DETAILED ACTION
Notice of Pre-AIA or AIA Status
The present application, filed on or after March 16, 2013, is being examined under the first inventor to file provisions of the AIA .
Election/Restrictions
Applicant’s election without traverse of Invention I in the reply filed on March 13, 2026 is acknowledged.
Claims 11-12, 16-18, 31-32, 41, and 48 are withdrawn from further consideration pursuant to 37 CFR 1.142(b) as being drawn to a nonelected invention, there being no allowable generic or linking claim. Election was made without traverse in the reply filed on March 13, 2026.
Status of Claims
Claims 1-6, 11-12, 16-19, 25, 28-32, 41, and 48 are pending.
Claims 11-12, 16-18, 31-32, 41, and 48 have been withdrawn from consideration.
Claims 1-6, 19, 25, and 28-30 are under examination.
Information Disclosure Statement
The information disclosure statements filed on September 6, 2024 and March 13, 2026 are acknowledged and have been considered by the examiner.
The listing of references in the specification is not a proper information disclosure statement. 37 CFR 1.98(b) requires a list of all patents, publications, or other information submitted for consideration by the Office, and MPEP § 609.04(a) states, "the list may not be incorporated into the specification but must be submitted in a separate paper." Therefore, unless the references have been cited by the examiner on form PTO-892, they have not been considered.
Drawings
The drawings are objected to because of the following informalities: the plots provided in Figure 11 are at an insufficient resolution. The majority of the text labels and axes labels on the individual plots are too blurry to read. Appropriate correction is required.
Specification
The disclosure is objected to because of the following informalities: the title page on the first page of the instant specification filed November 28, 2023 describes the document as a “provisional application.” However, the instant application under examination is a nonprovisional application. Appropriate correction is required.
Claim Interpretation
In claim 2, a limitation is presented requiring the ligand to be recombinant high-density lipoprotein. While the phrase “recombinant lipoprotein” is expressly defined in the instant disclosure, the specification speaks to high density lipoprotein mimicking structures. Therefore, the examiner interprets the phrase “recombinant lipoprotein” in this context to refer to lipoprotein-mimicking ligands.
Claim 28 includes a limitation of the composition of claim 1 being “formulated as a unit dose.” On page 24 of the instant specification, the term “unit dose” is defined as “a formulation of the compound or composition such that the formulation is prepared in a manner sufficient to provide a single therapeutically effective dose of the active ingredient to a patient in a single administration.” MPEP §211.01 states “where an explicit definition is provided by the applicant for a term, that definition will control the interpretation of the term as it is used in the claim.” Thus, claim 28 is interpreted to require a formulation in which a single administration of the composition is therapeutically effective.
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.
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 1-3, 5, and 6 are rejected under 35 U.S.C. 103 as being unpatentable over Raut (Raut, S.; et al., J. Pharmacol. Expr. Ther., 2020 – provided by applicant in IDS filed September 6, 2024) as evidenced by Williams (Williams, D.L.; et al., J. Biol. Chem., 2000) further in view of Shim (Shim, M.S.; et al., Biomaterials, 2010) and Thermo (Thermo Scientific DSS and BS3 Instruction Manual, MAN0011240, 2018).
Raut teaches a self-assembling HDL mimetic nanomicelle comprising a myristic acid conjugated 5A peptide, MYR-5A (pg. 113, Abstract and pg. 119, Fig. 8C). Raut discloses that the 5A peptide is a modified apolipoprotein A-I mimetic peptide possessing the same sequence as SEQ ID NO 1 (pg. 114, paragraph 4 and Fig. 1). Raut further teaches loading the MYR-5A nanomicelle with the drugs doxorubicin and valrubicin (pg. 115, Drug/Dye-Loaded Nanoparticles Preparation and Characterization).
As evidenced by Williams, apolipoprotein A-I is a ligand for scavenger receptor class B type 1 (SR-B1) (pg. 18902, Discussion, paragraph 1).
Raut does not teach crosslinking the nanomicelle with disuccinimidyl suberate (DSS).
Shim teaches a micelle comprising polyethylene glycol-conjugated poly(ketalized serine) [PEG-poly(kSer)] (pg. 3404, Abstract and pg. 3406, Fig. 1). Shim teaches loading the micelle with DNA for therapeutic gene delivery (pg. 3405, section 2.3). Shim discloses that these DNA-loaded micelles possessed diameters in the range of 100 nm to 150 nm (pg. 3407, section 3.2 and pg. 3408, Fig. 3A). Shim also teaches crosslinking the micelle using bis(sulfosuccinimidyl)suberate (BS3) (pg. 3407, section 2.3). Shim teaches that crosslinking the micelle improved transfection efficiency (pg. 3404, Abstract) and increased micelle stability by avoiding premature micelle disassembly in serum before cellular internalization, (pg. 3409, Section 3.5).
Thermo describes product information for DSS and BS3 crosslinkers (pg. 1, Title). Thermo provides the structures of DSS and BS3 and teaches that BS3 is an analog of DSS with increased water solubility (pg. 1, Introduction, sentence 1). Thermo teaches that both DSS and BS3 belong to the N-hydroxysuccinimide ester (NHS-ester) class of crosslinking agents (pg. 1, Introduction, sentence 1). Thermo teaches that both DSS and BS3 have “essentially identical reactivity toward primary amines” (pg. 1, Introduction, paragraph 2). Thermo describes that the crosslinking reactions performed using BS3 and DSS result in the reaction of the ester groups with primary amines to form stable amides, resulting in the release of NHS (pg. 1, Introduction, paragraph 1). As evidenced by their structures, the region between the esters in the unreacted DSS and BS3 structures is identical; therefore, the product of crosslinking primary amines with either DSS or BS3 would have an identical structure.
A person of ordinary skill in the art would have recognized that both Raut and Shim teach nanoscale micelle particles that can be used to encapsulate and deliver therapeutic agents. It would also be recognized that the BS3 crosslinking taught by Shim increased the stability of the micelle, thereby improving it. Additionally, it would be understood that DSS and BS3 are interchangeable crosslinking agents that produce products with the same structure.
Therefore, it would have been obvious to one of ordinary skill in the art before the effective filing date of the claimed invention to modify the MYR-5A nanomicelle of Raut with the crosslinking method of Shim, substituting BS3 with DSS, as taught by Thermo. This would yield the predictable result of a nanomicelle comprising an SR-B1 ligand (as evidenced by Williams) with increased stability still capable of transporting therapeutic agents.
Regarding claim 1, Raut teaches MYR-5A nanomicelles (pg. 113, Abstract). Raut teaches that these nanomicelles possess self-assembly properties (pg. 113, Abstract). The 5A peptide is a modified Apolipoprotein A-I peptide that is a ligand for SR-B1 (Raut pg. 114, paragraph 4 and Williams pg. 18902, Discussion, paragraph 1). Shim also teaches nanomicelles, as the PEG-poly(kSer) micelles have diameters around 100 nm to 150 nm (pg. 3408, Fig. 3A). Shim teaches crosslinking the nanomicelles using BS3, a homobifunctional NHS ester crosslinking agent (pg. 3047, section 2.6). Thermo teaches that DSS is an analog of BS3 and is a similar NHS ester crosslinking agent whose use would produce primary amines with the same crosslinked structure (pg. 1, Structures and Introduction). Therefore, the combined teachings of Raut, Williams, Shim, and Thermo render claim 1 obvious.
Regarding claim 2, the nanomicelle of Raut is an HDL mimetic particle (pg. 113, Title). Furthermore, it comprises a recombinant 5A peptide conjugated to myristic acid (pg. 113, Abstract). The 5A peptide is a mimetic of an apolipoprotein (pg. 114, left column, last paragraph). Therefore, the combined teachings of Raut, Williams, Shim, and Thermo render claim 2 obvious.
Regarding claim 3, the nanomicelle of Raut comprises a myristic acid conjugated-5A peptide (pg. 113, Abstract). Therefore, the combined teachings of Raut, Williams, Shim, and Thermo render claim 3 obvious.
Regarding claims 5 and 6, Raut teaches loading the nanomicelle with the therapeutic agents doxorubicin and valrubicin, which are small molecules (pg. 115, Drug/Dye-Loaded Nanoparticles Preparation and Characterization). Additionally, Shim teaches loading crosslinked nanomicelles with a nucleic acid (pg. 3407, section 2.6). Therefore, the combined teachings of Raut, Williams, Shim, and Thermo render claims 5 and 6 obvious.
Claims 1, 2, and 4 are rejected under 35 U.S.C. 103 as being unpatentable over Lacko (WO 2020/106605 A1) as evidenced by Williams (Williams, D.L.; et al., J. Biol. Chem., 2000) further in view of Shim (Shim, M.S.; et al., Biomaterials, 2010) and Thermo (Thermo Scientific DSS and BS3 Instruction Manual, MAN0011240, 2018).
Lacko teaches recombinant HDL nanoparticles comprising phosphatidylcholine, cholesterol, cholesterol oleate, apolipoprotein A-I, and sodium cholate (recombinant in the sense that the individual components are recombined to form the product) (pg. 11, rHDL preparation). Lacko also teaches loading the rHDL particles with a 99mTc radioimaging tracer (pg. 13, Liposome and HDL labeling efficiencies).
As evidenced by Williams, apolipoprotein A-I is a ligand for scavenger receptor class B type 1 (SR-B1) (pg. 18902, Discussion, paragraph 1).
Lacko does not teach crosslinking the nanoparticle with disuccinimidyl suberate (DSS).
Shim teaches a micelle comprising polyethylene glycol-conjugated poly(ketalized serine) [PEG-poly(kSer)] (pg. 3404, Abstract and pg. 3406, Fig. 1). Shim teaches loading the micelle with DNA for therapeutic gene delivery (pg. 3405, section 2.3). Shim discloses that these DNA-loaded micelles possessed diameters in the range of 100 nm to 150 nm (pg. 3407, section 3.2 and pg. 3408, Fig. 3A). Shim also teaches crosslinking the micelle using bis(sulfosuccinimidyl)suberate (BS3) (pg. 3407, section 2.3). Shim teaches that crosslinking the micelle improved transfection efficiency (pg. 3404, Abstract) and increased micelle stability by avoiding premature micelle disassembly in serum before cellular internalization, (pg. 3409, Section 3.5).
Thermo describes product information for DSS and BS3 crosslinkers (pg. 1, Title). Thermo provides the structures of DSS and BS3 and teaches that BS3 is an analog of DSS with increased water solubility (pg. 1, Introduction, sentence 1). Thermo teaches that both DSS and BS3 belong to the N-hydroxysuccinimide ester (NHS-ester) class of crosslinking agents (pg. 1, Introduction, sentence 1). Thermo teaches that both DSS and BS3 have “essentially identical reactivity toward primary amines” (pg. 1, Introduction, paragraph 2). Thermo describes that the crosslinking reactions performed using BS3 and DSS result in the reaction of the ester groups with primary amines to form stable amides, resulting in the release of NHS (pg. 1, Introduction, paragraph 1). As evidenced by their structures, the region between the esters in the unreacted DSS and BS3 structures is identical; therefore, the product of crosslinking primary amines with either DSS or BS3 would have an identical structure.
A person of ordinary skill in the art would have recognized that both Lacko and Shim teach nanoscale micelle particles that can be used to transport and target pharmacological agents. It would also be recognized that the BS3 crosslinking taught by Shim increased the stability of the micelle, improving the particles. Additionally, it would be understood that DSS and BS3 are interchangeable crosslinking agents that produce products with the same structure.
Therefore, it would have been obvious to one of ordinary skill in the art before the effective filing date of the claimed invention to modify the rHDL nanomicelle of Raut with the crosslinking method of Shim, substituting BS3 with DSS, as taught by Thermo. This would yield the predictable result of a nanomicelle comprising an SR-B1 ligand (as evidenced by Williams) with increased stability still capable of transporting therapeutic agents.
Regarding claim 1, Lacko teaches rHDL nanoparticles (pg. 11, rHDL preparation). The rHDL comprises Apolipoprotein A-I, which is a ligand for SR-B1 (Lacko pg. 11, rHDL preparation and Williams pg. 18902, Discussion, paragraph 1). Shim also teaches nanomicelles, as the PEG-poly(kSer) micelles have diameters around 100 nm to 150 nm (pg. 3408, Fig. 3A). Shim teaches crosslinking the nanomicelles using BS3, a homobifunctional NHS ester crosslinking agent (pg. 3047, section 2.6). Thermo teaches that DSS is an analog of BS3 and is a similar NHS ester crosslinking agent whose use would produce primary amines with the same crosslinked structure (pg. 1, Structures and Introduction). Therefore, the combined teachings of Lacko, Williams, Shim, and Thermo render claim 1 obvious.
Regarding claim 2, the nanoparticles of Lacko are rHDL comprising phosphatidylcholine, cholesterol, cholesterol oleate, cholate, and apolipoprotein A-I (pg. 11, rHDL preparation). Apo A-I is a ligand for SR-B1 (Williams pg. 18902, Discussion, paragraph 1). Therefore, the combined teachings of Lacko, Williams, Shim, and Thermo render claim 3 obvious.
Regarding claim 4, Lacko teaches rHDL nanoparticles comprising cholesterol oleate (pg. 11, rHDL preparation). Therefore, the combined teachings of Lacko, Williams, Shim, and Thermo render claims 5 and 6 obvious.
Claims 19, 25, and 28-30 are rejected under 35 U.S.C. 103 as being unpatentable over Raut, Williams, Shim, and Thermo as applied to claims 1, 3, 5, and 6 above, and further in view of Shenoy (WO 2022/125713 A1).
As described above, these references combine to teach a therapeutic agent-loaded, DSS-crosslinked nanomicelle comprising an SR-B1 ligand. Raut teaches a self-assembling HDL mimetic nanomicelle comprising a myristic acid conjugated 5A peptide, MYR-5A (pg. 113, Abstract and pg. 119, Fig. 8C). The 5A peptide is a modified apolipoprotein A-I mimetic, which is a ligand of SR-B1 (Williams, pg. 18902, Discussion, paragraph 1). Raut further teaches loading the MYR-5A nanomicelle with doxorubicin and valrubicin (pg. 115, Drug/Dye-Loaded Nanoparticles Preparation and Characterization). Shim also teaches a nanomicelle (pg. 3404, Abstract and pg. 3406, Fig. 1) and loading it with DNA (pg. 3405, section 2.3). Shim teaches crosslinking the micelle using bis(sulfosuccinimidyl)suberate (BS3) (pg. 3407, section 2.3) improved transfection efficiency (pg. 3404, Abstract) and increased micelle stability by avoiding premature micelle disassembly in serum before cellular internalization, (pg. 3409, Section 3.5). Thermo teaches that DSS and BS3 are interchangeable crosslinking agents that produce products with the same structure (pg. 1, Introduction).
The combined teachings of Raut, Williams, Shim, and Thermo do not teach applying nanomicelles to prepare pharmaceutical formulations, kits, unit dose formulations, systemic administration, or formulations for dosing by additional routes.
Shenoy teaches polymeric micelles with a hydrophobic core and hydrophilic exterior (pg. 7, paragraph 32). Shenoy discloses that these micelles are 10 nm to 500 nm in size (pg. 10, paragraph 41), which makes them nanomicelles. Shenoy also teaches loading the nanomicelle with therapeutic agents (pg. 10, paragraph 42), specifically therapeutic mRNA (pg. 11, paragraphs 44-45). Shenoy further teaches including the nanomicelle in a kit (pg. 24, paragraph 92). Shenoy also teaches preparing a pharmaceutical composition of the mRNA-loaded nanomicelle and adding pharmaceutically acceptable carriers (pg. 18, paragraphs 66-68). Shenoy also teaches preparing the nanomicelle for oral and parental administration routes including intravenous dosing (pg. 19, paragraphs 69-70).
A person of ordinary skill in the art would have recognized that Raut, Shim, and Shenoy teach nanoscale micelle particles that can be used to encapsulate and deliver therapeutic agents. It would also be recognized that Shenoy describes applications of loaded nanomicelles in kits and pharmaceutical formulations for administration, which are known strategies in the pharmaceutical field to prepare a pharmaceutically active composition for use in subjects.
Therefore, it would have been obvious to one of ordinary skill in the art before the effective filing date of the claimed invention to modify the therapeutic agent-loaded, DSS-crosslinked MYR-5A nanomicelle of Raut, Williams, Shim, and Thermo with the formulation strategies of Shenoy. This would yield the predictable result of nanomicelle prepared for therapeutic use in subjects.
Regarding claim 19, Shenoy teaches preparing a pharmaceutical formulation of a therapeutic-loaded nanomicelle (pg. 18, paragraph 66) and incorporating pharmaceutically acceptable carriers, which includes excipients such as buffers (pg. 18, paragraphs 67-68).
Regarding claim 25, Shenoy teaches incorporating the therapeutic-loaded nanomicelle in a kit (pg. 24, paragraph 92).
Regarding claim 28, Shenoy teaches that effective doses may be administered in a single administration (pg. 20, paragraph 75). Dosing in a single administration reads on the claim limitation “unit dose.”
Regarding claims 29 and 30, Shenoy teaches formulation for parental administration routes (pg. 19, paragraph 70). This includes intravenous dosing, which is a form of systemic administration. Other routes of administration disclosed include intrathecal, intramuscular, and subcutaneous.
Therefore, the combined teachings of Raut, Williams, Shim, Thermo, and Shenoy render claims 19, 25, and 28-30 obvious.
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, 5, and 6 are rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1-13, 15-17, and 24-31 of U.S. Patent No. 9,314,532 in view of Shim and Thermo.
The claims of U.S. Patent No. 9,314,532 (the ‘532 patent) are drawn toward a drug delivery vehicle comprising a drug composition and a poly-amino-acid subunit comprising a targeting amino acid chain with affinity to SR-B1 conjugated to a fatty acid.
The conflicting patent does not teach crosslinking the drug delivery particle with DSS.
As described above, Shim teaches crosslinking a therapeutic-loaded nanomicelle using bis(sulfosuccinimidyl)suberate (BS3) (pg. 3407, section 2.3) improved transfection efficiency (pg. 3404, Abstract) and increased micelle stability by avoiding premature micelle disassembly in serum before cellular internalization, (pg. 3409, Section 3.5). Thermo teaches that DSS and BS3 are interchangeable crosslinking agents that produce products with the same structure (pg. 1, Introduction).
A person of ordinary skill in the art would have recognized that both the ‘532 patent and Shim teach drug delivery nanoparticles. It would also be recognized that the BS3 crosslinking taught by Shim increased the stability of the micelle, thereby improving it. Additionally, it would be understood that DSS and BS3 are interchangeable crosslinking agents that produce products with the same structure.
Therefore, it would have been obvious to one of ordinary skill in the art before the effective filing date of the claimed invention to modify the drug delivery particle of the ‘532 patent with the crosslinking method of Shim, substituting BS3 with DSS, as taught by Thermo. This would yield the predictable result of a nanomicelle comprising a peptide targeting SR-B1 with increased stability capable of transporting therapeutic agents.
Regarding instant claim 1, conflicting claim 1 is drawn to a drug delivery vehicle composition comprising a poly-amino-acid subunit with affinity to SR-B1. This requires the presence of an SR-B1 ligand. Additionally, conflicting claim 16 requires the diameter of the drug delivery vehicle to be 20 nm to 300 nm, which reads on the nanomicelle limitation. Furthermore, Shim teaches crosslinking nanomicelles increases stability (pg. 3404, Abstract) and Thermo teaches that DSS is an equivalent alternative to the BS3 crosslinking reagent used by Shim (pg. 1, Introduction).
Regarding instant claims 5 and 6, conflicting claim 17 of the ‘532 patent requires the drug delivery composition to comprise drug compositions that are hydrophobic drugs, cytotoxic drugs, antibody drugs, protein or peptide drugs, mimetic peptide drugs, nucleic acid drugs, or vaccine drugs. These are therapeutic agents.
Claims 2 and 3 are rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1-13, 15-17, and 24-31 of U.S. Patent No. 9,314,532 in view of Shim and Thermo and further in view of Raut.
As described above, the claims of U.S. Patent No. 9,314,532 are drawn toward a drug delivery vehicle comprising a drug composition and a poly-amino-acid subunit comprising a targeting amino acid chain with affinity to SR-B1 conjugated to a fatty acid. Additionally, Shim teaches crosslinking a drug delivery nanomicelle using BS3 (pg. 3407, section 2.3) and Thermo teaches that DSS is an equivalent alternative to BS3 (pg. 1, Introduction).
The ’532 patent, Shim, and Thermo do not require the nanomicelle to comprise myristic acid conjugated 5A peptide.
Raut teaches a self-assembling HDL mimetic nanomicelle comprising a myristic acid conjugated 5A peptide, MYR-5A (pg. 113, Abstract and pg. 119, Fig. 8C). Raut discloses that the 5A peptide is a modified apolipoprotein A-I mimetic peptide possessing the same sequence as instant SEQ ID NO 1 and SEQ ID NO 20 from the ‘532 patent (pg. 114, paragraph 4 and Fig. 1). Raut further teaches loading the MYR-5A nanomicelle with the drugs doxorubicin and valrubicin (pg. 115, Drug/Dye-Loaded Nanoparticles Preparation and Characterization).
A person of ordinary skill in the art would have recognized that the ‘532 patent, Shim, and Raut teach nanoscale drug delivery particles. It would also be recognized that Raut describes that MYR-5A is an effective nanomicelle building block for targeted drug delivery.
Therefore, it would have been obvious to one of ordinary skill in the art before the effective filing date of the claimed invention to modify the DSS-crosslinked nanomicelle drug delivery vehicle taught through the combination of the ‘532 patent, Shim, and Thermo with the selection of MYR-5A as the targeted poly-amino-acid subunit for the drug delivery vehicle, as taught by Raut. This would yield the predictable result of an SR-B1 targeting nanomicelle for drug delivery.
Regarding instant claim 2, conflicting claim 15 includes an embodiment in which apolipoprotein A-I protein is included in the composition. Raut teaches that the inclusion of Apo A-I or mimetics of Apo A-I in a micelle make the micelle an HDL mimetic (pg. 114, left column, paragraph 2).
Regarding instant claim 3, conflicting claim 1 requires an SR-B1 ligand peptide similar to (70% sequence identity) SEQ ID NO 20, 63, 64, 65, or 66 from the ‘532 patent. The ‘532 SEQ ID NO 20 sequence is identical to the 5A peptide sequence provided in the instant application. Conflicting claim 1 also requires the peptide to be conjugated to a fatty acid. Furthermore, conflicting claim 4 requires the SR-B1 targeting peptide to be conjugated to myristic acid. Additionally, Raut teaches a nanomicelle comprising MYR-5A (pg. 114, Fig. 1).
Claims 19, 25, and 28-30 are rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1-13, 15-17, and 24-31 of U.S. Patent No. 9,314,532 in view of Shim and Thermo and further in view of Shenoy.
As described above, the claims of U.S. Patent No. 9,314,532 are drawn toward a drug delivery vehicle comprising a drug composition and a poly-amino-acid subunit comprising a targeting amino acid chain with affinity to SR-B1 conjugated to a fatty acid. Additionally, Shim teaches crosslinking a drug delivery nanomicelle using BS3 (pg. 3407, section 2.3) and Thermo teaches that DSS is an equivalent alternative to BS3 (pg. 1, Introduction).
The ’532 patent, Shim, and Thermo do not teach applying nanomicelles to prepare pharmaceutical formulations, kits, unit dose formulations, systemic administration, or formulations for dosing by additional routes.
Shenoy teaches polymeric micelles with a hydrophobic core and hydrophilic exterior (pg. 7, paragraph 32). Shenoy discloses that these micelles are 10 nm to 500 nm in size (pg. 10, paragraph 41), which makes them nanomicelles. Shenoy also teaches loading the nanomicelle with therapeutic agents (pg. 10, paragraph 42), specifically therapeutic mRNA (pg. 11, paragraphs 44-45). Shenoy further teaches including the nanomicelle in a kit (pg. 24, paragraph 92). Shenoy also teaches preparing a pharmaceutical composition of the mRNA-loaded nanomicelle and adding pharmaceutically acceptable carriers (pg. 18, paragraphs 66-68). Shenoy also teaches preparing the nanomicelle for oral and parental administration routes including intravenous dosing (pg. 19, paragraphs 69-70).
A person of ordinary skill in the art would have recognized that the ‘532 patent, Shim, and Shenoy teach nanoscale drug delivery particles. It would also be recognized that Shenoy describes applications of loaded nanomicelles in kits and pharmaceutical formulations for administration, which are known strategies in the pharmaceutical field to prepare a pharmaceutically active composition for use in subjects.
Therefore, it would have been obvious to one of ordinary skill in the art before the effective filing date of the claimed invention to modify the DSS-crosslinked nanomicelle drug delivery vehicle taught through the combination of the ‘532 patent, Shim, and Thermo with the formulation strategies of Shenoy. This would yield the predictable result of nanomicelle prepared for therapeutic use in subjects.
Regarding claim 19, Shenoy teaches preparing a pharmaceutical formulation of a therapeutic-loaded nanomicelle (pg. 18, paragraph 66) and incorporating pharmaceutically acceptable carriers, which includes excipients such as buffers (pg. 18, paragraphs 67-68).
Regarding claim 25, Shenoy teaches incorporating the therapeutic-loaded nanomicelle in a kit (pg. 24, paragraph 92).
Regarding claim 28, Shenoy teaches that effective doses may be administered in a single administration (pg. 20, paragraph 75). Dosing in a single administration reads on the claim limitation “unit dose.”
Regarding claims 29 and 30, Shenoy teaches formulation for parental administration routes (pg. 19, paragraph 70). This includes intravenous dosing, which is a form of systemic administration. Other routes of administration disclosed include intrathecal, intramuscular, and subcutaneous.
Claims 1, and 19 are rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1-3 of U.S. Patent No. 12,208,146 in view of Shim and Thermo.
The claims of U.S. Patent No. 12,208,146 (the ‘146 patent) are drawn toward reconstituted high density lipoprotein (rHDL) particles.
The conflicting patent does not teach crosslinking the particle with DSS.
As described above, Shim teaches crosslinking a therapeutic-loaded nanomicelle using bis(sulfosuccinimidyl)suberate (BS3) (pg. 3407, section 2.3) improved transfection efficiency (pg. 3404, Abstract) and increased micelle stability by avoiding premature micelle disassembly in serum before cellular internalization, (pg. 3409, Section 3.5). Thermo teaches that DSS and BS3 are interchangeable crosslinking agents that produce products with the same structure (pg. 1, Introduction).
A person of ordinary skill in the art would have recognized that both the ‘146 patent and Shim teach pharmaceutical delivery nanoparticles. It would also be recognized that the BS3 crosslinking taught by Shim increased the stability of the micelle, thereby improving it. Additionally, it would be understood that DSS and BS3 are interchangeable crosslinking agents that produce products with the same structure.
Therefore, it would have been obvious to one of ordinary skill in the art before the effective filing date of the claimed invention to modify the rHDL particle of the ‘146 patent with the crosslinking method of Shim, substituting BS3 with DSS, as taught by Thermo. This would yield the predictable result of a nanomicelle comprising recombinant HDL with increased stability capable of transporting therapeutic agents.
Regarding instant claim 1, conflicting claim 1 is drawn to a particles of reconstituted HDL particles. Reconstituted HDL reads on the limitation of recombinant high-density lipoprotein (see Claim interpretation). Additionally HDL is a ligand of SR-B1. Furthermore, Shim teaches crosslinking nanomicelles increases stability (pg. 3404, Abstract) and Thermo teaches that DSS is an equivalent alternative to the BS3 crosslinking reagent used by Shim (pg. 1, Introduction).
Regarding instant claim 19, conflicting claim 3 of the ‘146 patent is drawn to a composition comprising rHDL and a pharmaceutically acceptable carrier.
Claims 25, and 28-30 are rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1-3 of U.S. Patent No. 12,208,146 in view of Shim and Thermo and further in view of Shenoy.
As described above, the claims of U.S. Patent No. 12,208,146 are drawn toward rHDL particles. Additionally, Shim teaches crosslinking a drug delivery nanomicelle using BS3 (pg. 3407, section 2.3) and Thermo teaches that DSS is an equivalent alternative to BS3 (pg. 1, Introduction).
The ’146 patent, Shim, and Thermo do not teach applying nanomicelles to prepare kits, unit dose formulations, systemic administration, or formulations for dosing by additional routes.
Shenoy teaches polymeric micelles with a hydrophobic core and hydrophilic exterior (pg. 7, paragraph 32). Shenoy discloses that these micelles are 10 nm to 500 nm in size (pg. 10, paragraph 41), which makes them nanomicelles. Shenoy also teaches loading the nanomicelle with therapeutic agents (pg. 10, paragraph 42), specifically therapeutic mRNA (pg. 11, paragraphs 44-45). Shenoy further teaches including the nanomicelle in a kit (pg. 24, paragraph 92). Shenoy also teaches preparing a pharmaceutical composition of the mRNA-loaded nanomicelle and adding pharmaceutically acceptable carriers (pg. 18, paragraphs 66-68). Shenoy also teaches preparing the nanomicelle for oral and parental administration routes including intravenous dosing (pg. 19, paragraphs 69-70).
A person of ordinary skill in the art would have recognized that the ‘146 patent, Shim, and Shenoy teach nanoscale drug delivery particles. It would also be recognized that Shenoy describes applications of loaded nanomicelles in kits and pharmaceutical formulations for administration, which are known strategies in the pharmaceutical field to prepare a pharmaceutically active composition for use in subjects.
Therefore, it would have been obvious to one of ordinary skill in the art before the effective filing date of the claimed invention to modify the DSS-crosslinked rHDL nanomicelle taught through the combination of the ‘146 patent, Shim, and Thermo with the formulation strategies of Shenoy. This would yield the predictable result of nanomicelle prepared for therapeutic use in subjects.
Regarding claim 25, Shenoy teaches incorporating the therapeutic-loaded nanomicelle in a kit (pg. 24, paragraph 92).
Regarding claim 28, Shenoy teaches that effective doses may be administered in a single administration (pg. 20, paragraph 75). Dosing in a single administration reads on the claim limitation “unit dose.”
Regarding claims 29 and 30, Shenoy teaches formulation for parental administration routes (pg. 19, paragraph 70). This includes intravenous dosing, which is a form of systemic administration. Other routes of administration disclosed include intrathecal, intramuscular, and subcutaneous.
Conclusion
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/E.P.M./Examiner, Art Unit 1612
/SAHANA S KAUP/Supervisory Primary Examiner, Art Unit 1612
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