and 95 are rejected under 35 U.S.C. 103 as being unpatentable over Kakizawa et al. (Biomacromolecules, 2001) in view of Urello et al. (Biomacromolecules 2020).
Applicant Claims
The instant application claims a cationic carrier unit comprising
[CC]-L1-[CM]-L2-[HM] (Schema I);
[CC]-L1-[HM]-L2-[CM] (Schema II);
[HM]-L1-[CM]-L2-[CC] (Schema III);
[HM]-L1-[CC]-L2-[CM] (Schema IV);
[CM]-L1-[CC]-L2-[HM] (Schema V);
or [CM]-L1-[HM]-L2-[CC] (Schema VI); wherein CC is a cationic carrier moiety (lysine as elected) ;CM is a crosslinking moiety (lysine-thiol as elected) ;HM is a hydrophobic moiety (lysine-vitamin B3 as elected); and,L1 and L2 are independently optional linkers, and wherein the number of HM is less than about 50% relative to [CC] and [CM].
Determination of the Scope and Content of the Prior Art
(MPEP §2141.01)
Kakizawa et al. is directed to glutathione-sensitive stabilization of block copolymer micelles composed of antisense DNA and thiolated poly(ethylene glycol)-block-poly(L-lysine) as a potential carrier for systemic delivery of antisense DNA. Antisense oligonucleotide (ODN) has emerged as a potential new drug which inhibits the intracellular expression of disease-causing genes. The ability of ODN in clinical use, however, is still insufficient due to instability in biological fluids and a low uptake efficiency into the target cell. To circumvent these obstacles, two general approaches have been studied: chemical modification of ODN and the utilization of delivery systems. Taught are polymeric micelles composed of blocks of copolymers of poly(ethylene glycol) (PEG) and poly(amino acid) as delivery vehicles of anticancer drugs. Recently candidate of drugs has been expanded to include proteins, plasmid DNA, and oligonucleotides. To entrap negatively charged DNA into the core of micelles, block copolymers of PEG with positively charged poly(l-lysine )(PLL) was utilized to induce micelle formation through electrostatic interaction. Eventually, the block copolymer, PEG-PLL, and DNA spontaneously associate in aqueous milieu to form the polymeric micelle with the core of polyion complex between DNA and the PLL segment of the block copolymer. Although this produced remarkable improvement in protection from enzyme attack, the ability of the micelle entrapping ODN is still not sufficient in the bloodstream and the circulating life of oligonucleotides complexed with PEG-PLL after IV injection was not much different than of free ODN (page 491). Increasing the stabilization of PIC micelles was achieved by crosslinking of the inner core of micelles through disulfide bonds. Disulfide bonds were chosen because the bond is known to be stable in the blood and cleaved inside the cell (page 491). Once inside the cell the disulfide linkage should be degrading leading to the release of the entrapped DNA (page 492). Shown in Scheme 1 is the introduction of thiol groups into the lysine residues:
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Introduction of thiol groups on the PLL segment causes a decrease in the charge density of PLL, which may influence the property of the resultant PIC micelles. It should be noted that the charge density of polymer strands is one of the main factors affecting the association behavior of oppositely charged polyelectrolytes, particularly the observation of a critical charge density to form multimolecular associates. Thiolation degrees of 10 and 26% of the amino groups were used. This corresponds to an average of 3.9- and 10-unit substitutions of 39 lysine residues in each polymer (page 493, right column; page 494, left column). Increasing the molecule weight of the PEG segment may permit the system to achieve sufficient stabilization (page 494-495 bridging paragraph).
Ascertainment of the Difference Between Scope the Prior Art and the Claims
(MPEP §2141.02)
While Kakizawa et al. teach a cationic carrier unit comprising a cationic carrier moiety (lysine), crosslinking moiety (lysine-thiol), a water soluble polymer (PEG) and an anionic payload which is an oligonucleotide and discusses stability issues with the delivery of oligonucleotides, Kaikara et al. does not teach the inclusion of lysine-vitamin B3. However, this deficiency is cured by Urello et al.
Urello et al. is directed to metabolite-based modification of poly (L-lysine) for improved gene delivery. Electrostatic interactions between DNA and cationic materials drive self-assembly of nano- or microparticle structures with size and shape controlled by material type and condensation conditions. Formulation of DNA into nanoparticles improves cell uptake due to charge neutralization and protection from degradation in the extracellular space; however, internalization by endocytosis results in sequestration into acidic lysosome compartments. To overcome the biological barrier of lysosome entrapment, materials may be engineered to contain protonatable groups such as secondary or tertiary amines with pKa’s between 4 and 7 that become ionized at low pH and facilitate cytoplasmic entry of DNA. This property aids in the cellular release of nucleic acids within target cells by creating an osmotic imbalance that ruptures the vesicle and/or destabilizes the lysosome membrane, allowing contents to escape into the cytosol (3596, left column). Current DNA delivery systems are limited in vivo by low stability, high toxicity and inefficient cytoplasmic entry of nucleic acid cargo. Materials have been designed to contain features such as disulfide crosslinks to increase stability. However, translation of gene-delivery technologies into pharmaceutical formulations has been lacking. Possible reasons could be due to difficulties in achieving optimal balance among formulation properties (page 9596, right column). Taught are multipurpose modifiers that increase the transfection efficiency of the classic polymeric gene delivery material poly(L-lysine). Modifiers were employed to enable (i) enhancing buffering properties tuned to allow protonation during the pH transition that occurs during cellular internalization and lysosomal trafficking, (ii) stability enhancement through non-electrostatic interactions, and (iii) increased biocompatibility through the use of metabolite-based core units. These multipurpose modifiers contained tertiary amines and polarizable functional groups comprising sulfur or conjugated pi systems. Moreover, these sulfur- and π system-containing species were inspired by the natural metabolites nicotinic acid (niacin or vitamin B3) and thiomorpholine. Thiomorpholine has intrinsic buffering properties, whereas niacin required addition of a morpholine ring to impart desired buffering functionality. Modifiers contained activated esters for simple coupling to primary amines of lysine, allowing a range of materials with different properties to be prepared from each modifier. PLL modification with morpholine-niacin or thiomorpholine resulted in both enhanced buffering capacity over the pH range of 7.4–4.5 and higher nanoparticle stability in vitro and in vivo. Modified PLLs showed improved transfection without associated toxicity or pH-dependent membrane activity. Finally, muscle expression was achieved for over 6 weeks with niacin-modified PLL-DNA nanoparticles following intramuscular injection in mice (page 3597). Exemplified are Poly(L-lysine) and PEG-Poly(L-lysine) with the modifications. The PEG-PLL is taught has having 50 lysine units. (page 3597). As shown in scheme 1, the number of MN range from 0 to 20 (R2, m) wherein the non-modified lysine are 50-m (R2,n).
Finding of Prima Facie Obviousness Rationale and Motivation
(MPEP §2142-2143)
It would have been obvious to one of ordinary skill in the art before the effective filing date of the claimed invention to combine the teachings of Kakizawa et al. and Urello et al. and incorporate nicotinic acid modification in the PEG-polylysine of Kakizawa et al. One skilled in the art would have been motivated to incorporate the morpholine-niacin of Urello et al. in order to enhance transfection of the oligonucleotide as taught by Urello et al. Since both Kakizawa et al. and Urello et al. are concerned with oligonucleotide delivery via PEG-PLL and both recognize the stability issues associated with these delivery systems, one skilled in the art would have a reasonable expectation of success. Urello et al. recognizes that the incorporation of disulfides, which are taught by Kakizawa et al., enhance stability but not transfection. Thus, the combination of the thiol groups Kakizawa et al. and the morpholine-niacin of Urello et al. would be expected to enhance stability of the delivery system as well as enhance transfection of the oligonucleotide.
Regarding the claimed scheme of claim 1 and 17, Kakizawa et al. teaches a block polymer. The first block is PEG followed by PLL. As shown in Scheme 1 of Kakizawa the polymer then has a block of lysine (CC) followed by a block of thiol derivative (CM). Further attachment of the morpholine-lysine (HM) would result in Schema I/I’.
Regarding the claimed number of HM, Urello et al. teaches a total of 50 lysine and the morpholine-niacin is at most on 20 which is less than about 50%.
Regarding claim 13 and 19, both Kakizawa et al. and Urello et al. teach a PEG-PLL wherein PEG reads on WP.
Regarding claims 24 and 29, lysine is taught as the cationic amino acid.
Regarding claims 32-33, a thiol group attached to lysine is taught.
Regarding claim 51-52, lysine linked to vitamin B3 is taught.
Regarding claim 30, 58 and 60 both Kakizawa et al. and Urello et al. teaches total lengths of lysine chains falling within the scope claimed. Furthermore, Kakizawa et al. teaches thiolation degrees of 10 and 26% of the amino groups were used. This corresponds to an average of 3.9- and 10-unit substitutions of 39 lysine residues in each polymer (page 493, right column; page 494, left column). Since the thiol is taught for stabilization and the morpholine-niacin is taught for transfection efficiency, one skilled in the art would manipulate the amount of the various components of the cationic carrier to achieve the desired effect. Since the positive charge is required to complex with the negatively charged oligonucleotide, one skilled in the art would recognize there needs to be a sufficient number of cationic charge in order to complex with the negatively charged oligonucleotide in order to have a complex for delivery. 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.
Regarding claim 63, Kakizawa et al. teaches for efficient delivery of drugs to the target site, it is essential to reduce the nonspecific capture by the reticuloendothelial systems (RES) located in the liver and the spleen. DNA/PLL complexes adsorb plasma proteins on their surface, which presumably promotes the subsequent uptake by phagocytes of the RES. Hence, the PEG layer surrounding PIC is particularly advantageous for DNA/polycation delivery systems (page 493, last paragraph). Urello et al. teaches that DNA expression with PEG-PLL(MN) nanoparticles was 20% greater than PEI, demonstrating the potential of PEGylated nanoparticles to deliver DNA into cells even the presence of complex biological milieu. Targeting ligands can overcome reliance on chloroquine. The addition of cell-targeting ligands would be beneficial (page 3603). Therefore, both Kakizawa et al. and Urello et al. suggest that PEG can be used to improve delivery to the desired cells. Both also suggest that a targeting ligand can be attached with Urello et al. expressly suggesting its benefit. It would have been obvious to one of ordinary skill in the art before the effective filing date of the claimed invention to combine the teachings of Kakizawa et al. and Urello et al. and utilize a targeting ligand in order to improve uptake as suggested by Urello et al.
Regarding claims 73 and 86, a micelle is taught by Kakizawa et al. which is complexed with an anionic oligonucleotide (aka nucleic acid). Kakizawa et al. teaches one of the major obstacles, other than stability, is the low efficiency of the uptake of oligonucleotides into cells. This can be improved by utilizing the receptor-mediated endocytosis mechanism using ligand-installed PIC micelles prepared from PEG-PLL with a ligand attached to the terminal end of the PEG (page 497).
Regarding claim 95, exemplified by Kakizawa et al. dialysis of the crosslinked micelles against PBS (page 492, right column) which results in a pharmaceutical composition of the crosslinked micelles and PBS.
Claim 7, 9, 89 and 93 are rejected under 35 U.S.C. 103 as being unpatentable over Kakizawa et al. in view of Urello et al. as applied to claims 1, 13, 17, 19, 24, 29-30, 32-33, 51-52, 58, 60, 63, 73, 86 and 95 above and in further view of Vermeulen et al. (USPGPUB No. 20100184209) and Couturier et al. (PLoS One, 2014) as evidenced by Lewkowicz et al. (J Neurosci, 2015).
Applicant Claims
The instant application claims wherein the anionic payload comprises a nucleotide sequence having less than 200 nucleotides in length. The instant application claims the nucleic acid comprises the nucleotide sequence as set forth in SEQ ID NO: 18. The instant application claims the nucleic acid comprises at least one nucleoside analog, wherein the nucleoside analog comprises Locked Nucleic Acid (LNA); 2'-O-alkyl-RNA; 2'-amino-DNA; 2'-fluoro-DNA; arabino nucleic acid (ANA); 2'- fluoro-ANA, hexitol nucleic acid (HNA), intercalating nucleic acid (INA), constrained ethyl nucleoside (cEt), 2'-O-methyl nucleic acid (2'-OMe), 2'-O-methoxyethyl nucleic acid (2'- MOE), or any combination thereof.
Determination of the Scope and Content of the Prior Art
(MPEP §2141.01)
The teachings of Kakizawa et al. and Urello et al. are set forth above.
Ascertainment of the Difference Between Scope the Prior Art and the Claims
(MPEP §2141.02)
While Kakizawa et al. teaches an anionic nucleic acid, Kakizawa et al. does not expressly teach a modified nucleic acid or a sequence as set forth in SEQ ID NO: 18. However, these deficiencies are cured by Vermeulen et al. and Couturier et al. as evidenced by Lewkowicz et al.
Vermeulen et al. is directed to composition and methods for inhibiting gene silencing by RNA interference (RNAi). The RNAi inhibitors have a reverse complement region to the target molecule of interest (e.g. miRNA) (abstract). As claimed the inhibitor has a 2’ modification. These include 2’-O-alkyl (claim 5-6). The inhibitors of the invention can be used to inhibit a broad range of miRNA (paragraph 0165). The present invention through the use of modified polynucleotides one may improve the efficacy of RNA interference applications (paragraph 0060). Cationic polymers are taught (paragraph 0133).
One inhibitor taught is SEQ ID No: 420:
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Which has 100% identity to instantly claimed SEQ ID NO: 18 (Qy):
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Couturier et al. is directed to niacin in pharmaceutical doses alters microRNA expression in skeletal muscle of obese Zucker rats. Shown in table 1 is the most strongly up-regulated and down-regulated miRNAs in M. rectus femoris of obese Zucker rats fed either control diet or high-niacin diet. One of the down-regulated miRNA is miR-485-3p.
As evidenced by Lewkowicz et al., the NCBI assession No. of miR-485-3p is MIMTA0003129.
Finding of Prima Facie Obviousness Rationale and Motivation
(MPEP §2142-2143)
It would have been obvious to one of ordinary skill in the art before the effective filing date of the claimed invention to combine the teachings of Kakizawa et al., Urello et al., Vermeulen et al. and Couturier et al. and utilize an miR inhibitor with the cationic carrier. One skilled in the art would have been motivated to utilize the cationic carrier with an miR inhibitor in order to enhance delivery of the oligonucleotide. Since Kakizawa et al. suggests the use of the cationic carrier with oligonucleotides there is a reasonable expectation of success.
It would have been obvious to one of ordinary skill in the art before the effective filing date of the claimed invention to combine the teachings of Kakizawa et al., Urello et al., Vermeulen et al. and Couturier et al. and utilize a modified nucleic acid. One skilled in the art would have been motivated to utilize a modified nucleic acid in order to improve the efficacy of RNA interference applications as taught by Vermeulen et al.
Regarding claims 7 and 9, the exemplified inhibitors are less than 30 and greater than 10.
Regarding claim 93, as set forth above Vermeulen et al. teaches a sequence with 100% identity with instantly claimed SEQ ID No: 18. It would have been obvious to one of ordinary skill in the art before the effective filing date of the claimed invention to combine the teachings of Kakizawa et al., Urello et al., Vermeulen et al. and Couturier et al. and utilize SEQ ID NO:420 with the carrier as Couturier et al. teaches that niacin administration down regulates miR-485-3p. This particular inhibitor of Vermeulen et al., as evidenced by Lewkowicz et al. is a miR-485-3p inhibitor which would be expected to down regulate (aka inhibit) this miR. Therefore, one skilled in the art would have been motivated to utilize inhibitor SEQ ID NO: 420 and niacin as both are taught for the same purpose. As a general principle it is prima facie obvious to combine two compositions each of which is taught by the prior art to be useful for the same purpose, in order to form a third composition to be used for the very same purpose, the idea of combining them flows logically from their having been individually taught in the prior art. See In re Kerkhoven, 626 F.2d 846, 850, 205 USPQ 1069, 1072 (CCPA 1980) MPEP 2144.06.
Response to Arguments
Applicants’ arguments filed August 20 2026 have been fully considered but they are not persuasive.
Applicants argue that as acknowledged by the Office, Kakizawa does not teach a cationic carrier comprising a hydrophobic moiety comprising lysine-vitamin B3. It is argued that the Office asserts Urello overcomes these deficiencies of Kakizawa, however, Applicants argue that Urello fails to overcome the deficiencies. Urello discloses morpholino-niacin and does not teach the use of an unmodified lysine-vitamin B3 as recited in the pending claims. Applicants point to their table 1 which shows vitamin B3 compared to morpholine-niacin of Urello. The compound of Urello is structurally and chemical distinct from the vitamin B3 moiety recited in the pending claims. Urello attributes the beneficial properties of the morpholine-niacin moiety to the morpholine ring. It is argued that Vermeulen, Couturier and Lewkowicz do not cure the deficiencies of Kakizawa and Urello.
Regarding Applicants’ arguments, nothing in the claims excludes additional functionality from being present. The attachment of the morpholino-niacin of Urello via the carboxylic acid to lysine would result in lysine-vitamin B3 as required by the claims. Applicants argue on page 7 or the remarks filed the scope of the term hydrophobic moiety which includes (i) complement the therapeutic or prophylactic activity of the payload, (ii) modulate the therapeutic or prophylactic activity of the payload. The payload in the instant claims and Kakizawa et al. is an oligonucleotide. The morpholino-niacin of Urello is taught as enhancing transfection of the oligonucleotides meaning that this compound complements the therapeutic or prophylactic activity of the payload. Therefore, a morpholino group is not excluded by the recitation hydrophobic moiety. While claim 51 recites the hydrophobic moiety is one or more amino acids linked to a vitamin and 51 recites the vitamin is vitamin B3, the examiner does not interpret this as excluding additional hydrophobic moieties from being present. These claims require an amino acid (aka lysine) and a vitamin B3. The recitation morpholino-niacin is a vitamin B3 as nothing in the claims limit the scope of the vitamin B3 to consist of niacin. The use of this vitamin B3 still results in lysine covalently bound to a vitamin B3 which is required by the claims. Therefore, Applicants are taking a much narrower interpretation of the claims than currently presented as nothing in the claim limits the scope of the hydrophobic moiety to consist of lysine covalently bound to niacin.
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, 7, 9, 13, 17, 19, 24, 29-30, 32-33, 51-52, 58, 60, 63, 73, 86, 89 and 95 are rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1-23 of U.S. Patent No. 11839624 in view of Kakizawa et al. Although the conflicting claims are not identical, they are not patentably distinct from each other because both sets of claims overlap in scope.
The instant application claims a cationic carrier unit comprising
[CC]-L1-[CM]-L2-[HM] (Schema I);
[CC]-L1-[HM]-L2-[CM] (Schema II);
[HM]-L1-[CM]-L2-[CC] (Schema III);
[HM]-L1-[CC]-L2-[CM] (Schema IV);
[CM]-L1-[CC]-L2-[HM] (Schema V);
or [CM]-L1-[HM]-L2-[CC] (Schema VI); wherein CC is a cationic carrier moiety (lysine as elected) ;CM is a crosslinking moiety (lysine-thiol as elected) ;HM is a hydrophobic moiety (lysine-vitamin B3 as elected); andL1 and L2 are independently optional linkers, and wherein the number of HM is less than about 50% relative to [CC] and [CM].
Patent ‘624 claims a micelle comprising a plurality of cationic carrier units and an anionic payload, wherein each cationic carrier unit comprises (i) a water-soluble biopolymer moiety comprising polyethylene glycol (PEG) (instantly claimed WP), (ii) a positively charged carrier moiety polylysine comprising which comprises lysine units (reading on instantly claimed CC), (iii) an adjuvant moiety comprising 20 to 50 vitamin B3 units (reading on instantly claimed HM), and (iv) a targeting moiety comprising a ligand that can be transported by large neutral amino acid transporter 1 (LAT1) (reading on targeting moiety of claim 63), wherein the polylysine comprises (a) some lysine units covalently linked to the adjuvant moiety (“AM-linked lysine unit”) and (b) some lysine units that are positively charged, wherein each AM-linked lysine unit is covalently linked to a vitamin B3 unit, wherein the charged carrier moieties of the plurality of cationic carrier units and the anionic payload are associated with each other via a covalent bond, a non-covalent bond, or an ionic bond, and wherein the water-soluble biopolymer moiety comprising PEG and the positively charged carrier moiety comprising polylysine are attached to each other directly or through a bifunctional linker (claim 1). Payload includes nucleic acids such as miRNA, antisense and antimir (claim 5).
While Patent ‘624 claims a cationic carrier, Patent ‘624 does not expressly claim a thiolated portion (i.e. instantly claimed CC). However, this deficiency is cured by Kakizawa et al.
Kakizawa et al. is directed to glutathione-sensitive stabilization of block copolymer micelles composed of antisense DNA and thiolated poly(ethylene glycol)-block-poly(L-lysine) as a potential carrier for systemic delivery of antisense DNA. Antisense oligonucleotide (ODN) has emerged as a potential new drug which inhibits the intracellular expression of disease-causing genes. The ability of ODN in clinical use, however, is still insufficient due to instability in biological fluids and a low uptake efficiency into the target cell. To circumvent these obstacles, two general approaches have been studied: chemical modification of ODN and the utilization of delivery systems. Taught are polymeric micelles composed of blocks of copolymers of poly(ethylene glycol) (PEG) and poly(amino acid) as delivery vehicles of anticancer drugs. Recently candidate of drugs has been expanded to include proteins, plasmid DNA, and oligonucleotides. To entrap negatively charged DNA into the core of micelles, block copolymers of PEG with positively charged poly(l-lysine )(PLL) was utilized to induce micelle formation through electrostatic interaction. Eventually, the block copolymer, PEG-PLL, and DNA spontaneously associate in aqueous milieu to form the polymeric micelle with the core of polyion complex between DNA and the PLL segment of the block copolymer. Although this produced remarkable improvement in protection from enzyme attack, the ability of the micelle entrapping ODN is still not sufficient in the bloodstream and the circulating life of oligonucleotides complexed with PEG-PLL after IV injection was not much different than of free ODN (page 491). Increasing the stabilization of PIC micelles was achieved by crosslinking of the inner core of micelles through disulfide bonds. Disulfide bonds were chosen because the bond is known to be stable in the blood and cleaved inside the cell (page 491). Once inside the cell the disulfide linkage should be degrading leading to the release of the entrapped DNA (page 492). Shown in Scheme 1 is the introduction of thiol groups into the lysine residues:
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Introduction of thiol groups on the PLL segment causes a decrease in the charge density of PLL, which may influence the property of the resultant PIC micelles. It should be noted that the charge density of polymer strands is one of the main factors affecting the association behavior of oppositely charged polyelectrolytes, particularly the observation of a critical charge density to form multimolecular associates. Thiolation degrees of 10 and 26% of the amino groups were used. This corresponds to an average of 3.9- and 10-unit substitutions of 39 lysine residues in each polymer (page 493, right column; page 494, left column). Increasing the molecule weight of the PEG segment may permit the system to achieve sufficient stabilization (page 494-495 bridging paragraph).
It would have been obvious to one of ordinary skill in the art before the effective filing date of the claimed invention to combine the teachings of Patent ‘624 and Kakizawa et al. and thiolate a portion of the lysine groups of the cationic carrier. One skilled in the art would have been motivated to thiolate a portion of the lysines in order to increase stability as taught by Kakizawa et al. There is a reasonable expectation of success as both Patent ‘624 and Kakizawa et al. teach micelles formation for complexation with an anionic oligonucleotide. This suggests claims 1, 13, 17, 19, 24, 29, 32, 33, 51, 52, 63, 73, 86 and 95.
Regarding claim 7, 9, Patent ‘624 claims a nucleotide sequence having 5 to 30 nucleotides in length (claim 7).
Regarding claim 30, Patent ‘624 claims the polylysine claims between 25 and 100 lysines which overlaps the instant claims. In the case where the claimed ranges "overlap or lie inside ranges disclosed by the prior art" a prima facie case of obviousness exists. In re Wertheim, 541 F.2d 257, 191 USPQ 90 (CCPA 1976); In re Woodruff, 919 F.2d 1575, 16 USPQ2d 1934 (Fed. Cir. 1990). Note MPEP 2144.05.
Regarding claims 58 and 60, Patent ‘624 claims an overlapping number of lysine and vitamin B3 units. Kakizawa et al. teaches thiolation degrees of 10 and 26% of the amino groups were used. This corresponds to an average of 3.9- and 10-unit substitutions of 39 lysine residues in each polymer (page 493, right column; page 494, left column). Since the thiol is taught for stabilization, one skilled in the art would manipulate the amount of the various components of the cationic carrier to achieve the desired effect. Since the positive charge is required to complex with the negatively charged oligonucleotide, one skilled in the art would recognize there needs to be a sufficient number of cationic charge in order to complex with the negatively charged oligonucleotide in order to have a complex for delivery. 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.
Regarding claim 89, Patent ‘624 claims the same in claim 6.
Claim 93 is rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1-23 of U.S. Patent No. 11839624 in view of Kakizawa et al. as applied to claims 1, 7, 9, 13, 17, 19, 24, 29-30, 32-33, 51-52, 58, 60, 63, 73, 86, 89 and 95 above and in further view of Vermeulen et al. and Couturier et al. as evidenced by Lewkowicz et al. Although the conflicting claims are not identical, they are not patentably distinct from each other because both sets of claims overlap in scope.
The instant application claims wherein the nucleic acid comprises the nucleotide sequence as set forth in SEQ ID NO: 18 (miR-485 3p inhibitor).
The teachings of Patent ‘624 and Kakizawa et al. are set forth above.
While Patent ‘624 claims a nucleic acid payload and teaches vitamin B3 with the cationic carrier, Kakizawa et al. does not expressly claim a sequence as set forth in SEQ ID NO: 18. However, this deficiency is cured by Vermeulen et al. and Couturier et al.
Vermeulen et al. is directed to composition and methods for inhibiting gene silencing by RNA interference (RNAi). The RNAi inhibitors have a reverse complement region to the target molecule of interest (e.g. miRNA) (abstract). As claimed the inhibitor has a 2’ modification. These include 2’-O-alkyl (claim 5-6). The inhibitors of the invention can be used to inhibit a broad range of miRNA (paragraph 0165). The present invention through the use of modified polynucleotides one may improve the efficacy of RNA interference applications (paragraph 0060). Cationic polymers taught (paragraph 0133).
One inhibitor taught is SEQ ID No: 420:
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Which has 100% identity to instantly claimed SEQ ID NO: 18 (Qy):
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Couturier et al. is directed to niacin in pharmaceutical doses alters microRNA expression in skeletal muscle of obese Zucker rats. Shown in table 1 is the most strongly up-regulated and down-regulated miRNAs in M. rectus femoris of obese Zucker rats fed either control diet or high-niacin diet. One of the down-regulated miRNA is miR-485-3p.
As evidenced by Lewkowicz et al., the NCBI assession No. of miR-485-3p is MIMTA0003129.
Regarding claim 93, as set forth above Vermeulen et al. teaches a sequence with 100% identity with instantly claimed SEQ ID No: 18. It would have been obvious to one of ordinary skill in the art before the effective filing date of the claimed invention to combine the teachings of Patent ‘624, Kakizawa et al., Vermeulen et al. and Couturier et al. and utilize SEQ ID NO:420 with the carrier of Patent ‘624 as Couturier et al. teaches that niacin administration down regulates miR-485-3p. This particular inhibitor of Vermeulen et al., as evidenced by Lewkowicz et al. is a miR-485-3p inhibitor which would be expected to down regulate (aka inhibit) this miR. Therefore, one skilled in the art would have been motivated to utilize inhibitor SEQ ID NO: 420 and niacin (aka vitamin B3) as both are taught for the same purpose. As a general principle it is prima facie obvious to combine two compositions each of which is taught by the prior art to be useful for the same purpose, in order to form a third composition to be used for the very same purpose, the idea of combining them flows logically from their having been individually taught in the prior art. See In re Kerkhoven, 626 F.2d 846, 850, 205 USPQ 1069, 1072 (CCPA 1980) MPEP 2144.06. One skilled in the art would have a reasonable expectation of success as Patent ‘624 claims a nucleic acid payload.
Claims 1, 7, 9, 13, 17, 19, 24, 29-30, 32-33, 51-52, 58, 60, 63, 73, 86, 93 and 95 are provisionally rejected on the ground of nonstatutory double patenting as being unpatentable over claims 74 and 93-112 of copending Application No. 17622518 (USPGPUB No. 20220257790) in view of Kakizawa et al. Although the conflicting claims are not identical, they are not patentably distinct from each other because both sets of claims overlap in scope.
This is a provisional nonstatutory double patenting rejection because the patentably indistinct claims have not in fact been patented.
The instant claims are set forth above.
Copending ‘518 claims a method of preparing a cationic carrier unit comprising synthesizing the cationic carrier unit, wherein the cationic unit comprises:(i) a water-soluble biopolymer moiety comprising polyethylene glycol (PEG) units (reading on instantly claimed WP); (ii) a positively charged carrier moiety comprising a polylysine which comprises lysine units (reading on instant CC); and (iii) an adjuvant moiety comprising one or more vitamin B3 units (reading on instantly claimed HM); and (iv) a targeting moiety that is capable of targeting a central nervous system (reading on instant claim 63) ; wherein the polylysine comprises (a) some lysine units covalently linked to the adjuvant moiety ("AM-linked lysine unit") and (b) some lysine units that are positively charged, wherein each AM-linked lysine unit is covalently linked to a vitamin B3 unit, and wherein the water-soluble biopolymer moiety and the positively charged carrier moiety are attached to each other directly or through a bifunctional linker. Making micelles is claimed (claim 93).
While Copending ‘518 claims a cationic carrier, Copending ‘518 does not expressly claim a thiolated portion (i.e. instantly claimed CC). However, this deficiency is cured by Kakizawa et al.
The teachings of Kakizawa et al. are set forth above.
It would have been obvious to one of ordinary skill in the art before the effective filing date of the claimed invention to combine the teachings of copending ‘518 and Kakizawa et al. and thiolate a portion of the lysine groups of the cationic carrier. One skilled in the art would have been motivated to thiolate a portion of the lysines in order to increase stability as taught by Kakizawa et al. There is a reasonable expectation of success as both copending ‘518 and Kakizawa et al. teach micelles formation for complexation with an anionic oligonucleotide. This suggests claims 1, 13, 17, 19, 24, 29, 32, 33, 51, 52, 63, 73, 86 and 95.
Regarding claim 7, 9, copending ‘518 claims a nucleotide sequence having 5 to 30 nucleotides in length (claim 99).
Regarding claim 30, copending ‘518 claims the polylysine claims between 30 and 80 lysines which overlaps the instant claims. In the case where the claimed ranges "overlap or lie inside ranges disclosed by the prior art" a prima facie case of obviousness exists. In re Wertheim, 541 F.2d 257, 191 USPQ 90 (CCPA 1976); In re Woodruff, 919 F.2d 1575, 16 USPQ2d 1934 (Fed. Cir. 1990). Note MPEP 2144.05.
Regarding claims 58 and 60, copending ‘518 claims an overlapping number of lysine and vitamin B3 units. Kakizawa et al. teaches thiolation degrees of 10 and 26% of the amino groups were used. This corresponds to an average of 3.9- and 10-unit substitutions of 39 lysine residues in each polymer (page 493, right column; page 494, left column). Since the thiol is taught for stabilization, one skilled in the art would manipulate the amount of the various components of the cationic carrier to achieve the desired effect. Since the positive charge is required to complex with the negatively charged oligonucleotide, one skilled in the art would recognize there needs to be a sufficient number of cationic charge in order to complex with the negatively charged oligonucleotide in order to have a complex for delivery. 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.
Regarding claim 93, copending ‘518 claims an antimir that is SEQ ID NO: 18 which has 100% identity to instantly claimed SEQ ID NO: 18 (Qy) as set forth below:
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Claim 89 is provisionally rejected on the ground of nonstatutory double patenting as being unpatentable over claims 74 and 93-112 of copending Application No. 17622518 (USPGPUB No. 20220257790) in view of Kakizawa et al. as applied to claims 1, 7, 9, 13, 17, 19, 24, 29-30, 32-33, 51-52, 58, 60, 63, 73, 86, 93 and 95 above and in further view of Vermeulen et al. Although the conflicting claims are not identical, they are not patentably distinct from each other because both sets of claims overlap in scope.
This is a provisional nonstatutory double patenting rejection.
The instant application claims the nucleic acid comprises at least one nucleoside analog, wherein the nucleoside analog comprises Locked Nucleic Acid (LNA); 2'-O-alkyl-RNA; 2'-amino-DNA; 2'-fluoro-DNA; arabino nucleic acid (ANA); 2'- fluoro-ANA, hexitol nucleic acid (HNA), intercalating nucleic acid (INA), constrained ethyl nucleoside (cEt), 2'-O-methyl nucleic acid (2'-OMe), 2'-O-methoxyethyl nucleic acid (2'- MOE), or any combination thereof.
The teachings of copending ‘518 are set forth above.
While copending ‘518 claims nucleic acids and the same sequence as instantly claimed, copending ‘518 does not expressly claim modifications. However, this deficiency is cured by Vermeulen et al.
The teachings of Vermeulen et al. are set forth above.
It would have been obvious to one of ordinary skill in the art before the effective filing date of the claimed invention to combine the teachings of Copending ‘518, Kakizawa et al. and Vermeulen et al. and utilize a modified nucleic acid. One skilled in the art would have been motivated to utilize a modified nucleic acid in order to improve the efficacy of RNA interference applications as taught by Vermeulen et al.
Response to Arguments
Applicants’ arguments filed August 20 2026 have been fully considered but they are not persuasive.
Applicants argue that (1) the instant claims require that the number of HM to be less than about 50% relative to CC and CM and patent ‘624 is silent on this element. The office does not allege the cited references teach or suggest this element of pending claim 1. Therefore, the Office has failed to establish a prima facie case of obviousness.
Regarding Applicants’ first argument, the rejection (see pages 23-24) clearly indicates that the polylysine taught overlaps the instant claims and that patent ‘624 claims an overlapping number of lysine and vitamin B3 units (i.e. the hydrophobic moiety). Furthermore, the rejection clearly discusses optimization of the positive charge. Therefore, while patent ‘624 does not expressly state the number of HM is less than about 50% relative to CC and CM, the examiner cannot agree that this limitation is not obvious and not addressed in the previous office action.
Applicants argue that (2) the instant claims require that the number of HM to be less than about 50% relative to CC and CM and copending ‘518 is silent on this element. The office does not allege the cited references teach or suggest this element of pending claim 1. Therefore, the Office has failed to establish a prima facie case of obviousness.
Regarding Applicants’ second argument, the rejection (see pages 28-29) clearly indicates that the polylysine taught overlaps the instant claims and that copending ‘518 claims an overlapping number of lysine and vitamin B3 units (i.e. the hydrophobic moiety). Furthermore, the rejection clearly discusses optimization of the positive charge. Therefore, while copending ‘518 does not expressly state that the number of HM is less than about 50% relative to CC and CM, the examiner cannot agree that this limitation is not obvious and not addressed in the previous office action.
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.
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/ABIGAIL VANHORN/ Primary Examiner, Art Unit 1636
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