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 .
Applicant’s response filed 09/17/2025 has been received and considered entered. This is a response to amendments and arguments filed 09/17/2025.
Election/Restrictions
Applicant’s election without traverse of Group I (claims 1-29) in the reply filed on 10 November 2024 is considered FINAL.
Claim 30 drawn to Group III (a method of treating a genetic condition using a modified cell) was withdrawn from further consideration, in the non-final office action mailed 03/18/2025, pursuant to 37 CFR 1.142(b) as being drawn to nonelected inventions, there being no allowable generic or linking claim. Election was made without traverse in the reply filed on 10 November 2024.
Claims Status
Claim 12 is/are cancelled. Claims 1-11, 13-30 is/are currently pending with claim 30 withdrawn. Claims 1-11, 13-29 is/are under examination.
Information Disclosure Statement
The listing of references in the specification is not a proper information disclosure statement. 37 CFR 1.98(b) requires a list of all patents, publications, or other information submitted for consideration by the Office, and MPEP § 609.04(a) states, "the list may not be incorporated into the specification but must be submitted in a separate paper." Therefore, unless the references have been cited by the examiner on form PTO-892, they have not been considered.
Claim Rejections - 35 USC § 103
In the event the determination of the status of the application as subject to AIA 35 U.S.C. 102 and 103 (or as subject to pre-AIA 35 U.S.C. 102 and 103) is incorrect, any correction of the statutory basis (i.e., changing from AIA to pre-AIA ) for the rejection will not be considered a new ground of rejection if the prior art relied upon, and the rationale supporting the rejection, would be the same under either status.
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.
Claim(s) 1-6, 8-11, and 22-23 is/are rejected under 35 U.S.C. 103 as being unpatentable over Gong (US 20190099381 A1: EFD 08/28/2017). This is a new grounds of rejection necessitated by amendment.
Regarding claim 1, Gong teaches a polymer nanocapsule comprising a polymer shell and a ribonucleoprotein complex, wherein the polymer shell comprises at least one positively-charged monomer (described in Gong as cationic monomers), at least one neutral monomer (described in Gong as non-ionic monomers) (claim 1), and a crosslinker (paragraph [0063]; claim 1). Gong teaches that the cationic monomer has the structure of Formula (I) (claim 19):
Formula (I):
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Wherein R1 is H or methyl, R2 and R-3 are independently H, methyl, or ethyl, X is O or NH, and n is 0, 1, 2, 3, 4, 5, or 6 (claim 19). The cationic monomer formula recited in the instant claims (Formulas IA and IB) encompass salts of Gong Formula I, as it would be obvious to an artisan that the amine group of Formula I would carry the charge of the salt, producing salts of instant Formulas IA and IB. Gong teaches that the neutral monomer has the structure of Formula III, encompassing the following structure:
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Wherein R is H or methyl, encompassing multiple embodiments of instant Formula IF. Gong also teaches non-biodegradable nanoparticles comprising N,N’-methylenediacrylamide (BAA) as a crosslinker (see structure below, BAA is an embodiment of instant Formula IE) (paragraphs [0081], [0088]):
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While Gong does not teach that the nanoparticles comprise two or more different cationic monomers, it would have been obvious to an artisan at the time of filing to incorporate multiple different cationic monomers, with different inherent characteristics derived from different structures, with structures encompassed by the structural formula I, as an obvious variant and as a form of combining equivalents known for the same purpose (see MPEP 2144.06(I)).
Regarding claim 2, Gong teaches that the ribonucleoprotein complex comprises an endonuclease and a guide RNA (claim 1).
Regarding claim 3, Gong teaches that the endonuclease is a Cas protein (claim 1).
Regarding claim 4, Gong teaches that the Cas protein is a Type II Cas protein (Cas9) (claim 1).
Regarding claim 5, Gong teaches that the Cas protein is a Cas9 protein (claim 1).
Regarding claim 6, Gong teaches that the target gene (i.e. the gene that is targeted by the ribonucleoprotein complex, guided by the gRNA) is CCR5 or HBB (hemoglobin beta) (paragraph [0027]).
Regarding claim 8, Gong teaches that the polymer nanocapsule further comprises at least one targeting moiety (claims 27, 28).
Regarding claim 9, Gong teaches that the at least one targeting moiety is an antibody (paragraph [0072]).
Regarding claim 10, Gong teaches that the polymer shell comprises at least one stabilizing moiety (paragraph [0005] teaches that PEG chains help solubilize the nanocapsule; claim 1) (the instant specification defines a stabilizing moiety as a moiety which provides one of multiple benefits including increased solubility, paragraph [0408]).
Regarding claim 11, Gong teaches that the polymer nanocapsule comprises PEG acrylolyl monomers (claim 1; paragraph [0005] teaches that PEG chains help solubilize the nanocapsule).
Regarding claim 22, Gong teaches a composition comprising the polymer nanocapsule and a pharmaceutically-acceptable carrier or excipient (paragraph [0074]).
Regarding claim 23, Gong teaches a method of exposing a cell to the polymer nanocapsules (claim 29).
Claim(s) 1 and 23-26 is/are rejected under 35 U.S.C. 103 as being unpatentable over Gong (US 20190099381 A1: EFD 08/28/2017), as applied to claim 1 above, in view of Pierelli (2001). This rejection is maintained.
The teachings of Gong render obvious the limitations of claim 1, as discussed above.
Regarding claim 23, Gong teaches a method of exposing a cell to the polymer nanocapsules (claim 29).
Regarding claim 24, while Gong does not explicitly state that the nanocapsule can be configured to target hematopoietic stem cells, Gong does teach that the targeting moiety can target CD105 (paragraph [0021]), which was known in the art at the time of filing to be a surface antigen on hematopoietic stem cells (see Pierelli, 2009).
Regarding claim 25, while Gong does not explicitly state that the nanocapsule can be configured to target CD34+ hematopoietic stem cells, Gong does teach that the targeting moiety can target CD105 (paragraph [0021]), which was known in the art at the time of filing to be a surface antigen on CD34+ hematopoietic stem cells (see Pierelli, 2009).
Regarding claim 26, Gong teaches that cells can be contacted with the nanocapsule in vivo or ex vivo (paragraphs [0004], [0074]), and that the subject to which the nanocapsules are administered is a mammal, including a human (paragraph [0074]). Specifically, Gong teaches that the compositions and methods can be used to treat human disease (paragraph [0004]). If the composition is administered in vivo to a mammal, it would inherently target autologous hematopoietic stem cells, as autologous cells are by definition derived from the same organism.
Claim(s) 13-16, and 18-21 is/are rejected under 35 U.S.C. 103 as being unpatentable over Gong (US 20190099381 A1: EFD 08/28/2017), in view of Pierelli (2001) and Mercadal (2000). This rejection is amended because of claim amendments and is maintained.
Regarding claim 13, Gong teaches a polymer nanocapsule comprising a polymer shell and a ribonucleoprotein complex (claim 1), wherein the polymer nanocapsule includes at least one targeting moiety (claims 27, 28), wherein the at least one targeting moiety is coupled to the polymer nanocapsule (claims 27, 28), and wherein the polymer nanocapsule further comprises at least one stabilizing moiety having a hydrophilic group (paragraph [0005] teaches that PEG chains help solubilize the nanocapsule; claim 1 teaches that the polymer nanocapsule comprises PEG acryloyl monomers) (the instant specification defines a stabilizing moiety as a moiety which provides one of multiple benefits including increased solubility, paragraph [0408]). Gong also teaches that the targeting moiety is conjugated to the PEG groups of the nanocapsule (paragraph [0072]). Furthermore, while Gong does not explicitly state that the nanocapsule can be configured to target hematopoietic stem cells, Gong does teach that the targeting moiety can target CD105 (paragraph [0021]), which was known in the art at the time of filing to be a surface antigen on hematopoietic stem cells (see Pierelli, 2009). Gong teaches that the polymer nanocapsule comprises a polymer shell and a ribonucleoprotein complex, wherein the polymer shell comprises at least one positively-charged monomer (described in Gong as cationic monomers), at least one neutral monomer (described in Gong as non-ionic monomers) (claim 1), and a crosslinker (paragraph [0063]; claim 1). Gong teaches that the cationic monomer has the structure of Formula (I) (claim 19):
Formula (I):
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Wherein R1 is H or methyl, R2 and R-3 are independently H, methyl, or ethyl, X is O or NH, and n is 0, 1, 2, 3, 4, 5, or 6 (claim 19). The cationic monomer formula recited in the instant claims (Formulas IA and IB) encompass salts of Gong Formula I, as it would be obvious to an artisan that the amine group of Formula I would carry the charge of the salt, producing salts of instant Formulas IA and IB. Gong teaches that the neutral monomer has the structure of Formula III, encompassing the following structure:
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Wherein R is H or methyl, encompassing multiple embodiments of instant Formula IF. Gong also teaches non-biodegradable nanoparticles comprising N,N’-methylenediacrylamide (BAA) as a crosslinker (see structure below, BAA is an embodiment of instant Formula IE) (paragraphs [0081], [0088]):
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Regarding claim 14, Gong teaches that the ribonucleoprotein complex targets HBB (hemoglobin beta) (paragraph [0027]). As the guide RNA is what targets the ribonucleoprotein complex to a specific nucleotide sequence, for the ribonucleoprotein complex to target the HBB gene requires that the guide RNA targets the HBB gene.
Regarding claim 15, Gong teaches that the at least one targeting moiety comprises an antibody (paragraph [0072]).
Regarding claim 16, Gong teaches that the hydrophilic group of the at least one stabilizing moiety comprises a polyethylene glycol group (claim 1).
Regarding claim 18, Gong teaches that the polymer shell further comprises a neutral monomer (described in Gong as a non-ionic monomer) and a crosslinker (paragraph [0063]; claim 1).
Regarding claim 19, Gong teaches that the neutral (non-ionic) monomer is acrylamide (paragraphs [0046]-[0047]). While acrylamide is not listed by name, acrylamide fits the description of Formula III of paragraphs [0046]-[0047]).
Regarding claim 20, Gong teaches that the crosslinker is N,N’-methylene bisacrylamide (also known as N,N’-methylenediacrylamide, BAA; see paragraph [0081]).
Regarding claim 21, Gong teaches that the positively charged monomer is N-(3-aminopropyl)methacrylamide hydrochloride (paragraphs [0081], [0091]).
However, Gong does not teach that the targeting moiety is coupled to the polymer nanocapsule through a disulfide bond (required by claim 13).
Mercadal teaches that antibodies can be conjugated to PEG-conjugated nanoparticles using disulfide bonds.
Regarding claim 13, Mercadal teaches that an antibody can be conjugated to the PEG terminus of a PEG-conjugated monomer in a nanoparticle through a disulfide bond (abstract; page 300).
While Gong teaches that the targeting moiety is conjugated to the polymer nanocapsule, Gong does not teach the specific modality of this conjugation. Mercadal provides a mechanism by which an antibody can be conjugated to a PEG-containing nanoparticle. While the nanoparticle of Mercadal is a liposome (distinct from the polymer nanocapsules of Gong), the antibody is specifically conjugated through a disulfide bond to the PEG terminal group of the liposome monomers. As the nanocapsules of Gong also have monomers with PEG terminal groups, and Gong teaches that the antibody targeting group is conjugated specifically to the PEG terminal group, it would have been obvious to a person of ordinary skill at the time of filing that any known mechanism of conjugating an antibody to a PEG group could function to conjugate the antibody of Gong to the PEG groups on the nanocapsules of Gong. Furthermore, Gong teaches that disulfide bonds, such as those described as comprising part of the nanocapsule polymer shell of Gong and those taught by Mercadal which conjugate an antibody to a PEG terminal group, are beneficial for the structure of a polymer nanocapsule intended for the delivery of a payload molecule (here, a ribonucleoprotein complex) to a cell, as the disulfide bonds protect the nanocapsule and encapsulated molecule(s) in the extracellular environment, but are degraded inside the cell (after endocytosis), releasing the contents of the nanocapsule into the cell (paragraph [0006] of Gong). It would therefore have been further obvious to a person of ordinary skill in the art at the time of filing that disulfide bonds (as taught by Mercadal) could be selected for the conjugation of antibody targeting groups to the polymer shell of Gong to both protect this conjugation of antibodies to the nanocapsules in the extracellular environment (in order to ensure that all nanocapsules retain their targeting abilities) and also allow for the further degradation of the nanocapsule inside the targeted cells.
Claim(s) 1, 6-7, and 27-29 is/are rejected under 35 U.S.C. 103 as being unpatentable over Gong (US 20190099381 A1: EFD 08/28/2017), as applied to claim 1 above, in view of Yin (US 20180187186 A1). This rejection is maintained.
The teachings of Gong render obvious the limitations of claim 1, as discussed above.
Regarding claim 6, Gong teaches that the target gene (i.e. the gene that is targeted by the ribonucleoprotein complex, guided by the gRNA) is CCR5 or HBB (hemoglobin beta) (paragraph [0027]).
However, Gong does not teach specific gRNA sequences which target the CCR5 or HBB gene.
Yin teaches a gRNA sequence which targets the HBB gene.
Regarding claims 7 and 27-28, Yin teaches a gRNA sequence of SEQ ID NO:123 (SEQ ID NO:123 of Yin comprises a sequence with 100% identity to SEQ ID NO:3 of the instant application, see below), which targets the HBB gene (paragraph [0457]).
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Regarding claim 29, Yin teaches a gRNA sequence of SEQ ID NO:123 (SEQ ID NO:123 of Yin comprises a sequence with 100% identity to SEQ ID NO:3 of the instant application, see above), which targets the HBB gene (paragraph [0457]). This sequence (instant SEQ ID NO:3) is fully complementary to SEQ ID NO:38 of the instant application (see below), and thus would inherently target this sequence.
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While Gong teaches that the ribonucleoprotein complex can be configured to target the HBB gene, Gong does not teach a specific gRNA sequence which facilitates this gene targeting. Yin does teach such a gRNA sequence, as shown above, and furthermore, a gRNA sequence comprising a sequence having 100% identity with the claimed gRNA of claim 7. It would have been obvious to a person of ordinary skill in the art at the time of filing that in order to target the HBB gene, as taught by Gong, a gRNA would need to be designed which targets the HBB gene; as Yin teaches a gRNA which targets the HBB gene, it would have been further obvious that the gRNA sequence taught by Yin could be used to facility the targeting of the HBB gene as taught by Gong.
Claim(s) 13 and 17 is/are rejected under 35 U.S.C. 103 as being unpatentable over Gong (US 20190099381 A1: EFD 08/28/2017), Pierelli (2001), and Mercadal (2000), as applied to claim 13 above, and further in view of Tour (WO 2013052158 A2).
The teachings of Gong, Pierelli, and Mercadal are discussed above and can be combined to render obvious claim 13.
However, the combined teachings of Gong, Pierelli, and Mercadal do not render obvious the limitation of claim 17 that the nanocapsule polymer shell comprise polypropylene glycol (PPG) as a stabilizing moiety.
Tour teaches that PPG can be used as a stabilizing moiety in a polymer nanocapsule.
Regarding claim 17, Tour teaches a nanocapsule (named a “nanovector” in Tong) which comprises a targeting moiety and a solubilizing moiety (claims 1, 8) (the instant specification defines a stabilizing moiety as a moiety which provides one of multiple benefits including increased solubility, paragraph [0408]). Tour further teaches that the stabilizing moiety is polypropylene glycol (claim 9). As polypropylene glycol is a polymer of propylene glycol, it is inherently a repeat group (it by definition comprises repeats of the monomer propylene glycol).
While Gong, Pierelli, and Mercadal do not teach that the stabilizing or solubilizing moiety can be PPG in addition to or instead of PEG, Tour teaches that in similar nanoparticles to those of Gong (based on the limitations of claim 13), PPG can be used in addition to or instead of PEG, with the implication that PPG and PEG are obvious alternatives and variants which achieve the same desired result (increased solubility of the nanocapsule). It therefore would have been obvious to a person of ordinary skill in the art at the time of filing that PPG was an obvious substitution for PEG in a polymer nanocapsule as a component which would increase the solubility of the nanocapsule—a quality which would be crucial for the ability of a nanocapsule administered into water-based fluids (such as the blood) to reach target cells in vivo and not aggregate (paragraph [0075] of Gong, the nanocapsules can be administered intravenously).
Response to Arguments
Applicant's arguments filed 09/17/2025 have been fully considered but they are not persuasive.
Applicant has argued that amendments to claims 1 and 13 and the cancellation of claim 12 render moot rejections of claims under 35 USC 103. However, as discussed above, the amendments of claims 1 and 13 do not overcome the teachings of Gong, and thus the rejections of the pending claims under 35 USC 103 are maintained.
Conclusion
Applicant's amendment necessitated the new ground(s) of rejection presented in this Office action. Accordingly, THIS ACTION IS MADE FINAL. See MPEP § 706.07(a). Applicant is reminded of the extension of time policy as set forth in 37 CFR 1.136(a).
A shortened statutory period for reply to this final action is set to expire THREE MONTHS from the mailing date of this action. In the event a first reply is filed within TWO MONTHS of the mailing date of this final action and the advisory action is not mailed until after the end of the THREE-MONTH shortened statutory period, then the shortened statutory period will expire on the date the advisory action is mailed, and any nonprovisional extension fee (37 CFR 1.17(a)) pursuant to 37 CFR 1.136(a) will be calculated from the mailing date of the advisory action. In no event, however, will the statutory period for reply expire later than SIX MONTHS from the mailing date of this final action.
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/AFRICA M MCLEOD/ Examiner, Art Unit 1635
/RAM R SHUKLA/ Supervisory Patent Examiner, Art Unit 1635