Notice of Pre-AIA or AIA Status
The present application, filed on or after March 16, 2013, is being examined under the first inventor to file provisions of the AIA .
Detailed Action
This action is in response to the papers filed September 19, 2025.
Claim Amendments
Applicant’s amendment to the claims filed 09/19/2025 is acknowledged.
Claims 4-8, 11, 15-18, 20-25, 27-30, 32-34, 36-37, 39, 41, 45, 48-52, 54-59, 61-63, 65-67, 69-70, 72, 74, 77-81, 83-84, 86-90, 92-98, 101-103, 106-109, 111-112, and 115 have been cancelled.
Claims 1-3, 9-10, 12-14, 19, 26, 31, 35, 38, 40, 42-44, 46-47, 53, 60, 64, 68, 71, 73, 75-76, 82, 85, 91, 99-100, 104-105, 110, 113-114, 116-119 are pending.
Claims 40, 42-44, 46-47, 53, 60, 64, 68, 71, and 73 are withdrawn from further consideration pursuant to 37 CFR 1.142(b) as being drawn to a nonelected invention.
Claims 1-3, 9-10, 12-14, 19, 26, 31, 35, 38, 75-76, 82, 85, 91, 99-100, 104-105, 110, 113-114, 116-119 are under examination.
Election/Restrictions
Applicant’s reply filed 09/19/2025 to the Requirement for Restriction/Election mailed 05/22/2025.
Applicant elected with traverse the invention of:
Group 1, drawn to a target cell delivery lipid nanoparticle (LNP), and a pharmaceutical composition comprising thereof;
a LNP composition having the ionizable lipid of Compound I-301, the phospholipid of DSPC, the structural lipid of cholesterol or a cholesterol/β-sitosterol blend, and the PEG lipid of Compound 428; and
a payload of an mRNA encoding EPO.
The traversal is on the grounds that there would be no serious burden if all inventions were searched and examined together. This is not found persuasive because search burden is not a requirement for restriction of claims subject to the international “Unity of Invention” standard. Therefore, the requirement is still deemed proper and is therefore made final.
Claims 40, 42-44, 46-47, 53, 60, 64, 68, 71, and 73 are withdrawn from further consideration pursuant to 37 CFR 1.142(b), as being drawn to a nonelected invention, there being no allowable generic or linking claim. Applicant timely traversed the restriction/election requirement in the reply filed on 09/19/2025.
Priority
The instant application 17/632,938 was filed on 02/04/2022. This application is a national stage of international application PCT/US2020/045213 filed 08/06/2020, claiming priority based on U.S. Provisional Patent Application No. 62/884,133 filed 08/07/2019.
Information Disclosure Statement
The information disclosure statements (IDS) submitted on 09/07/2022 and 09/19/2025 have been considered.
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, or by applicant in an information disclosure statement (IDS), they have not been considered.
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 1-3, 9-10, 12-14, 19, 26, 31, 35, 38, 75-76, 82, 91, 99-100, 104-105, 110, 113-114, 116-119 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.
Claims 1-3, 9-10, 38 and 85 each describe the claimed lipid nanoparticle (LNP) in terms of an improved functional or biological property relative to a “reference LNP.” The recitations are indefinite because the “reference LNP” is undefined. Therefore, one of ordinary skill in the art would not be reasonably apprised of the degree that the recited functional/biological properties are improved by. For example, it would be unclear if a LNP that has a greater function relative to a first reference LNP but lesser function relative to a second reference LNP would infringe on the claims.
For these reasons, one of ordinary skill in the art would not be reasonably apprised of the scope of the invention. Dependent claims are included in the basis of the rejection because they do not correct the deficiencies of the claim upon which they depend.
Claim 13 is 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 13 recites “a cell having a high engulfing capacity.” The term “high” in claim 13 is a relative term which renders the claim indefinite. The term “high” is not defined by the claim, the specification does not provide a standard for ascertaining the requisite degree, and one of ordinary skill in the art would not be reasonably apprised of the scope of the invention. In particular, it is unclear what degree or level of engulfing capacity is required by the claim.
For these reasons, one of ordinary skill in the art would not be reasonably apprised of the scope of the invention.
Claim 19 is 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 19 recites a plurality of biological activities which are “enhanced.” The term “enhanced” is not defined by the claims, the specification does not provide a standard for ascertaining the requisite degree, and one of ordinary skill in the art would not be reasonably apprised of the scope of the invention. In particular, it is unclear what degree or level each biological activity is required by the claim.
For these reasons, one of ordinary skill in the art would not be reasonably apprised of the scope of the invention.
Claims 30-31 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 31 recites that the payload is an mRNA encoding a protein of interest other than “an immune cell payload.” The term “immune cell payload” is neither defined by the claim nor the specification, and one of ordinary skill in the art would not be reasonably apprised of the scope of the invention. In particular, it is unclear what constitutes “an immune cell payload” as opposed to any other payload.
For these reasons, one of ordinary skill in the art would not be reasonably apprised of the scope of the invention. Dependent claims are included in the basis of the rejection because they do not correct the deficiencies of the claim upon which they depend.
Claim 76 is 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 76 recites that the ionizable lipid “comprises is a racemic mixture of the amino lipid.” The recitation is indefinite because it is unclear if the ionizable “comprises” or “is” a racemic mixture of the amino lipid.
For these reasons, one of ordinary skill in the art would not be reasonably apprised of the scope of the invention.
Claims 26, 31 and 35 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 26 recites that the payload is “a nucleic acid molecule chosen from RNA, mRNA, dsRNA, siRNA, antisense RNA, ribozyme, CRISPR/Cas9, ssDNA, or DNA.” Where applicant acts as his or her own lexicographer to specifically define a term of a claim contrary to its ordinary meaning, the written description must clearly redefine the claim term and set forth the uncommon definition so as to put one reasonably skilled in the art on notice that the applicant intended to so redefine that claim term. Process Control Corp. v. HydReclaim Corp., 190 F.3d 1350, 1357, 52 USPQ2d 1029, 1033 (Fed. Cir. 1999). In this case, the recitation is indefinite because CRISPR/Cas9 is not a “nucleic acid molecule,” contrary to the claims. Rather, in the art, Cas9 is a known protein, and the term “CRISPR/Cas9” refers to a genome editing tool comprising Cas9 protein complexed with a ribonucleotide, e.g., a gRNA. Therefore, because the specification does not clearly redefine the term, the scope of the claims is indefinite.
For these reasons, one of ordinary skill in the art would not be reasonably apprised of the scope of the invention. Dependent claims are included in the basis of the rejection because they do not correct the deficiencies of the claim upon which they depend.
Claim 35 is 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 35 recites a that “the enzyme is associated with a rare disease.” The term “rare” is a relative term not defined by the claims, the specification does not provide a standard for ascertaining the requisite degree, and one of ordinary skill in the art would not be reasonably apprised of the scope of the invention. In particular, it is unclear what degree or level of occurrence of a disease in a given population would be considered “rare” as opposed to “common.”
For these reasons, one of ordinary skill in the art would not be reasonably apprised of the scope of the invention.
Claim 105 is 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 105 recites a that the PEG-lipid is “PEG-c-DOMG.” The term “PEG-c-DOMG” is neither defined by the claims nor the specification, and one of ordinary skill in the art would not be reasonably apprised of the scope of the invention. In particular, it is unclear what chemical structure constitutes “PEG-c-DOMG” as opposed to any other PEG-lipid.
For these reasons, one of ordinary skill in the art would not be reasonably apprised of the scope of the invention.
Claim Rejections - 35 USC § 102 & 103
The following is a quotation of the appropriate paragraphs of 35 U.S.C. 102 that form the basis for the rejections under this section made in this Office action:
A person shall be entitled to a patent unless –
(a)(1) the claimed invention was patented, described in a printed publication, or in public use, on sale, or otherwise available to the public before the effective filing date of the claimed invention.
(a)(2) the claimed invention was described in a patent issued under section 151, or in an application for patent published or deemed published under section 122(b), in which the patent or application, as the case may be, names another inventor and was effectively filed before the effective filing date of the claimed invention.
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.
Claims 1-3, 9-10, 12-14, 19, 26, 31, 35, 38, 75-76, 82, 85, 91, 99-100, 104-105, 110, 113, 117-119 are rejected under 35 U.S.C. 102(a)(1) as being anticipated by WO 2017/049245 A2 to Benenato et al.
Benenato discloses a lipid nanoparticle (LNP) comprising an mRNA encoding a polypeptide of interest. See, e.g., Abstract; see paragraph 20.
The lipid nanoparticle comprises an ionizable lipid (see, e.g. par. 189), a structural lipid (see, e.g., par. 191), a phospholipid (see, e.g., par. 192-193), a payload (see, e.g., par. 195-202), and a PEG-lipid (see, e.g., par. 190).
Claim 1 further recites the following functional property and/or intended use limitations:
wherein the target cell delivery LNP results in one, two, three-or all of: (a) enhanced payload level in a target cell, organ, cellular compartment, or fluid compartment relative to a different target cell, organ, cellular compartment, or fluid compartment, or relative to a reference LNP; or (b) enhanced lipid level in a target cell, organ, cellular compartment, or fluid compartment, relative to a different target cell, organ, cellular compartment, or fluid compartment, or relative to a reference LNP; or (c) expression and/or activity of payload in greater than 30% of total liver cells.
Claim scope is not limited by claim language that suggests or makes optional but does not require steps to be performed, or by claim language that does not limit a claim to a particular structure. See MPEP 2111.04. In this case, the above limitations indicate an intended use of, or functional property of, the claimed LNP without positively limiting the claimed LNP to a particular structure. A recitation of an intended use or functional property of the claimed product must result in a structural difference between the claimed product and that of the prior art to patentably distinguish the claimed product from the prior art. If the prior art structure is capable of performing the intended use, or if the functional property naturally flows from the prior art structure, then the prior art reads on the intended use or functional property limitation. There is no requirement that the prior art expressly teach or suggest an intended use or functional property limitation. In this case, the claimed structure is taught or suggested by the cited prior art references, and, therefore, recitation of the above functional property and/or intended use limitations does not patentably distinguish the claimed invention from the prior art.
For these reasons, Benenato anticipates claim 1.
Regarding the dependent claims:
Benenato further discloses that the LNP is formulated for systemic delivery (see, e.g., par. 328, 369, 668), as recited or encompassed by claim 12.
Benenato further discloses that the payload is an mRNA encoding EPO (see, e.g., par. 198-199, 677), as recited or encompassed by claims 19, 26, 31, and 35
Benenato further discloses ionizable lipids comprising an amino lipid having a squaramide head group, e.g., Compound 182 on page 50, or comprising Compound 49 on page 32, as recited or encompassed by claims 75-76, 82, and 91.
Benenato further discloses that the phospholipid is DSPC (see, e.g., par. 192-193), as recited or encompassed by claims 99-100.
Benenato further discloses PEG-lipids, e.g., PEG-DMG (see, e.g., par. 190), as recited or encompassed by claims 104-105.
Benenato further discloses that the lipid nanoparticle comprises about 50 mol % of ionizable lipid, about 10 mol % of phospholipid, about 38.5 mol % of structural lipid, and about 1.5 mol % of PEG lipid (see, e.g., par. 318), as recited or encompassed by claims 110 and 113.
Benenato further discloses that the LNP is formulated in a pharmaceutical composition with a pharmaceutically acceptable carrier at least 95% pure, in accordance with general guidelines for formulation and manufacture of pharmaceutical compositions (see, e.g., par. 329-330), as recited or encompassed by claims 117-119.
Dependent claims 2-3, 9-10, 12-14, 19, 38, 85, and 100 further recite the following functional property and/or intended use limitations:
wherein the target cell is a liver cell [claim 2];
(a) results in expression and/or activity of payload in greater than of total liver cells, (b) results in enhanced payload level in liver cells relative to a reference LNP; (c) results in about 1.5-fold, 2-fold, 3-fold, 4-fold, 5-fold, or 6-fold increase in liver cell expression relative to a reference LNP, (d) has an increased efficiency of cytosolic delivery as compared to a reference LNP, and/or (e) results in one, two, or all of (i) greater Maximum Concentration Observed (Cmax) in the liver relative to plasma, (ii) greater half-life (t1/2) in the liver relative to plasma, (iii) greater% Extrapolated Area under the Concentration Time Curve (AUC % Extrap) in the liver relative to plasma [claim 3];
has an improved parameter in vivo relative to a reference LNP, wherein said improved parameter is chosen from one, two, three, four, five, six, seven, or all or any combination of the following: (1) enhanced payload level in the liver, (2) enhanced serum stability to a subject, (3) reduced immunogenicity, (4) increased bioavailability, (5) enhanced liver distribution, (6) enhanced tissue concentration of lipid and/or payload in the liver, (7) enhanced endosomal escape, or (8) slower lipid metabolism in the liver relative to the spleen [claim 9];
results in one or both of (1) an increased response rate defined by a specified threshold of liver cell
transfection greater than a reference LNP, or (2) at least 30% liver cell transfection [claim 10];
the target cell delivery LNP is formulated for systemic delivery or administered systemically [claim 12];
delivers the payload to a cell capable of protein synthesis and/or a cell having a high engulfing capacity [claim 13];
delivers the payload to (a) a liver cell, a hepatocyte, a hepatic stellate cell, a Kupffer cell, or a liver sinusoidal
cell, or a combination thereof, (b) a non-immune cell, (c) a splenic cell, or (d) a cell chosen from an ovarian cell, a lung cell, an intestinal cell, a heart cell, a skin cell, an eye cell or a brain cell, or a skeletal muscle cell [claim 14];
(a) an intracellular concentration of the nucleic acid molecule in the target cell is enhanced, (b) uptake of the nucleic acid molecule by the target cell is enhanced, (c) an activity of the nucleic acid molecule in the target cell is enhanced, (d) expression of the nucleic acid molecule in the target cell is enhanced, (e) an activity of a protein encoded by the nucleic acid molecule in the target cell is enhanced, (f) expression of a protein encoded by the nucleic acid molecule in the target cell is enhanced, and/or (g) delivery is enhanced in vivo [claim 19];
is administered at a dose that is at least 10% lower compared to the dose of a reference LNP [claim 38];
the cell is a liver cell, or the cell is a splenic cell [claim 82];
the reference LNP (a) comprises an ionizable lipid having Formula I-XII, (b) does not comprise an ionizable lipid having a chiral center, (c) does not comprise an ionizable lipid comprising more than one branched alky chains, (d) does not comprise a cyclic-substituted amino lipid, (e) does not comprise a carbocyclic-substituted amino lipid, and/or (f) does not comprise a cycloalkenyl-substituted amino lipid [claim 85]; and
the cell is a liver cell [claim 100].
Claim scope is not limited by claim language that suggests or makes optional but does not require steps to be performed, or by claim language that does not limit a claim to a particular structure. See MPEP 2111.04. In this case, the above limitations indicate an intended use of, or functional property of, the claimed LNP without positively limiting the claimed LNP to a particular structure. A recitation of an intended use or functional property of the claimed product must result in a structural difference between the claimed product and that of the prior art to patentably distinguish the claimed product from the prior art. If the prior art structure is capable of performing the intended use, or if the functional property naturally flows from the prior art structure, then the prior art reads on the intended use or functional property limitation. There is no requirement that the prior art expressly teach or suggest an intended use or functional property limitation. In this case, the claimed structure is taught or suggested by the cited prior art references, and, therefore, recitation of the above functional property and/or intended use limitations does not patentably distinguish the claimed invention from the prior art.
Claims 1-3, 9-10, 12-14, 19, 26, 31, 35, 38, 75-76, 82, 85, 91, 99-100, 104-105, 110, 113, 116-119 are rejected under 35 U.S.C. 102(a)(1) as being anticipated by WO 2017/201340 A2 to Ticho et al.
Ticho discloses a lipid nanoparticle (LNP) comprising an mRNA encoding a polypeptide of interest. See, e.g., Abstract.
The lipid nanoparticle comprises an ionizable lipid, a sterol (i.e., structural lipid), a non-cationic lipid, a payload, and a PEG-modified lipid. See, e.g., pg. 3.
Claim 1 further recites the following functional property and/or intended use limitations:
wherein the target cell delivery LNP results in one, two, three-or all of: (a) enhanced payload level in a target cell, organ, cellular compartment, or fluid compartment relative to a different target cell, organ, cellular compartment, or fluid compartment, or relative to a reference LNP; or (b) enhanced lipid level in a target cell, organ, cellular compartment, or fluid compartment, relative to a different target cell, organ, cellular compartment, or fluid compartment, or relative to a reference LNP; or (c) expression and/or activity of payload in greater than 30% of total liver cells.
Claim scope is not limited by claim language that suggests or makes optional but does not require steps to be performed, or by claim language that does not limit a claim to a particular structure. See MPEP 2111.04. In this case, the above limitations indicate an intended use of, or functional property of, the claimed LNP without positively limiting the claimed LNP to a particular structure. A recitation of an intended use or functional property of the claimed product must result in a structural difference between the claimed product and that of the prior art to patentably distinguish the claimed product from the prior art. If the prior art structure is capable of performing the intended use, or if the functional property naturally flows from the prior art structure, then the prior art reads on the intended use or functional property limitation. There is no requirement that the prior art expressly teach or suggest an intended use or functional property limitation. In this case, the claimed structure is taught or suggested by the cited prior art references, and, therefore, recitation of the above functional property and/or intended use limitations does not patentably distinguish the claimed invention from the prior art.
For these reasons, Ticho anticipates claim 1.
Regarding the dependent claims:
Ticho further discloses that the LNP is formulated for systemic delivery (see, e.g., pg. 23, 109, 256-257), as recited or encompassed by claim 12.
Ticho further discloses that the payload is an mRNA encoding a relaxin polypeptide (see, e.g., pg. 240), as recited or encompassed by claims 19, 26, 31, and 35
Ticho further discloses ionizable lipids comprising an amino lipid having a squaramide head group, e.g., Compound 182 on page 172, or comprising Compound 49 on page 153, as recited or encompassed by claims 75-76, 82, 91, and 116.
Ticho further discloses that the phospholipid is DSPC (see, e.g., pg. 205), as recited or encompassed by claims 99-100, and 116.
Ticho further discloses that the PEG-lipids, e.g., Compound P-428 on page 227, as recited or encompassed by claims 104-105, and 116.
Ticho further discloses that the structural lipid is cholesterol (see, e.g., pg. 218), as recited or encompassed by claim 116.
Ticho further discloses that the lipid nanoparticle comprises about 50 mol % of ionizable lipid, about 10 mol % of phospholipid, about 38.5 mol % of structural lipid, and about 1.5 mol % of PEG lipid (see, e.g., pg. 234), as recited or encompassed by claims 110, 113 and 116.
Ticho further discloses that the LNP is formulated in a pharmaceutical composition with a pharmaceutically acceptable carrier at least 95% pure, in accordance with general guidelines for formulation and manufacture of pharmaceutical compositions (see, e.g., par. 108, 275-276), as recited or encompassed by claims 117-119.
Dependent claims 2-3, 9-10, 12-14, 19, 38, 85, and 100 further recite the following functional property and/or intended use limitations:
wherein the target cell is a liver cell [claim 2];
(a) results in expression and/or activity of payload in greater than of total liver cells, (b) results in enhanced payload level in liver cells relative to a reference LNP; (c) results in about 1.5-fold, 2-fold, 3-fold, 4-fold, 5-fold, or 6-fold increase in liver cell expression relative to a reference LNP, (d) has an increased efficiency of cytosolic delivery as compared to a reference LNP, and/or (e) results in one, two, or all of (i) greater Maximum Concentration Observed (Cmax) in the liver relative to plasma, (ii) greater half-life (t1/2) in the liver relative to plasma, (iii) greater% Extrapolated Area under the Concentration Time Curve (AUC % Extrap) in the liver relative to plasma [claim 3];
has an improved parameter in vivo relative to a reference LNP, wherein said improved parameter is chosen from one, two, three, four, five, six, seven, or all or any combination of the following: (1) enhanced payload level in the liver, (2) enhanced serum stability to a subject, (3) reduced immunogenicity, (4) increased bioavailability, (5) enhanced liver distribution, (6) enhanced tissue concentration of lipid and/or payload in the liver, (7) enhanced endosomal escape, or (8) slower lipid metabolism in the liver relative to the spleen [claim 9];
results in one or both of (1) an increased response rate defined by a specified threshold of liver cell
transfection greater than a reference LNP, or (2) at least 30% liver cell transfection [claim 10];
the target cell delivery LNP is formulated for systemic delivery or administered systemically [claim 12];
delivers the payload to a cell capable of protein synthesis and/or a cell having a high engulfing capacity [claim 13];
delivers the payload to (a) a liver cell, a hepatocyte, a hepatic stellate cell, a Kupffer cell, or a liver sinusoidal
cell, or a combination thereof, (b) a non-immune cell, (c) a splenic cell, or (d) a cell chosen from an ovarian cell, a lung cell, an intestinal cell, a heart cell, a skin cell, an eye cell or a brain cell, or a skeletal muscle cell [claim 14];
(a) an intracellular concentration of the nucleic acid molecule in the target cell is enhanced, (b) uptake of the nucleic acid molecule by the target cell is enhanced, (c) an activity of the nucleic acid molecule in the target cell is enhanced, (d) expression of the nucleic acid molecule in the target cell is enhanced, (e) an activity of a protein encoded by the nucleic acid molecule in the target cell is enhanced, (f) expression of a protein encoded by the nucleic acid molecule in the target cell is enhanced, and/or (g) delivery is enhanced in vivo [claim 19];
is administered at a dose that is at least 10% lower compared to the dose of a reference LNP [claim 38];
the cell is a liver cell, or the cell is a splenic cell [claim 82];
the reference LNP (a) comprises an ionizable lipid having Formula I-XII, (b) does not comprise an ionizable lipid having a chiral center, (c) does not comprise an ionizable lipid comprising more than one branched alky chains, (d) does not comprise a cyclic-substituted amino lipid, (e) does not comprise a carbocyclic-substituted amino lipid, and/or (f) does not comprise a cycloalkenyl-substituted amino lipid [claim 85]; and
the cell is a liver cell [claim 100].
Claim scope is not limited by claim language that suggests or makes optional but does not require steps to be performed, or by claim language that does not limit a claim to a particular structure. See MPEP 2111.04. In this case, the above limitations indicate an intended use of, or functional property of, the claimed LNP without positively limiting the claimed LNP to a particular structure. A recitation of an intended use or functional property of the claimed product must result in a structural difference between the claimed product and that of the prior art to patentably distinguish the claimed product from the prior art. If the prior art structure is capable of performing the intended use, or if the functional property naturally flows from the prior art structure, then the prior art reads on the intended use or functional property limitation. There is no requirement that the prior art expressly teach or suggest an intended use or functional property limitation. In this case, the claimed structure is taught or suggested by the cited prior art references, and, therefore, recitation of the above functional property and/or intended use limitations does not patentably distinguish the claimed invention from the prior art.
Claims 1-3, 9-10, 12-14, 19, 26, 31, 35, 38, 75-76, 82, 85, 91, 99-100, 104-105, 110, 113, 117-119 are rejected under 35 U.S.C. 102(a)(1) and (a)(2) as being anticipated by WO 2018/170306 A1 to Benenato et al.
Benenato discloses a lipid nanoparticle (LNP) comprising an mRNA encoding a polypeptide of interest. See, e.g., Abstract; par. 4-5.
The lipid nanoparticle comprises an ionizable lipid, a structural lipid, a phospholipid, a payload, and a PEG lipid. See, e.g., par. 5.
Claim 1 further recites the following functional property and/or intended use limitations:
wherein the target cell delivery LNP results in one, two, three-or all of: (a) enhanced payload level in a target cell, organ, cellular compartment, or fluid compartment relative to a different target cell, organ, cellular compartment, or fluid compartment, or relative to a reference LNP; or (b) enhanced lipid level in a target cell, organ, cellular compartment, or fluid compartment, relative to a different target cell, organ, cellular compartment, or fluid compartment, or relative to a reference LNP; or (c) expression and/or activity of payload in greater than 30% of total liver cells.
Claim scope is not limited by claim language that suggests or makes optional but does not require steps to be performed, or by claim language that does not limit a claim to a particular structure. See MPEP 2111.04. In this case, the above limitations indicate an intended use of, or functional property of, the claimed LNP without positively limiting the claimed LNP to a particular structure. A recitation of an intended use or functional property of the claimed product must result in a structural difference between the claimed product and that of the prior art to patentably distinguish the claimed product from the prior art. If the prior art structure is capable of performing the intended use, or if the functional property naturally flows from the prior art structure, then the prior art reads on the intended use or functional property limitation. There is no requirement that the prior art expressly teach or suggest an intended use or functional property limitation. In this case, the claimed structure is taught or suggested by the cited prior art references, and, therefore, recitation of the above functional property and/or intended use limitations does not patentably distinguish the claimed invention from the prior art.
For these reasons, Benenato anticipates claim 1.
Regarding the dependent claims:
Benenato further discloses that the LNP is formulated for systemic delivery (see, e.g., par. 44, 230, 243, 420-429), as recited or encompassed by claim 12.
Benenato further discloses that the payload is an mRNA encoding EPO polypeptide (see, e.g., par. 44, 283), as recited or encompassed by claims 19, 26, 31, and 35
Benenato further discloses ionizable lipids comprising an amino lipid having a squaramide head group, e.g., Compound 301 on pages 342-343, as recited or encompassed by claims 75-76, 82, and 91.
Benenato further discloses that the phospholipid is DSPC (see, e.g., par. 278), as recited or encompassed by claims 99-100.
Benenato further discloses that the PEG-lipids, e.g., PEG-DMG (see, e.g., par. 275), as recited or encompassed by claims 104-105.
Benenato further discloses that the lipid nanoparticle comprises about 50 mol % of ionizable lipid, about 10 mol % of phospholipid, about 38.5 mol % of structural lipid, and about 1.5 mol % of PEG lipid (see, e.g., par. 404, 456), as recited or encompassed by claims 110 and 113.
Benenato further discloses that the LNP is formulated in a pharmaceutical composition with a pharmaceutically acceptable carrier at least 95% pure, in accordance with general guidelines for formulation and manufacture of pharmaceutical compositions (see, e.g., par. 415-416), as recited or encompassed by claims 117-119.
Dependent claims 2-3, 9-10, 12-14, 19, 38, 85, and 100 further recite the following functional property and/or intended use limitations:
wherein the target cell is a liver cell [claim 2];
(a) results in expression and/or activity of payload in greater than of total liver cells, (b) results in enhanced payload level in liver cells relative to a reference LNP; (c) results in about 1.5-fold, 2-fold, 3-fold, 4-fold, 5-fold, or 6-fold increase in liver cell expression relative to a reference LNP, (d) has an increased efficiency of cytosolic delivery as compared to a reference LNP, and/or (e) results in one, two, or all of (i) greater Maximum Concentration Observed (Cmax) in the liver relative to plasma, (ii) greater half-life (t1/2) in the liver relative to plasma, (iii) greater% Extrapolated Area under the Concentration Time Curve (AUC % Extrap) in the liver relative to plasma [claim 3];
has an improved parameter in vivo relative to a reference LNP, wherein said improved parameter is chosen from one, two, three, four, five, six, seven, or all or any combination of the following: (1) enhanced payload level in the liver, (2) enhanced serum stability to a subject, (3) reduced immunogenicity, (4) increased bioavailability, (5) enhanced liver distribution, (6) enhanced tissue concentration of lipid and/or payload in the liver, (7) enhanced endosomal escape, or (8) slower lipid metabolism in the liver relative to the spleen [claim 9];
results in one or both of (1) an increased response rate defined by a specified threshold of liver cell
transfection greater than a reference LNP, or (2) at least 30% liver cell transfection [claim 10];
the target cell delivery LNP is formulated for systemic delivery or administered systemically [claim 12];
delivers the payload to a cell capable of protein synthesis and/or a cell having a high engulfing capacity [claim 13];
delivers the payload to (a) a liver cell, a hepatocyte, a hepatic stellate cell, a Kupffer cell, or a liver sinusoidal
cell, or a combination thereof, (b) a non-immune cell, (c) a splenic cell, or (d) a cell chosen from an ovarian cell, a lung cell, an intestinal cell, a heart cell, a skin cell, an eye cell or a brain cell, or a skeletal muscle cell [claim 14];
(a) an intracellular concentration of the nucleic acid molecule in the target cell is enhanced, (b) uptake of the nucleic acid molecule by the target cell is enhanced, (c) an activity of the nucleic acid molecule in the target cell is enhanced, (d) expression of the nucleic acid molecule in the target cell is enhanced, (e) an activity of a protein encoded by the nucleic acid molecule in the target cell is enhanced, (f) expression of a protein encoded by the nucleic acid molecule in the target cell is enhanced, and/or (g) delivery is enhanced in vivo [claim 19];
is administered at a dose that is at least 10% lower compared to the dose of a reference LNP [claim 38];
the cell is a liver cell, or the cell is a splenic cell [claim 82];
the reference LNP (a) comprises an ionizable lipid having Formula I-XII, (b) does not comprise an ionizable lipid having a chiral center, (c) does not comprise an ionizable lipid comprising more than one branched alky chains, (d) does not comprise a cyclic-substituted amino lipid, (e) does not comprise a carbocyclic-substituted amino lipid, and/or (f) does not comprise a cycloalkenyl-substituted amino lipid [claim 85]; and
the cell is a liver cell [claim 100].
Claim scope is not limited by claim language that suggests or makes optional but does not require steps to be performed, or by claim language that does not limit a claim to a particular structure. See MPEP 2111.04. In this case, the above limitations indicate an intended use of, or functional property of, the claimed LNP without positively limiting the claimed LNP to a particular structure. A recitation of an intended use or functional property of the claimed product must result in a structural difference between the claimed product and that of the prior art to patentably distinguish the claimed product from the prior art. If the prior art structure is capable of performing the intended use, or if the functional property naturally flows from the prior art structure, then the prior art reads on the intended use or functional property limitation. There is no requirement that the prior art expressly teach or suggest an intended use or functional property limitation. In this case, the claimed structure is taught or suggested by the cited prior art references, and, therefore, recitation of the above functional property and/or intended use limitations does not patentably distinguish the claimed invention from the prior art.
Claims 114 and 116 are rejected under 35 U.S.C. 103 as being unpatentable over WO 2018/170306 A1 to Benenato et al., as applied to claims 1-3, 9-10, 12-14, 19, 26, 31, 35, 38, 75-76, 82, 85, 91, 99-100, 104-105, 110, 113, 117-119 above; in further view of WO 2017/201340 A2 to Ticho et al.
Regarding dependent claims 114 and 116, Benenato further discloses that the structural lipid is cholesterol (see, e.g., par. 276, 404, 440, 456). However, Benenato does not disclose that the PEG lipid is Compound P-428.
Prior to the effective filing date of the instantly claimed invention, Ticho is relevant prior art for teaching a lipid nanoparticle (LNP) comprising an mRNA encoding a polypeptide of interest. See, e.g., Abstract. The lipid nanoparticle comprises an ionizable lipid, a sterol (i.e., structural lipid), a non-cationic lipid, a payload, and a PEG-modified lipid. See, e.g., pg. 3. Ticho further discloses that the PEG lipid is Compound P-428 (see, e.g., pg. 227, 234), as instantly claimed.
Therefore, prior to the effective filing date of the instantly claimed invention, it would have been prima facie obvious to one of ordinary skill in the art to modify the LNP of Benenato, such that the PEG lipid is Compound P-428, as taught by Ticho, with a reasonable expectation of success because Benenato teaches that the LNP should comprise a PEG lipid, and Ticho provides PEG lipids, including Compound P-428, for increasing the stability and/or circulation time of the therapeutic mRNA polynucleotide. See, e.g., pg. 32, 240, of Ticho.
Accordingly, claims 114 and 116 would have been prima facie obvious over the prior art.
Claims 1-3, 9-10, 12-14, 19, 26, 31, 35, 38, 75-76, 82, 85, 91, 99-100, 104-105, 110, 113-114, 116-119 are rejected under 35 U.S.C. 102(a)(2) as being anticipated by WO 2020/061367 A1 to Benenato et al.
Benenato discloses a lipid nanoparticle (LNP) comprising an mRNA encoding a polypeptide of interest. See, e.g., Abstract.
The lipid nanoparticle comprises an ionizable lipid, a structural lipid, a phospholipid, a payload, and a PEG lipid. See, e.g., par. 4-5.
Claim 1 further recites the following functional property and/or intended use limitations:
wherein the target cell delivery LNP results in one, two, three-or all of: (a) enhanced payload level in a target cell, organ, cellular compartment, or fluid compartment relative to a different target cell, organ, cellular compartment, or fluid compartment, or relative to a reference LNP; or (b) enhanced lipid level in a target cell, organ, cellular compartment, or fluid compartment, relative to a different target cell, organ, cellular compartment, or fluid compartment, or relative to a reference LNP; or (c) expression and/or activity of payload in greater than 30% of total liver cells.
Claim scope is not limited by claim language that suggests or makes optional but does not require steps to be performed, or by claim language that does not limit a claim to a particular structure. See MPEP 2111.04. In this case, the above limitations indicate an intended use of, or functional property of, the claimed LNP without positively limiting the claimed LNP to a particular structure. A recitation of an intended use or functional property of the claimed product must result in a structural difference between the claimed product and that of the prior art to patentably distinguish the claimed product from the prior art. If the prior art structure is capable of performing the intended use, or if the functional property naturally flows from the prior art structure, then the prior art reads on the intended use or functional property limitation. There is no requirement that the prior art expressly teach or suggest an intended use or functional property limitation. In this case, the claimed structure is taught or suggested by the cited prior art references, and, therefore, recitation of the above functional property and/or intended use limitations does not patentably distinguish the claimed invention from the prior art.
For these reasons, Benenato anticipates claim 1.
Regarding the dependent claims:
Benenato further discloses that the LNP is formulated for systemic delivery (see, e.g., par. 30, 297, 299, 500-507), as recited or encompassed by claim 12.
Benenato further discloses that the payload is an mRNA encoding EPO polypeptide (see, e.g., par. 30, 361), as recited or encompassed by claims 19, 26, 31, and 35.
Benenato further discloses ionizable lipids comprising an amino lipid having a squaramide head group or Compound I-301, e.g., Compounds 352, 384 and 385 on pages 103 and 105, as recited or encompassed by claims 75-76, 82, 91, 114 and 116.
Benenato further discloses that the phospholipid is DSPC (see, e.g., par. 347, 482, 559), as recited or encompassed by claims 99-100, 114 and 116.
Benenato further discloses that the PEG-lipid is PEG-DMG (see, e.g., par. 344, 482), or Compound P-428, e.g., PEG 2 on page 10, as recited or encompassed by claims 104-105, 114 and 116.
Benenato further discloses that the structural lipid is cholesterol (see, e.g., par. 345, 482), as recited or encompassed by claims 114 and 116.
Benenato further discloses that the lipid nanoparticle comprises about 50 mol % of ionizable lipid, about 10 mol % of phospholipid, about 38.5 mol % of structural lipid, and about 1.5 mol % of PEG lipid (see, e.g., par. 482), as recited or encompassed by claims 110, 113 and 116.
Benenato further discloses that the LNP is formulated in a pharmaceutical composition with a pharmaceutically acceptable carrier at least 95% pure, in accordance with general guidelines for formulation and manufacture of pharmaceutical compositions (see, e.g., par. 493-494), as recited or encompassed by claims 117-119.
Dependent claims 2-3, 9-10, 12-14, 19, 38, 85, and 100 further recite the following functional property and/or intended use limitations:
wherein the target cell is a liver cell [claim 2];
(a) results in expression and/or activity of payload in greater than of total liver cells, (b) results in enhanced payload level in liver cells relative to a reference LNP; (c) results in about 1.5-fold, 2-fold, 3-fold, 4-fold, 5-fold, or 6-fold increase in liver cell expression relative to a reference LNP, (d) has an increased efficiency of cytosolic delivery as compared to a reference LNP, and/or (e) results in one, two, or all of (i) greater Maximum Concentration Observed (Cmax) in the liver relative to plasma, (ii) greater half-life (t1/2) in the liver relative to plasma, (iii) greater% Extrapolated Area under the Concentration Time Curve (AUC % Extrap) in the liver relative to plasma [claim 3];
has an improved parameter in vivo relative to a reference LNP, wherein said improved parameter is chosen from one, two, three, four, five, six, seven, or all or any combination of the following: (1) enhanced payload level in the liver, (2) enhanced serum stability to a subject, (3) reduced immunogenicity, (4) increased bioavailability, (5) enhanced liver distribution, (6) enhanced tissue concentration of lipid and/or payload in the liver, (7) enhanced endosomal escape, or (8) slower lipid metabolism in the liver relative to the spleen [claim 9];
results in one or both of (1) an increased response rate defined by a specified threshold of liver cell
transfection greater than a reference LNP, or (2) at least 30% liver cell transfection [claim 10];
the target cell delivery LNP is formulated for systemic delivery or administered systemically [claim 12];
delivers the payload to a cell capable of protein synthesis and/or a cell having a high engulfing capacity [claim 13];
delivers the payload to (a) a liver cell, a hepatocyte, a hepatic stellate cell, a Kupffer cell, or a liver sinusoidal
cell, or a combination thereof, (b) a non-immune cell, (c) a splenic cell, or (d) a cell chosen from an ovarian cell, a lung cell, an intestinal cell, a heart cell, a skin cell, an eye cell or a brain cell, or a skeletal muscle cell [claim 14];
(a) an intracellular concentration of the nucleic acid molecule in the target cell is enhanced, (b) uptake of the nucleic acid molecule by the target cell is enhanced, (c) an activity of the nucleic acid molecule in the target cell is enhanced, (d) expression of the nucleic acid molecule in the target cell is enhanced, (e) an activity of a protein encoded by the nucleic acid molecule in the target cell is enhanced, (f) expression of a protein encoded by the nucleic acid molecule in the target cell is enhanced, and/or (g) delivery is enhanced in vivo [claim 19];
is administered at a dose that is at least 10% lower compared to the dose of a reference LNP [claim 38];
the cell is a liver cell, or the cell is a splenic cell [claim 82];
the reference LNP (a) comprises an ionizable lipid having Formula I-XII, (b) does not comprise an ionizable lipid having a chiral center, (c) does not comprise an ionizable lipid comprising more than one branched alky chains, (d) does not comprise a cyclic-substituted amino lipid, (e) does not comprise a carbocyclic-substituted amino lipid, and/or (f) does not comprise a cycloalkenyl-substituted amino lipid [claim 85]; and
the cell is a liver cell [claim 100].
Claim scope is not limited by claim language that suggests or makes optional but does not require steps to be performed, or by claim language that does not limit a claim to a particular structure. See MPEP 2111.04. In this case, the above limitations indicate an intended use of, or functional property of, the claimed LNP without positively limiting the claimed LNP to a particular structure. A recitation of an intended use or functional property of the claimed product must result in a structural difference between the claimed product and that of the prior art to patentably distinguish the claimed product from the prior art. If the prior art structure is capable of performing the intended use, or if the functional property naturally flows from the prior art structure, then the prior art reads on the intended use or functional property limitation. There is no requirement that the prior art expressly teach or suggest an intended use or functional property limitation. In this case, the claimed structure is taught or suggested by the cited prior art references, and, therefore, recitation of the above functional property and/or intended use limitations does not patentably distinguish the claimed invention from the prior art.
Claims 1-3, 9-10, 12-14, 19, 26, 31, 35, 38, 75-76, 82, 85, 91, 99-100, 104-105, 110, 113-114, 116-119 are rejected under 35 U.S.C. 102(a)(2) as being anticipated by WO 2019/152557 A1 to Besin et al.
Besin discloses a lipid nanoparticle (LNP) comprising an mRNA encoding a polypeptide of interest. See, e.g., Abstract.
The lipid nanoparticle comprises an ionizable lipid, a structural lipid, a phospholipid, a payload, and a PEG lipid. See, e.g., pg. 1.
Claim 1 further recites the following functional property and/or