DETAILED ACTION
Status of Claims
Claims 1-2, 4-5, 8-9, 15-16, 22, 24, 28, 36, 46, 51, 53, 56, 73 and 75-78 are currently pending and are the subject of this Office Action. This is the first Office Action on the merits of the claims. The present application, filed on or after March 16, 2013, is being examined under the first inventor to file provisions of the AIA .
Status of Office Action: Non-Final
Claim Rejections – 35 U.S.C. § 112 - Indefiniteness
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.
Claims 1-2, 4-5, 8-9, 15-16, 22, 24, 28, 36, 46, 51, 53, 56, 73 and 75-78 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 pre-AIA , that applicant regards as the invention.
A. Claim 1 recites a “PEG5000 PEGylated lipid” wherein the use of the terms, “PEG5000” is unclear as to whether of not a PEG with a molecular weight of 5000 is required since claim 36 uses the terminology, “PEG5000, DSPE-PEG5000, DSPE-PEG5000-OH.” In this regard, it is noted that the Board has held: “if a claim is amenable to two or more plausible claim constructions, the USPTO is justified in requiring the applicant to more precisely define the metes and bounds of the claimed invention by holding the claim unpatentable under 35 U.S.C. §112, second paragraph, as indefinite.” Ex parte Miyazaki, 89 USPQ2d 1207, 1211 (BPAI 2008) (expanded panel). Subsequent claims 1-2, 4-5, 8-9, 15-16, 22, 24, 28, 36, 46, 51, 53, 56, 73 and 75-78 depend on claim 1 and are thus, indefinite as well.
B. Claim 16 contains the trademark/trade name “doggybone™ DNA.” Where a trademark or trade name is used in a claim as a limitation to identify or describe a particular material or product, the claim does not comply with the requirements of 35 U.S.C. § 112, second paragraph. See Ex parte Simpson, 218 USPQ 1020 (Bd. App. 1982). The claim scope is uncertain since the trademark or trade name cannot be used properly to identify any particular material or product. A trademark or trade name is used to identify a source of goods, and not the goods themselves. Thus, a trademark or trade name does not identify or describe the goods associated with the trademark or trade name. In the present case, the trademark/trade name is used to identify/describe a particular DNA configuration and, accordingly, the identification/description is indefinite.
Further clarification is required.
Claim Rejections – 35 U.S.C. § 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 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 pre-AIA 35 U.S.C. § 103(a) 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 C.F.R. § 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 1-2, 4-5, 15-16, 22, 24, 28, 36, 53, 56, 73 and 76 are rejected under 35 U.S.C. § 103 as being unpatentable over MUZYKANTOV (US 2020/0093936 A1, Publ. Mar. 26, 2020; 04/24/2024 IDS; hereinafter, “Muzykantov”).
Muzykantov is directed to:
THERAPEUTIC TARGETING OF LIPID NANOPARTICLES
ABSTRACT
The present invention relates to compositions comprising a delivery vehicle conjugated to a targeting domain, wherein the delivery vehicle comprises at least one agent, and wherein the targeting domain specifically binds to an endothelial marker. The invention also relates to methods of treating or preventing neurological or pulmonary conditions using the described compositions.
Muzykantov, title & abstract. In this regard, Muzykantov discloses a claim embodiment drawn to a composition comprising a lipid nanoparticle delivery vehicle conjugated to a targeting domain:
1. A composition comprising a delivery vehicle conjugated to a targeting domain, wherein the delivery vehicle comprises at least one agent, and wherein the targeting domain specifically binds to an endothelial marker of the vasculature, wherein the marker is selected from the group consisting of ICAM-1, PECAM-1, VCAM-1, ACE, APP, PV1, P-selectin, E-selectin, and VE-cadherin.
2. The composition of claim 1, wherein the delivery vehicle is selected from the group consisting of a liposome, a lipid nanoparticle, and a micelle.
3. The composition of claim 1, wherein the delivery vehicle is a lipid nanoparticle.
4. The composition of claim 3, wherein the lipid nanoparticle comprises a PEG-lipid conjugated to the targeting domain.
5. The composition of claim 3, wherein the at least one agent is encapsulated in the lipid nanoparticle.
6. The composition of claim 1, wherein the at least one agent is selected from the group consisting of a therapeutic agent, an imaging agent, diagnostic agent, a contrast agent, a labeling agent, a detection agent, and a disinfectant.
7. The composition of claim 1, wherein the at least one agent is a therapeutic agent.
8. The composition of claim 7, wherein the therapeutic agent comprises a nucleic acid molecule.
(Muzykantov, claims 1-8)
Regarding independent claim 1 and the requirements:
1. ([…]) A pharmaceutical composition comprising:
a lipid nanoparticle (LNP), wherein the LNP comprises a cationic lipid, a sterol, a non-cationic lipid, and a PEG5000 PEGylated lipid;
a therapeutic nucleic acid (TNA);
and at least one pharmaceutically acceptable excipient; wherein the LNP comprises a single-chain variable fragment (scFv) linked to the LNP; and wherein the scFv is directed against an antigen present on the surface of a cell.
Muzykantov clearly teaches a composition comprising a lipid nanoparticle delivery vehicle conjugated to a targeting domain (Muzykantov, claims 1-8), WHEREBY it is noted:
a “delivery vehicle” (Muzykantov, claims 1-3) encompassing a “lipid nanoparticle” (Muzykantov, claims 2-3) relates to a “lipid nanoparticle (LNP)” of claim 1;
a “targeting domain” (Muzykantov, claim 1) relates to a “single-chain variable fragment (scFv)” of claim 1; and
“at least one agent” (Muzykantov, claims 1 and 5-7) encompasses a “therapeutic agent” ((Muzykantov, claims 6-8) comprising a “nucleic acid molecule” (Muzykantov, claim 8) relates to a “therapeutic nucleic acid (TNA)” of claim 1;
wherein “delivery vehicle conjugated to a targeting domain” (Muzykantov, claim 1) relates to “wherein the LNP comprises a single-chain variable fragment (scFv) linked to the LNP” of claim 1.
However, it is noted that:
(i) although Muzykantov teaches “[i]n some embodiments, such lipid nanoparticles comprise a cationic lipid (e.g., a lipid of Formula (I), (II) or (III)) and one or more excipient selected from neutral lipids, charged lipids, steroids and polymer conjugated lipids (e.g., a pegylated lipid such as a pegylated lipid of structure (IV), such as compound IVa)” (Muzykantov, par. [0101]),
(a) wherein a “cationic lipid” of Muzykantov’s “Formula (I), (II)” (Muzykantov, par. [0101]) include:
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(Muzykantov, par. [0158]) relates to a “cationic lipid” of claim 1, and is encompassed by a “cationic lipid” that is “represented by Formula (XX)” of claim 28:
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;
(b) wherein “one or more excipient” (Muzykantov, par. [0101]) encompasses “a sterol, such as cholesterol” (Muzykantov, par. [0252]) relates to a “sterol” of claims 1 and 36; as well as “cholesterol” of claim 36;
(c) wherein “one or more excipient selected from neutral lipids” (Muzykantov, par. [0101]) encompass “distearoyl-phosphatidylethanolamine (DSPE)” (Muzykantov, par. [0252]) relates to a “non-cationic lipid” of claims 1 and 36, as well as “distearoyl-sn-glycero-phosphoethanolamine (DSPE)” of claim 36;
(d) wherein a “pegylated lipid” (Muzykantov, par. [0101]) encompasses “Pegylated lipids” that are “known in the art and include 1-(monomethoxy-polyethyleneglycol)-2,3-dimyristoylglycerol (PEG-s-DMG) and the like” (Muzykantov, par. [0253]), which relates to a “PEG5000 PEGylated lipid” of claims 1 and 36, as well as “1-(monomethoxy-polyethyleneglycol)-2,3-dimyristoylglycerol (DMG-PEG)” of claim 36; AND
(ii) although Muzykantov teaches a “targeting domain” encompassing “an antibody, or antibody fragment” and “single chain Fv (scFv) fragments thereof”:
[0395] Antibodies
[0396] In one embodiment, the targeting domain of the invention comprises an antibody, or antibody fragment. In certain embodiments, the antibody targeting domain specifically binds to a target of interest. Such antibodies include polyclonal antibodies, monoclonal antibodies, Fab and single chain Fv (scFv) fragments thereof, bispecific antibodies, heteroconjugates, human and humanized antibodies.
(Muzykantov, par. [0395]-[0396]) that “binds with an antigen or epitope” (Muzykantov, par. [0048]), wherein “[i]n certain embodiments, the LNP comprises one or more targeting moieties that targets the LNP to a cell or cell population,” e.g., “the targeting domain is a ligand which directs the LNP to a receptor found on a cell surface” (Muzykantov, par. [0263]), which relates to “a single-chain variable fragment (scFv),” wherein “the scFv is directed against an antigen present on the surface of a cell” of claim 1, as well as “a cell expressing the cell-surface antigen for which the scFv is directed” of claim 24:
24. ([…]) The pharmaceutical composition of claim 1, wherein:
the composition is targeted to a cell expressing the cell-surface antigen for which the scFv is directed, or
wherein the composition is targeted to tumor cells: or
wherein the composition is targeted to liver cells: or
wherein the composition is targeted to hepatocytes in the liver.
Muzykantov DOES NOT EXPRESSLY TEACH a particular exemplary embodiment of a composition comprising a lipid nanoparticle delivery vehicle conjugated to a targeting domain (Muzykantov, claims 1-8) with (i) and (ii), as noted above, which would be obvious per Muzykantov’s broader disclosure. In this regard, it is noted that a reference is analyzed using its broadest teachings. MPEP § 2123 [R-5] states: “[W]hen a patent simply arranges old elements with each performing the same function it had been known to perform and yields no more than one would expect from such an arrangement, the combination is obvious.” KSR v. Teleflex, 127 S.Ct. 1727, 1740 (2007)(quoting Sakraida v. A.G. Pro, 425 U.S. 273, 282 (1976). “[W]hen the question is whether a patent claiming the combination of elements of prior art is obvious”, the relevant question is “whether the improvement is more than the predictable use of prior art elements according to their established functions.” (Id.). Addressing the issue of obviousness, the Supreme Court noted that the analysis under 35 USC 103 “need not seek out precise teachings directed to the specific subject matter of the challenged claim, for a court can take account of the inferences and creative steps that a person of ordinary skill in the art would employ.” KSR v. Teleflex, 127 S.Ct. 1727, 1741 (2007). The Court emphasized that “[a] person of ordinary skill is… a person of ordinary creativity, not an automaton.” Id. at 1742. Therefore, it would have been prima facie obvious to one of ordinary skill in the art before the effective filing date to rearrange the disclosed above cited components of Muzykantov in order to arrive at a composition comprising a lipid nanoparticle delivery vehicle conjugated to a targeting domain (Muzykantov, claims 1-8) with (i) and (ii).
Thus, Muzykantov renders claims 1, 24, 28 and 36 obvious.
Regarding claims 2 and 4-5 and the requirements:
2. ([…]) The pharmaceutical composition of claim 1, wherein the scFv is covalently linked to the LNP or the scFv is chemically conjugated to the LNP.
[…]
4. ([…]) The pharmaceutical composition of claim 2, wherein the scFv is chemically conjugated to the LNP via a non-cleavable linker or wherein the scFV is chemically conjugated to the LNP via a cleavable linker.
5. ([…]) The pharmaceutical composition of claim 4, wherein:
the non-cleavable linker is a maleimide-containing linker, or
the cleavable linker is a pyridyldisulfide (PDS)-containing linker.
Muzykantov teaches conjugation of targeting antibodies or control isotype-matched IgG to LNP particles via SATA-maleimide conjugation chemistry,” wherein a “LNP construct was modified with maleimide functioning group (DSPE-PEG-mal)”:
[0435] To target mRNA-loaded lipid nanoparticles to endothelial cells, LNPs were conjugated with mAb specific for PECAM and ICAM-1. Targeting antibodies or control isotype-matched IgG was conjugated to LNP particles via SATA-maleimide conjugation chemistry (Howard, et al., Mol. Pharm. 2015, 11, 2262-2270). The LNP construct was modified with maleimide functioning group (DSPE-PEG-mal) by a post-insertion technique with minor modifications (Ishida, et al., FEBS Lett. 1999, 460, 129-133). The antibody was functionalized with SATA (N-succinimidyl S-acetylthioacetate) (Sigma-Aldrich) to introduce sulfhydryl groups allowing conjugation to maleimide. […].
(Muzykantov, par. [0435]), which is a “maleimide-containing linker” of claim 5, a “non-cleavable linker” of claims 4-5, and “chemically conjugated” of claims 2 and 4. See MPEP § 2123 [R-5] regarding the obviousness of rearranging a reference according to the teachings of that same reference.
Thus, Muzykantov renders claims 2 and 4-5 obvious.
Regarding claim 15 and the requirements:
15. ([…]) The pharmaceutical composition of claim 1, wherein the TNA is encapsulated in the LNP.
Muzykantov discloses a claim embodiment, wherein “the at least one agent is encapsulated in the lipid nanoparticle” (Muzykantov, claim 5).
Thus, Muzykantov renders claim 15 obvious.
Regarding claims 16 and 56 and the requirements:
16. ([…]) The pharmaceutical composition of claim 1, wherein the TNA is selected from the group consisting of a minigenes, a plasmid, a minicircle, a small interfering RNA (siRNA), a microRNA (miRNA), an antisense oligonucleotide (ASO), a ribozyme, a closed-ended (ceDNA), a ministring DNA, a doggybone™ DNA, a protelomere closed ended DNA, a dumbbell linear DNA, a dicer-substrate dsRNA, a small hairpin RNA (shRNA), an asymmetrical interfering RNA (aiRNA), a microRNA (miRNA), a mRNA, a tRNA, a rRNA, a DNA viral vector, a viral RNA vector, a non-viral vector and any combination thereof.
[…]
56. ([…]) The pharmaceutical composition of claim 16, wherein the TNA comprises an expression cassette, and wherein the expression cassette comprises a promoter sequence and a transgene.
Muzykantov teaches: “In one embodiment of the invention, an antisense nucleic acid sequence, which is expressed by a plasmid vector is used as a therapeutic agent to inhibit the expression of a target protein” (Muzykantov, par. [0312]), which is a “plasmid” of claim 16, as well as “an expression cassette, and wherein the expression cassette comprises a promoter sequence and a transgene” of claim 56. See MPEP § 2123 [R-5] regarding the obviousness of rearranging a reference according to the teachings of that same reference.
Thus, Muzykantov renders claims 16 and 56 obvious.
Regarding claim 22, it is noted that the requirements:
22. ([…]) The pharmaceutical composition of claim 1, wherein the pharmaceutical composition is administered to a subject; wherein the subject is a human patient in need of treatment with LNP encapsulated with TNA.
are a recitation of intended use. In this regard, it is noted that recitations of intended use must result in a structural difference between the claimed invention and the prior art in order to patentably distinguish the claimed invention from the prior art. If the prior art structure is capable of performing the intended use, then it reads on the claim. See MPEP § 2103 (I)(C)). Since Muzykantov teaches the structure of the composition of instant claim 1, then it reasonably follows that Muzykantov’s composition would be capable of performing the intended use.
Thus, Muzykantov renders claim 22 obvious.
Regarding claim 53 and the requirements:
53. ([…]) The pharmaceutical composition of claim 1, wherein the LNP has a diameter ranging from about 40 nm to about 120 nm; a diameter of about 60 nm to about 80 nm; or a diameter of less than about 100 nm.
Muzykantov teaches:
[0102] In various embodiments, the lipid nanoparticles have a mean diameter of from about 30 nm to about 150 nm, from about 40 nm to about 150 nm, from about 50 nm to about 150 nm, from about 60 nm to about 130 nm, from about 70 nm to about 110 nm, from about 70 nm to about 100 nm, from about 80 nm to about 100 nm, from about 90 nm to about 100 nm, from about 70 to about 90 nm, from about 80 nm to about 90 nm, from about 70 nm to about 80 nm, or about 30 nm, 35 nm, 40 nm, 45 nm, 50 nm, 55 nm, 60 nm, 65 nm, 70 nm, 75 nm, 80 nm, 85 nm, 90 nm, 95 nm, 100 nm, 105 nm, 110 nm, 115 nm, 120 nm, 125 nm, 130 nm, 135 nm, 140 nm, 145 nm, or 150 nm. In one embodiment, the lipid nanoparticles have a mean diameter of about 83 nm. In one embodiment, the lipid nanoparticles have a mean diameter of about 102 nm. In one embodiment, the lipid nanoparticles have a mean diameter of about 103 nm. […].
(Muzykantov, par. [0102]). See MPEP § 2144.05 (I) regarding the obviousness of prior art overlapping claimed numerical ranges.
Thus, Muzykantov renders claim 53 obvious.
Regarding claim 73 and the requirements:
73. ([…]) A method of treating a cancer in a subject, said method comprising administering to the subject an effective amount of the pharmaceutical composition of claim 1.
Muzykantov teaches the treatment of a “pulmonary condition” including “cancer”:
[0009] In another aspect, the present invention relates to a method of treating or preventing a pulmonary condition of a subject, the method comprising administering to the subject the composition of the invention. In one embodiment, the pulmonary condition is selected from the group consisting of acute lung injury, pulmonary ischemia including organ transplantation, pulmonary embolism, pulmonary edema, pulmonary hypertension, fibrosis, infection, inflammation, emphysema, and cancer.
(Muzykantov, par. [0009]), which encompasses the active step requirements of claim 73 for “administering” for “treating a cancer in a subject.” It is further noted that an “effective amount” of the instant composition, is a result-effective variable, i.e., a variable which achieves a recognized result, before the determination of the optimum or workable ranges of said variable might be characterized as routine experimentation. In re Antonie, 559 F.2d 618, 195 USPQ 6 (CCPA 1977). Therefore, an ordinary skilled artisan would also be motivated to manipulate and optimize the dosage depending on a patient’s weight, age, tolerance, sex, and condition being treated.
Thus, Muzykantov renders claim 73 obvious.
Regarding claim 76 and the requirements:
76. ([…]) A method of delivering a therapeutic nucleic acid (TNA) or increasing the concentration of the TNA to the liver of a subject, said method comprising administering to the subject an effective amount of the pharmaceutical composition of claim 1.
Muzykantov discusses “cell type-specific delivery of mRNA” as a “major challenge,” and discloses “[u]pon systemic delivery, mRNA-LNPs mainly target the liver due to their ability to bind apolipoprotein E (apoE) and target apoE receptors on the surface of hepatocytes”:
[0545] Organ and cell type-specific delivery of mRNA after systemic administration is a major challenge. Upon systemic delivery, mRNA-LNPs mainly target the liver due to their ability to bind apolipoprotein E (apoE) and target apoE receptors on the surface of hepatocytes (Akinc et al, 2010, Mol. Ther., 18:1357-1364). Coupling affinity ligands, such as antibodies to specific target molecules, to the surface of nanocarriers provides an alternative approach for targeted delivery. Affinity targeting may provide more precise control of distribution in an organ and destination in the target cells (Shuvaev et al., 2015, J. Control. Release., 219:576-595).
(Muzykantov, par. [0545]), which relates to the requirements of claim 76 for “increasing the concentration of the TNA to the liver of a subject” and the active step of “administering.” See MPEP § 2123 [R-5] regarding the obviousness of rearranging a reference according to the teachings of that same reference.
Thus, Muzykantov renders claim 76 obvious.
Claim 8 is rejected under 35 U.S.C. § 103 as being unpatentable over MUZYKANTOV (US 2020/0093936 A1, Publ. Mar. 26, 2020; 04/24/2024 IDS; hereinafter, “Muzykantov”), as applied to claims 1-2, 4-5, 15-16, 22, 24, 28, 36, 53, 56, 73 and 76, above, and further in view of WAHLICH (Wahlich, J. et al., Nanomedicines for the Delivery of Biologics, Pharmaceutics, 11 (2019) pp 1-14; hereinafter “Wahlich”).
The teachings of Muzykantov, as set forth above, are hereby incorporated. However, Muzykantov DOES NOT TEACH the requirements of claim 8 for:
8. ([…]) The pharmaceutical composition of claim 1, wherein the scFv is linked to the LNP via transglutaminase-mediated conjugation.
which is well within the purview of the ordinarily skilled artisan.
Wahlich, for instance is directed to:
Nanomedicines for the Delivery of Biologics
Abstract
A special symposium of the Academy of Pharmaceutical Sciences Nanomedicines Focus Group reviewed the current status of the use of nanomedicines for the delivery of biologics drugs. This meeting was particularly timely with the recent approval of the first siRNA-containing product Onpattro™ (patisiran), which is formulated as a lipid nanoparticle for intravenous infusion, and the increasing interest in the use of nanomedicines for the oral delivery of biologics. The challenges in delivering such molecules were discussed with specific emphasis on the delivery both across and into cells. The latest developments in Molecular Envelope Technology® (Nanomerics Ltd, London, UK), liposomal drug delivery (both from an academic and industrial perspective), opportunities offered by the endocytic pathway, delivery using genetically engineered viral vectors (PsiOxus Technologies Ltd, Abingdon, UK), Transint™ technology (Applied Molecular Transport Inc., South San Francisco, CA, USA), which has the potential to deliver a wide range of macromolecules, and AstraZeneca’s initiatives in mRNA delivery were covered with a focus on their uses in difficult to treat diseases, including cancers. Preclinical data were presented for each of the technologies and where sufficiently advanced, plans for clinical studies as well as early clinical data. The meeting covered the work in progress in this exciting area and highlighted some key technologies to look out for in the future.
(Wahlich, title & abstract). In this regard, teaches:
Transglutaminase (TGase) is another enzyme well suited to selectively mediate polymer conjugation at specific glutamines but, as shown recently, also to lysine [29]. There are several transglutaminases from different sources with different site specificities and they work via a single step reaction on many native proteins without the need to add specific substrate sequences [30]. However, the glutamine must be in a “flexible” peptide sequence to adapt to the enzyme catalytic site to permit polymer conjugation. Importantly, the TGase conjugation strategy results in a heterogeneous product when there is more than one (flexible and accessible) glutamine. However, the flexibility can be manipulated to achieve specificity by changing the solvent used for the reaction [31]. By considering the positioning of the glutamine it is possible to direct binding to a region not implicated in the therapeutic interaction (and thus preserving the biological activity of the conjugate). The complicating factor is that transglutaminase is in solution and thus needs to be separated from the product. The transglutaminase can be immobilised which aids product separation and minimises subsequent reaction with the PEGylated product.
(Wahlich, p. 6, par. 3), which relates to claim 8.
In light of these teachings, it would have been prima facie obvious to one of ordinary skill in the art before the effective filing date to formulate Muzykantov’s lipid nanoparticle (as discussed above) with conjugation by TGase per Wahlich. One would have been motivated to do so with a reasonable expectation of success in order to obtain the advantage of selectively mediate polymer conjugation at specific glutamines” (Wahlich, p. 6, par. 3).
Thus, the prior art renders claim 8 obvious.
Claims 9 and 75 are rejected under 35 U.S.C. § 103 as being unpatentable over MUZYKANTOV (US 2020/0093936 A1, Publ. Mar. 26, 2020; 04/24/2024 IDS; hereinafter, “Muzykantov”), as applied to claims 1-2, 4-5, 15-16, 22, 24, 28, 36, 53, 56, 73 and 76, above, and further in view of MIZHARY (Mizhary, S., et al., Advanced Strategies in Immune Modulation of Cancer Using Lipid-Based Nanoparticles, Front. Immunol., 8 (February 05, 2017) pp. 1-7; hereinafter, “Mizhary”).
The teachings of Muzykantov, as set forth above, are hereby incorporated. However, Muzykantov DOES NOT TEACH the requirements of claims 9 and 75 for:
9. ([…]) The pharmaceutical composition of claim 1, wherein the antigen is a tumor-associated antigen (TAA) or a tumor-specific antigen (TSA).
[…]
75. ([…]) A method of delivering a therapeutic nucleic acid (TNA) or increasing the concentration of the TNA to a tumor in a subject, said method comprising administering to the subject an effective amount of the pharmaceutical composition of claim 1.
which is well within the purview of the ordinarily skilled artisan.
Mizhary, for instance is directed to:
Advanced Strategies in Immune Modulation of Cancer Using Lipid-Based Nanoparticles
Abstract
Immunotherapy has a great potential in advancing cancer treatment, especially in light of recent discoveries and therapeutic interventions that lead to complete response in specific subgroups of melanoma patients. By using the body’s own immune system, it is possible not only to specifically target and eliminate cancer cells while leaving healthy cells unharmed but also to elicit long-term protective response. Despite the promise, current immunotherapy is limited and fails in addressing all tumor types. This is probably due to the fact that a single treatment strategy is not sufficient in overcoming the complex antitumor immunity. The use of nanoparticle-based system for immunotherapy is a promising strategy that can simultaneously target multiple pathways with the same kinetics to enhance antitumor response. Here, we will highlight the recent advances in the field of cancer immunotherapy that utilize lipid-based nanoparticles as delivery vehicles and address the ongoing challenges and potential opportunities.
(Mizhary, title & abstract). In this regard, teaches “Tumor cells express TAA-derived peptides in context of MHC molecules that are recognized by TAA-specific-cytotoxic CD8+T-lymphocytes (CTL)” (Mizhary, p 1, par. 3, cont. on p. 2) for which “[e]fficient antitumor immunotherapy can be achieved by combining delivery of TAAs to APC along with removing tumor-derived negative regulators of immune cell activation” (Mizhary, p 2, par. 3), which relates to the requirements of claims 9 and 75.
In light of these teachings, it would have been prima facie obvious to one of ordinary skill in the art before the effective filing date to formulate Muzykantov’s lipid nanoparticle (as discussed above) to target “TAA-derived peptides” per Mizhary. One would have been motivated to do so with a reasonable expectation of success in order to obtain the advantage of “[e]fficient antitumor immunotherapy can be achieved by combining delivery of TAAs to APC along with removing tumor-derived negative regulators of immune cell activation” (Mizhary, p 2, par. 3).
Thus, the prior art renders claims 9 and 75 obvious.
Claims 46 and 77-78 are rejected under 35 U.S.C. § 103 as being unpatentable over MUZYKANTOV (US 2020/0093936 A1, Publ. Mar. 26, 2020; 04/24/2024 IDS; hereinafter, “Muzykantov”), as applied to claims 1-2, 4-5, 15-16, 22, 24, 28, 36, 53, 56, 73 and 76, above, and further in view of NAKAI (WO 2019/188867 A1, Publ. Mar. 10, 2019; as evidenced by US 2021/0023008 A1, Publ. Jan. 28, 2021 for English language translation; hereinafter, “Nakai”) and SIDDHARTH (WO 2018/170336 A1, Publ. Sep. 20, 2018; hereinafter, “Siddharth”).
Paragraph numbers for Nakai refer to US 2021/0023008 A1 as an English language translation of WO 2019/188867 A1. The teachings of Muzykantov, as set forth above, are hereby incorporated. However, Muzykantov DOES NOT TEACH the requirements of claims 46 and 77-78 for:
46. ([…]) The pharmaceutical composition of claim 28, wherein:
the cationic lipid is present at a molar percentage of about 30% to about 80%;
the sterol is present at a molar percentage of about 20% to about 50%;
the non-cationic lipid is present at a molar percentage of about 2% to about 20%;
the at least one PEGylated lipid is present at a molar percentage of about 2.1% to about 10%;
the LNP has a total lipid to TNA ratio of about 10:1 to about 40:1 and/or the scFv are present at a total amount of about 0.02 μg/μg of TNA to about 0.1 μg/μg of TNA.
[…]
77. ([…]) The pharmaceutical composition of claim 1, wherein the scFv is chemically conjugated to the LNP via PEG5000.
78. ([…]) The pharmaceutical composition of claim 1, wherein the PEGylated lipid to which the scFv is chemically conjugated or covalently linked is DSPE-PEG5000.
which is well within the purview of the ordinarily skilled artisan.
Nakai, for instance, is directed to:
NOVEL CATIONIC LIPID EXHIBITING IMPROVED INTRACELLULAR DYNAMICS
ABSTRACT
The invention provides a cationic lipid, a lipid membrane structure containing same, and use thereof. The cationic lipid is represented by the formula (1)
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wherein R1a, R1b, R2a, R2b, R3a, R3b, Xa, Xb, Ya, Yb, Za, and Zb are as defined in the specification.
Nakai, title & abstract; see also Nakai, par. [0025]-[0035] further defining Nakai’s “formula (1).” In this regard, Nakai exemplifies a “Preparation of mRNA-Encapsulated Particles” from “[a] lipid solution in ethanol was prepared by mixing 5 mM cationic lipid, 5 mM phospholipid and 5 mM cholesterol at desired ratios” and “further adding DMG-PEG2k”:
[Experimental Example 10] Preparation of
mRNA-Encapsulated Particles and Property
Evaluation
[0293] 1. Preparation of mRNA-Encapsulated LNP by Micro Flow Path Method
(1) Preparation of Ethanol Solution of Lipid
[0294] A lipid solution in ethanol was prepared by mixing 5 mM cationic lipid, 5 mM phospholipid and 5 mM cholesterol at desired ratios in a 5 mL tube to achieve the total lipid amount of 2550 nmol, further adding DMG-PEG2k (1 mM ethanol solution) in an amount corresponding to 1.5% of the total lipid amount, and adding ethanol to achieve a total volume of 510 μL.
(2) Preparation of Acidic Buffer Solution of Nucleic Acid
[0295] An acidic buffer solution of nucleic acid was prepared by weighing 10.8 μg of mRNA solution (concentration varies depending on the efficiency of in vitro translation and is generally 0.6-0.8 μg/μL) in a 5 mL tube and adding acidic malate buffer (20 mM, pH3.0, containing 30 mM NaCl) to make the total amount 1300 μL.
(3) Preparation of LNP preparation using micro flow path
[0296] The acidic buffer solution of nucleic acid and the ethanol solution of lipid were each weighed in a syringe. Using an ultra high-speed nanomedicament producing apparatus NanoAssmblr, LNP was prepared under the conditions of nucleic acid solution 3 mL/min, lipid solution 1 mL/min, and 1.2 mL thereof was collected in a 15 mL tube. 20 mM MES at pH6.5 (prepared with NaOH) (3000 μL) was added to the 15 mL tube, transferred to Amicon Ultra 4, centrifugation (25° C., 1000 g, 3 min) was repeated, and ultrafiltered and concentrated to about 300 μL by centrifugation. Thereafter, the volume was increased to 4 mL using PBS, and concentrated by repeating centrifugation (25° C., 1000 g, 3 min) again. Finally, PBS was used to adjust to the target lipid concentration.
2. Measurement of Particle Size and Surface Potential of Various mRNA-Encapsulated LNPs
[0297] The particle size and the surface potential were measured by the dynamic light scattering method. The particle size and one example of the surface potential of the various LNPs prepared by the method of the above-mentioned 1. are shown in Tables 14-21.
Nakai, par. [0293]-[0297], Ex. 10; see also Nakai, par. [0138] noting “LNP” as referring to “lipid nanoparticles” or “Lipid Nano Particle.” With respect to PEG size, Siddharth, for instance, is directed to:
Title: LIPID NANOPARTICLE FORMULATION
Abstract: The disclosure features novel lipids and compositions involving the same. Nanoparticle compositions include an ionizable lipid, a phospholipid, a first sterol or a tocopherol, and optionally a second sterol different from the first sterol. Nanoparticle compositions further including therapeutic and/or prophylactics such as RNA are useful in the delivery of therapeutic and/or prophylactics to mammalian cells or organs to, for example, regulate polypeptide, protein, or gene expression.
Siddarth, title & abstract. In this regard, Siddarth discloses claim embodiments drawn to a nanoparticle composition comprising an ionizable lipid, and further comprising a “PEG lipid” including a “PEG moiety having a size of from about 1000 Da to about 20 kDa”:
1. A nanoparticle composition comprising a lipid component comprising
an ionizable lipid,
a phospholipid,
a first sterol or a tocopherol, and
optionally a second sterol different from the first sterol wherein the molar ratio between the first and second sterols is between about 1:100 and 100:1, or the molar ratio between the tocopherol and second sterol is between about 1:100 and 100:1.
[…]
34. The nanoparticle composition of any one of the preceding claims, wherein the lipid component further comprises a PEG lipid.
[…]
36. The nanoparticle composition of claim 34 or 35, wherein the PEG lipid includes a PEG moiety having a size of from about 1000 Da to about 20 kDa.
37. The nanoparticle composition of any one of claims 34-36, wherein the PEG lipid is selected from
PNG
media_image4.png
200
400
media_image4.png
Greyscale
,
[…].
(Siddharth, claims 1, 34 and 36-37).
In light of these teachings, it would have been prima facie obvious to one of ordinary skill in the art before the effective filing date to formulate Muzykantov’s lipid nanoparticle (as discussed above) per Nakai and Siddharth. One would have been motivated to do so with a reasonable expectation of success in order to obtain the advantage of suitable lipid nanoparticle formulations known in the art. See MPEP § 2144.07 stating that the selection of a known material based on its suitability for its intended use is prima facie obvious, which cites Sinclair & Carroll Co. v. Interchemical Corp., 325 U.S. 327, 65 USPQ 297 (1945), wherein “Reading a list and selecting a known compound to meet known requirements is no more ingenious than selecting the last piece to put in the last opening in a jig-saw puzzle.” ).” In this regard, Nakai teaches overlapping amounts of:
“the cationic lipid of the present invention is contained in 5-100 mol %, preferably 10-90 mol %, more preferably 20-70 mol %, of the total lipid” (Nakai, par. [0140]); and
“[t]he content of other constituent components in the lipid membrane structure of the present invention is generally 5-95 mol %, preferably 10-90 mol %, more preferably 30-80 mol %” (Nakai, par. [0139]), namely a “sterol,” “non-cationic lipid” and “PEGylated lipid” of the instant claims.
See MPEP § 2123 [R-5] regarding the obviousness of rearranging a reference according to the teachings of that same reference. With regard to the claimed ratio of total lipid to TNA, it is noted that dosage/amount of active ingredient is a result-effective variable, i.e., a variable which achieves a recognized result, before the determination of the optimum or workable ranges of said variable might be characterized as routine experimentation. In re Antonie, 559 F.2d 618, 195 USPQ 6 (CCPA 1977). Therefore, an ordinary skilled artisan would also be motivated to manipulate and optimize the dosage depending on a patient’s weight, age, tolerance, sex, and condition being treated.
Thus, the prior art renders claims 46 and 77-78 obvious.
Claim 51 is rejected under 35 U.S.C. § 103 as being unpatentable over MUZYKANTOV (US 2020/0093936 A1, Publ. Mar. 26, 2020; 04/24/2024 IDS; hereinafter, “Muzykantov”), as applied to claims 1-2, 4-5, 15-16, 22, 24, 28, 36, 53, 56, 73 and 76, above, and further in view of TOGASHI (Togashi, R. et al., A hepatic pDNA delivery system based on an intracellular environment sensitive vitamin E-scaffold lipid-like material with the aid of an anti-inflammatory drug, J. Contr. Rel., 279 (2018) pp 262-270; hereinafter, “Togashi”).
The teachings of Muzykantov, as set forth above, are hereby incorporated. However, Muzykantov DOES NOT TEACH the requriements of claim 51 for:
51. ([…]) The pharmaceutical composition claim 1, further comprising dexamethasone palmitate.
which is well within the purview of the ordinarily skilled artisan.
Togashi, for instance is directed to:
A hepatic pDNA delivery system based on an intracellular environment sensitive vitamin E-scaffold lipid-like material with the aid of an anti-inflammatory drug
Abstract
Non-viral vectors are considered to be an attractive approach for gene delivery, since an artificial material is less immunogenic and oncogenic compared to a viral vector. We previously reported on the hepatic delivery of plasmid DNA (pDNA) by using lipid-like material (an SS-cleavable and pH-activated lipid-like material: ssPalm) which mounts two hydrophobic scaffolds, proton-accepting motifs (tertiary amines), and a cleavable unit (disulfide bonding). In the present study, we report on an advanced hepatic gene delivery system that uses a new type of ssPalm derivative: ssPalmE-Paz4-C2. The hepatic transgene expression of the intravenously administrated lipid nanoparticle (LNP) that was formed with the ssPalmE-Paz4-C2 (LNPssPalmE-Paz4-C2) was significantly higher than that of conventional LNPs formed with a myristic acid-scaffold ssPalm (LNPssPalmM). However, the LNPssPalmE-Paz4-C2 particle induced a severe innate immune response that involved the production of the pro-inflammatory cytokines (IL-6 and TNFα), intracellular DNA sensor-related cytokine (IL-1β) and interferon (IFNβ), even when a pDNA free from CpG-motifs was encapsulated. The production of the pro-inflammatory cytokines and the DNA sensor-related cytokines is attributed to the combination of vitamin E scaffolds and encapsulated pDNA. The depletion of macrophages by chlodronate-encapsulating liposomes dramatically reduced inflammatory gene expression. Based on the above findings, we conclude that the use of a certain type of non-viral carrier that shows a robust gene expression activity is attended by a risk of eliciting an innate immune response. When a highly hydrophobic derivative of dexamethasone, an anti-inflammatory glucocorticoid compound, was co-loaded to the particle, this inflammatory response was relieved, and gene expression efficiency was enhanced. It is thus concluded that the co-delivery of dexamethasone and pDNA is a promising approach for reducing these risks.
(Togashi, title & abstract). In this regard, teaches “dexamethasone palmitate” (Togashi, p. 266, par. 1), which relates to the requirements of claim 51.
In light of these teachings, it would have been prima facie obvious to one of ordinary skill in the art before the effective filing date to formulate Muzykantov’s lipid nanoparticle (as discussed above) with “dexamethasone palmitate” per Togashi. One would have been motivated to do so with a reasonable expectation of success in order to obtain the advantage of “a highly hydrophobic derivative of dexamethasone” for enhanced “gene expression efficiency” (Mizhary, p 2, par. 3).
Thus, the prior art renders claim 51 obvious.
Conclusion
Claims 1-2, 4-5, 8-9, 15-16, 22, 24, 28, 36, 46, 51, 53, 56, 73 and 75-78 are rejected. No claims are allowed.
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/DOMINIC LAZARO/Primary Examiner, Art Unit 1611
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