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 .
This action is in response to the papers filed on 03/27/2025. Claims 1, 3, 6, 7, 9 12, 13, 22, 28-30, 36, 37, 39, 46, 47, 54, 57, 65, and 66 are currently pending. Claims 1, 3, 6, 7, 9, 12, 13, 22, 28-30, 36, 37, 39, 46, 47, 54, and 57 are currently amended, claims 2, 4, 5, 8, 10, 11, 14-21, 23-27, 31-35, 38, 40-45, 48-53, 55, 56, and 58-64 are cancelled, and claims 65 and 66 are newly added claims by applicant’s amendment filed 03/27/2025.
Claims 1, 3, 6, 7, 9 12, 13, 22, 28-30, 36, 37, 39, 46, 47, 54, 57, 65, and 66 are examined on their merits to which the following grounds of rejection are applicable. Claim 1 is an independent claim.
Priority
The instant application is a 371 of PCT/US2023/061888 filed on 02/02/2023.
The instant application claims domestic benefit to US provisional patent application number 63/341,968 filed on 05/13/2022 and 63/306,071 filed on 02/02/2022.
Thus, the earliest possible priority for the instant application is 02/02/2022.
Information Disclosure Statement
The information disclosure statement (IDS) submitted on 03/27/2025 were filed after the mailing date of the current office action. The submission is in compliance with the provisions of 37 CFR 1.97.
Accordingly, the information disclosure statement is being considered by the examiner.
Claim Objections
Claim 3 is objected to because abbreviations such as pfu, TU, and VG in line 15, 16, and 20 respectively, should be spelled out at the first encounter in the claims. Appropriate correction is required.
Claim 22 is objected to because of incorrect spelling. It appears the word “potion” should recite “portion” in line 7.
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.
Claim 6, 7, 12,13, 22, 28-30, 36, and 47 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 6 recites the term “and/or” in line 3. It is unclear what the metes and bounds of this term, as “and” could be interpreted to include only F protein molecule or biologically active portion thereof, or both the F protein molecule or biologically active portion thereof and G protein or biologically active potion thereof, or, “or” would imply that the protein molecules are in the alternative. Appropriate correction is required. Claims 12, 13, 22, 28-30, and 36 are also included in the rejection as they directly or indirectly depend on claim 6.
Claims 12, 22, and 30 use parentheses to comment on or qualify part of the sentences. It is unclear whether the limitations in parentheses are meant to be limitations in the claims or whether they are only suggestions/examples. As such, the metes and bounds of the claims cannot be determined.
Claim 28 recites the phrase “a mutant NiV-G protein that exhibits reduced binding to Ephrin B2 or Ephrin B3”. It is unclear what the “reduced binding” is relative to as the claim does not recite a reference to make the comparison for binding to be considered “reduced”. As such, the metes and bounds of the claims cannot be determined.
Claim 47 is indefinite in its use of the term "optionally" at line 2. As written, it is unclear exactly what that applicant intends to claim. Therefore, the metes and bounds are unclear and the claim is rendered indefinite. Applicant must plainly recite what they intend to claim.
Claims 6, 7, 12, 13, 22, 28-30 are indefinite in their recitation of “a biologically active portion” or “a functionally active variant”. It is unclear which portion or portions of the F protein molecule and glycoprotein G protein from a Paramyxovirus envelope proteins are responsible for the claimed biological activity. The specification does not provide a clear definition, criteria, or examples of what would be considered “biologically active,” nor does it indicate the specific activity required for a portion to qualify as “biologically active.” Moreover, the claims are indefinite because it is unclear as to “the activity” or activities that are intended as being encompassed by the noted phrase. Peptides are known in the prior art to have numerous activities, both specific and general. For example, all peptides of a sufficient length are known to have the activity of eliciting an antibody or immune response. It is suggested that applicant clarify the intended meaning of the noted phrase.
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.
Claims 1, 3, 6, 7, 9, 12, 13, 22, 28-30, 36, 37, 39, 46, 47, 54, and 57 are rejected under 35 U.S.C. 103 as being unpatentable over Lee et al (US 20240279685 A1; hereafter termed “Lee ‘685”) further in view of Zhang et al (US 20200165594 A1), Grimm et al (Gene Therapy, 2003, pages 2412-2419), Lee et al (US 20150050242 A1; hereafter termed “Lee ‘242”), and Birnbaum et al (US 20200371088 A1).
Regarding claim 1, 54, 65, and 66, Lee ‘685 teaches a method of delivering an exogenous cargo (e.g., a fusosome nucleic acid, e.g., a viral nucleic acid, e.g., a lentiviral nucleic acid) to a subject, comprising administering to the subject an effective number of fusosomes and the effective amount or dose is administered for treatment of the disease, condition or disorder (para 0797). Lee ‘685 teaches “fusosome” refers to a bilayer of amphipathic lipids enclosing a lumen or cavity and a fusogen that interacts with the amphipathic lipid bilayer (para 0361). Lee ‘685 teaches that the fusosome has a re-targeting fusogen comprising a sequence from Henipavirus F and G proteins (i.e. envelope proteins from a paramyxovirus) (para 0173) and “re-targeted fusogen” refers to a fusogen that comprises a targeting moiety (para 0373). Lee ‘685 teaches that the method is capable of being delivered to a hepatocyte or liver cell and the exogenous agents or cargo can be delivered to treat a disease or disorder in a hepatocyte or liver cell (para 0722).
Lee ‘685 does not teach that the administration of the targeted lipid particle (i.e. fusosome with re-targeting fusogen) to a subject is explicitly a first dose and a second dose administered within two days, or within one day of each other and the overall dose is divided into two or more doses given successively (claim 1), wherein the method further comprises administration of a third dose of the targeted lipid particle (claim 54), wherein the third dose is administered ex vivo to the subject (claim 57), wherein the amount administered in the first and second dose is about the same (claim 65), and wherein the amount administered in the first dose, second dose, and third dose, is about the same (claim 65).
However, one of ordinary skill in the art would have considered the teachings of Zhang and Grimm as these references are analogous prior art pertaining to targeted lipid particles enclosing exogenous agents, such as AAVs, for treating diseases such as liver disease and the benefits of successive administration of AAVs in liver-related diseases.
Zhang teaches in vivo delivery of a composition comprising a vector, which can be an AAV, that is enclosed by a lipid particle capable of targeting cells such as hepatocytes (i.e. liver cells) (para 0327, para 0571, para 0711, para 1024). Zhang teaches daily intravenous injections of about 1, 3 or 5 mg/kg/day of a nucleic acid targeting-system (i.e. the vector) in a lipid particle and the daily treatment may be over about three days (para 0335).
Grimm teaches in vivo administration of AAV vectors (i.e. an exogenous agent) for treatment of liver-related diseases and that vector re-administration, particularly in the liver, might yield an additive effect because only a subpopulation of hepatocytes is susceptible to infection at a given time (page 2419, left col, para 2).
It would have been prima facie obvious to one of ordinary skill, in the art at the time of the effective filing date, to modify the teachings of a method of delivering an exogenous cargo comprising a fusosome for treating a diseased liver cell from Lee ‘685 and daily administration of target lipid particles which deliver exogenous cargo such as AAVs to liver cells from Zhang to administer the daily exogenous cargo in successive doses since Grimm teaches that treatment of liver disease, for example, may require re-administration of the AAV vector and that it might lead to an additive effect since it was known that only subpopulations of hepatocytes (i.e. liver cells) are susceptible to being infected by a vector at a given time. One would be motivated to do so to increase the number of cells being infected overall by the exogenous agent and hence, increase its efficacy and one would have a reasonable expectation of success.
Last, the instant claims 1, 54, 65, and 66 report a range of dosage administration numbers (1-3 doses) and any dosage amount. While these range of administration numbers and dosage amounts are not explicitly taught by the references Lee ‘685 and Grimm, it would have been prima facie obvious to one of ordinary skill in the art to consider the teaching of Grimm of re-administering an exogenous agent for additive effect when determining the administration number and dosage amount for the fusosomes taught by Lee ‘685. Therefore, the determination of the optimum or workable dosages would have been well within the practice of routine experimentation by the skilled artisan. Furthermore, absent any evidence demonstrating a patentable difference between the compositions and the criticality of the claimed administration number and dosage amount, the determination of the optimum or workable dosing regimen given the guidance of the prior art would have been generally prima facie obvious to the skilled artisan. Please see MPEP 2144.05 [R-2](II)(A) and In re Aller, 220 F. 2d 454, 456, 105 USPQ 233, 235 (CCPA 1955). ("[W]here the general conditions of claim are disclosed in the prior art, it is not inventive to discover the optimum or workable ranges by routine experimentation.").
Regarding claim 3, the teachings of Lee ‘685, Zhang, and Grimm render obvious claim claim 1. The combined teachings of Lee ‘685, Zhang, and Grimm do not teach wherein the total dose is from at or about: (i) 109 to about 1015pfu; (ii)108 TU/kg to at or about 1014 TU/kg of the subject's body weight; (iii)108 infectious units/kg to at or about 1014 infection of the subject’s body weight; (iv) from about 109 to about 1015TU/kg of the subject's body weight; or (v) 106 to about 109 VG/kg of the subject's body weight.
Zhang teaches daily intravenous injections of about 1, 3 or 5 mg/kg/day of a nucleic acid targeting-system (i.e. the vector) in a lipid particle and the daily treatment may be over about three days (para 0335). While Zhang does not teach the various ranges recited in claim 3, the determination of the optimum or workable dosages would have been well within the practice of routine experimentation by the skilled artisan. Furthermore, absent any evidence demonstrating a patentable difference between the compositions and the criticality of the claimed dosage range, the determination of the optimum or workable dosing regimen given the guidance of the prior art would have been generally prima facie obvious to the skilled artisan. Applicant is reminded that differences in concentration or temperature will not support the patentability of subject matter encompassed by the prior art unless there is evidence indicating such concentration or temperature is critical. "[W]here the general conditions of a claim are disclosed in the prior art, it is not inventive to discover the optimum or workable ranges by routine experimentation." In re Aller, 220 F.2d 454, 456, 105 USPQ 233, 235 (CCPA 1955) (Claimed process which was performed at a temperature between 40°C and 80°C and an acid concentration between 25% and 70% was held to be prima facie obvious over a reference process which differed from the claims only in that the reference process was performed at a temperature of 100°C and an acid concentration of 10%.); see also Peterson, 315 F.3d at 1330, 65 USPQ2d at 1382 ("The normal desire of scientists or artisans to improve upon what is already generally known provides the motivation to determine where in a disclosed set of percentage ranges is the optimum combination of percentages.") See MPEP 2144.05 II. A.
Regarding claim 6, 7, and 9, the teachings of Lee ‘685, Zhang, and Grimm render obvious claim claim 1. Moreover, Lee ‘685 teaches the fusosome comprises a henipavirus F protein molecule, wherein at least 33%, 35%, 40%, 45%, 50%, 55%, or 60% of henipavirus F protein molecule in the fusosome is active henipavirus F protein; and a henipavirus G protein molecule (para 0054-0057) and the henipavirus F protein molecule comprises a Hendra virus protein F sequence (para 0122), rendering obvious wherein the one or more Paramyxovirus envelope proteins comprises an F protein molecule or a biologically active portion thereof and/or a glycoprotein G (G protein) or a biologically active portion thereof (claim 6), wherein the one or more Paramyxovirus envelope proteins comprises an F protein molecule or a biologically active portion thereof from a Paramyxovirus and a glycoprotein G (G protein) or a biologically active portion thereof from a Paramyxovirus (claim 7), and wherein the Paramyxovirus is a Hendra virus (claim 9).
Regarding claim 12, the teachings of Lee ‘685, Zhang, and Grimm render obvious claim 1 and 6. Moreover, Lee ‘685 teaches the F protein is a wild-type Nipah virus F (NiV-F) protein or is a functionally active variant or biologically active portion thereof (para 0531), rendering obvious wherein the F protein or the biologically active portion thereof is a wild-type Nipah virus F (NiV-F) protein or is a functionally active variant or biologically active portion thereof.
Regarding claim 13, the teachings of Lee ‘685, Zhang, and Grimm render obvious claim 1 and 6.
However, Lee ‘685, Zhang, and Grimm do not teach wherein the F protein molecule or a biologically active portion thereof is a NiV-F protein that has the amino acid sequence (a) set forth in SEQ ID NO: 7, (b) SEQ ID NO: 11, (c) SEQ ID NO: 12, or (d) SEQ ID NO 2.
Lee ‘242 teaches lentiviral particles which have been pseudotyped with Nipah virus (NiV) fusion (F) and attachment (G) glycoproteins (NiVpp-F/G) and teaches a SEQ ID NO:2 which has 100% similarity match to SEQ ID NO: 7 of the instant application. See alignment below:
Qy = instant application SEQ ID NO:7, Db = Lee ‘242 SEQ ID NO: 2
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Regarding claim 22, the teachings of Lee ‘685, Zhang, and Grimm render obvious claim 1 and 6.
However, Lee ‘685 does not teach wherein the F protein or the biologically active portion thereof is a NiV-F protein that is a functionally active variant that comprises a point mutation on an N-linked glycosylation site of the wild-type NiV-F protein (SEQ ID NO:7) or a biologically active potion thereof.
Lee ‘242 teaches lentiviral particles which have been pseudotyped with Nipah virus (NiV) fusion (F) and attachment (G) glycoproteins (NiVpp-F/G) and that the efficiency of NiVpp transduction can be improved by engineering hyperfusogenic mutations in one or both of NiV-F and NiV-G (para 0043) which can be useful for maintaining the specificity and picomolar affinity of NiV-G for ephrinB2 and/or B3 while independently enhancing the entry efficiency of NiVpp (the pseudotyped with Nipah virus) (para 0043). Lee ‘242 teaches that mutation to the NiV-F glycoprotein is a mutation to an N-linked glycosylation site (para 0039).
It would have been prima facie obvious to one of ordinary skill, in the art at the time of the effective filing date, to modify the teachings of a Paramyxovirus envelope protein comprising an F protein molecule from Lee ‘685 to have a point mutation on an N-linked glycosylation site of the wild-type NiV-F protein as taught by Lee ‘242. One would be motivated to do so to improve the efficiency of transduction while maintaining the specificity and affinity of the NiVpp through generating mutations in the protein. As creating point mutations in the NiV-F proteins and inclusion of NiV-F proteins in envelope proteins is known in the art, one would have a reasonable expectation of success.
Regarding claim 28, the teachings of Lee ‘685, Zhang, and Grimm render obvious claim 1 and 6. Moreover, Lee ‘685 teaches that the fusosome has reduced affinity for EphrinB2 and/or Ephrin B3 compared to a wild-type henipavirus G protein (para 0133), rendering obvious wherein the G protein or the biologically active portion thereof is a mutant NiV-G protein that exhibits reduced binding to Ephrin B2 or Ephrin B3.
Regarding claim 29, the teachings of Lee ‘685, Zhang, and Grimm render obvious claim 1 and 6. Moreover, Lee ‘685 the G protein is a mutant G protein containing one or more amino acid substitutions selected from the group consisting of E501A, W504A, Q530A and E533A with reference to numbering set forth in SEQ ID NO:9 (para 0546). It is noted that SEQ ID NO: 9 of Lee ‘685 has 100% sequence identity to the instant application SEQ ID NO: 14, therefore the position substitutions are the same, and hence rendering obvious wherein the G protein or the biologically active portion thereof is a mutant NiV-G protein comprising one or more amino acid substitutions corresponding to amino acid substitutions selected from the group consisting of E501A, W504A, Q530A and E533A with reference to numbering set forth in SEQ ID NO:14.
Regarding claim 30, the teachings of Lee ‘685, Zhang, and Grimm render obvious claim 1 and 6.
However, Lee ‘685, Zhang, and Grimm do not teach wherein the G protein or the biologically active portion thereof is a NiV-G protein that: (a) is a biologically active portion that is truncated and lacks up to 40 contiguous amino acid residues at or near the N-terminus of the wild-type NiV-G protein (SEQ ID NO:14); or (b) is a biologically active portion that is truncated at the N-terminus of wild-type NiV-G and has the sequence set forth in any of SEQ ID NOS: 13, 14, or 19.
Lee ‘242 teaches lentiviral particles which have been pseudotyped with Nipah virus (NiV) fusion (F) and attachment (G) glycoproteins (NiVpp-F/G) and NiV-G glycoprotein can be a modified or variant form of the protein, such as a truncated NiV-G and deletions of 5, 10, 15, 20, 25, and 30 amino acids at or near the N-terminus of the NiV-G peptide were constructed (para 0039). Indeed, Lee teaches an amino acid sequence set forth in SEQ ID NO: 14 which is 98% identical to SEQ ID NO: 14 of the instant application and is truncated at the N-terminus of SEQ ID NO: 14. See alignment below:
SEQ ID NO: 14 = instant application WT NiV-G protein,
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SEQ ID NO: 15 = Lee ‘242 application truncated amino acids (pos 1-7) WT NiV-G protein
Regarding claim 36, the teachings Lee ‘685, Zhang, and Grimm render obvious claim 1 and 6.
However, Lee ‘685 does not teach wherein the F protein comprises the sequence set forth in SEQ ID NO. 12.
Lee ‘242 teaches lentiviral particles which have been pseudotyped with Nipah virus (NiV) fusion (F) and attachment (G) glycoproteins (NiVpp-F/G) and teaches a sequence set forth in SEQ ID NO: 4 which has 100% similarity to SEQ ID NO: 12 in the instant application. See alignment below:
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Qy = instant application SEQ ID NO:12, Db = Lee ‘242 SEQ ID NO: 4
Lee ‘685 and Lee ‘242 do not teach wherein the G protein comprises the sequence set forth in SEQ ID NO. 19.
Birnbaum teaches a viral envelope protein comprising at least one mutation that diminishes its native function (e.g., wild-type function of a non-mutated viral envelope protein) and the viral envelope protein may be a cocal virus G protein (para 0056). Birnbaum teaches a sequence set forth in SEQ ID NO: 23 with 100% similarity to SEQ ID NO: 19 of the instant application. See alignment below:
Qy = instant application SEQ ID NO:19, Db = Birnbaum SEQ ID NO: 23
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Regarding claim 37 and 39, the teachings of Lee ‘685, Zhang, and Grimm render obvious claim 1. Moreover, Lee ‘685 teaches the fusosome comprising the henipavirus (i.e. a paramyxovirus) G protein molecule further comprises a targeting domain that is exogenous to a wild-type henipavirus G protein and the targeting domain binds CD8, CD105, EpCAM, or Gria4, which are cell surface receptors, thus rendering obvious wherein at least one of the one or more Paramyxovirus envelope proteins are linked to a secondary moiety that is a targeting domain or a functional domain (claim 37) and the secondary moiety is a targeting domain and the targeting domain is specific for a cell surface receptor on a target cell.
Regarding claim 46, the teachings of Lee ‘685, Zhang, and Grimm render obvious claim 1. Moreover, Lee ‘685 teaches a fusosome comprising: optionally, an exogenous cargo, e.g., a fusosome nucleic acid, e.g., a viral nucleic acid (e.g., a lentiviral nucleic acid) (para 0068), rendering obvious wherein the exogenous agent is a nucleic acid.
Regarding claim 47, the teachings of Lee ‘685, Zhang, and Grimm render obvious claim 1. Moreover, Lee ‘685 teaches the fusosome contains an exogenous agent capable of targeting a T cell and the exogenous agent is a chimeric antigen receptor (CAR) (para 0729), rendering obvious wherein the exogenous agent is a nucleic acid encoding a payload gene, optionally wherein the nucleic acid encodes a chimeric antigen receptor (CAR).
Conclusion
No claims are allowed.
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/JULIANA IRENE CANDELARIA/ Examiner, Art Unit 1634
/MARIA G LEAVITT/ Supervisory Patent Examiner, Art Unit 1634
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