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 .
Priority
Acknowledgement is made of the claim of priority to provisional application no. 63/316,233. Accordingly, the instant claims are examined with an effective filing date of 3/3/2022.
Status of the Claims
Claims 1, 4, 6-18, 21-22, 25, 28, and 46 are pending and under current examination. Claims 2-3, 5, 19-20, 23-24, 26-27, 29-45, and 47-58 are cancelled.
Claim Objections
Claims 5 and 14 are objected to because of the following informalities:
Claim 5 recites the limitation “the plurality and hydrophobic domain or cationic charge domain”. This is grammatically incorrect and should be amended to read “the plurality and hydrophobic domains or cationic charge domains”.
Claim 14 recites the limitation “an ionizable amines”. This is grammatically incorrect and should be amended to read “an ionizable amine” or “ionizable amines”.
Appropriate correction is required.
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 4, 7-13, 18, and 25 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.
Regarding claim 4, the term “reduced” in claim 4 is a relative term which renders the claim indefinite. The term “reduced” 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 the instant case, one of ordinary skill in the art would be unable to discern how much the hydrophilic mask domains must reduce the cationic charge of the cationic charge domains of the construct.
Regarding claims 8 and 13, the claims does not recite the word “and” before the last element of the Markush group. This renders the claim indefinite because it fails to define a closed group. Please refer to MPEP 2173.05(h):
“When materials recited in a claim are so related as to constitute a proper Markush group, they may be recited in the conventional manner, or alternatively. For example, if ‘wherein R is a material selected from the group consisting of A, B, C and D’ is a proper limitation, then “wherein R is A, B, C or D” shall also be considered proper.”
Regarding claim 18, the claim recites the limitations “ASO”, “PMO”, and “PNA”. The instant specification provides no definition for these abbreviations, thereby rendering the claim indefinite.
Regarding claim 18, the term “small molecule therapeutic” in claim 4 is a relative term which renders the claim indefinite. The term “small” 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 the instant case, one of ordinary skill in the art would be unable to discern how small a therapeutic may be to qualify as a small molecule therapeutic as defined by the instant claim.
Regarding claim 18, the claim recites the limitation “combinations with any of these cargos as a single stranded and/or double stranded molecule”. This renders the claim indefinite because it is not clear if the limitation encompasses a single stranded and/or double stranded molecule in addition to the species recited by the claim or if the limitation encompasses only single or double stranded combinations of the recited species. Furthermore, it is unclear how a small molecule therapeutic, which may be of any molecular structure, could be a single and/or double stranded molecule.
Regarding claims 7, 9-12, and 25, claims depending from rejected claims have also been rejected because they incorporate all of the limitations of the claims from which they depend, but fail to resolve the indefiniteness concerns outlined above.
Claim Rejections - 35 USC § 102
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 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.
Claims 1, 4, 6, 8, 14, 18, and 22 are rejected under 35 U.S.C. 102(a)(1) as being anticipated by Hammond (U.S. Patent Application Publication No. 2020/0155692, publication year: 2020, cited in the IDS filed 8/26/2024), as evidenced by Israelachvili (Proc. Natl. Acad. Sci., pg. 8378-8379, publication year: 1997).
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Regarding claim 1, Hammond discloses a conjugated dendrimer represented by the structural formula:
wherein D is a cationic dendrimer having end groups EG, CSG is a charge shielding group, L is a linker, and each API is an active pharmaceutical ingredient. Each end group includes an amine moiety (Claim 1).
Regarding claim 4, Hammond discloses that the CSG is a polyethylene glycol (PEG) with 8 to 12 units and a molecular weight of equal or greater than 200 and less than 400 Da (Claims 2 and 3). The Examiner considers the term “charge shielding group” to read on the “reduced net cationic…charge” limitation of the instant claim 4. Israelachvili teaches the PEG is hydrophilic (pg. 8278, col. 1).
Regarding claim 6, Hammond discloses a linker between the API and CSG and EG of the conjugated dendrimer (Claim 1).
Regarding claims 8 and 14, Hammond discloses that each end group includes an amine moiety (Claim 1). The amine groups are primary amines ([0010] and Figure 1).
Regarding claim 18, Hammond discloses an exemplary conjugated dendrimer that comprises a modifies IGF1 protein as the API [0117].
Regarding claim 22, Hammond discloses an exemplary conjugated dendrimer that comprises a modifies IGF1 protein as the API. Modifications to the PEG and IGF1 protein facilitate linkage of the dendrimer and IGF1 in permanent fashion [0117]. The Examiner considers the disclosed linkage to read on the “covalent bond” limitation of the instant claim 22.
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.
This application currently names joint inventors. In considering patentability of the claims the examiner presumes that the subject matter of the various claims was commonly owned as of the effective filing date of the claimed invention(s) absent any evidence to the contrary. Applicant is advised of the obligation under 37 CFR 1.56 to point out the inventor and effective filing dates of each claim that was not commonly owned as of the effective filing date of the later invention in order for the examiner to consider the applicability of 35 U.S.C. 102(b)(2)(C) for any potential 35 U.S.C. 102(a)(2) prior art against the later invention.
Claims 1, 4, 6, 8, 10-14, 18, and 22 are rejected under 35 U.S.C. 103 as being unpatentable over Hammond (U.S. Patent Application Publication No. 2020/0155692, publication year: 2020, cited in the IDS filed 8/26/2024), as evidenced by Israelachvili (Proc. Natl. Acad. Sci., pg. 8378-8379, publication year: 1997).
Determination of the scope and the content of the prior art
(MPEP §2141.01)
Regarding claims 1, 4, 6, 8, 14, 18, and 22, Hammond teaches the relevant limitations as described in the anticipation rejection above.
Regarding claim 10, Hammond teaches that the charge-shielding group may comprise a fatty acid or phospholipid [0058].
Regarding claims 11 and 12, Hammond teaches that the charge-shielding group may be a polyacrylate [0058].
Regarding claim 13, Hammond teaches that the cationic dendrimer may comprise a triazine dendrimer [0057].
Ascertainment of the Difference Between Scope of the Prior Art and the Claims
(MPEP §2141.02)
Regarding claims 1, 4, 6, 8, 14, 18, and 22, Hammond teaches the relevant limitations as described in the anticipation rejection above.
Regarding claims 10-13, Hammond does not teach a single embodiment or example meeting all limitation of the invention of claims 10-13.
Finding of a Prima Facie Obviousness Rationale and Motivation
(MPEP §2142-2143)
Regarding claims 1, 4, 6, 8, 14, 18, and 22, as noted in the anticipation in the rejection above Hammond anticipated claims 1, 4, 6, 8, 14, 18, and 22; so in anticipating claims 1, 4, 6, 8, 14, 18, and 22, said claims are also considered obvious under 35 U.S.C. 103 over Hammond for the reasons set forth below (“lack of novelty is the epitome of obviousness” May, 574 F.2d at 1089, 197 USPQ at 607 (citing in re Pearson, 494 F.2d 1399, 1402, 181 USPQ 641, 644 (CCPA 1974))).
Regarding claims 10-13, within the broader scope of Hammond all of the limitations of the invention of claims 10-13 are met. It would have been prima facie obvious for one having ordinary skill in the art to choose the limitations in the instant claims from those disclosed by Hammond and arrive at this conclusion because such was contemplated by Hammond.
Claim 7 is rejected under 35 U.S.C. 103 as being unpatentable over Hammond (U.S. Patent Application Publication No. 2020/0155692, publication year: 2020, cited in the IDS filed 8/26/2024) as applied to claims 1, 4, 6, 8, 10-14, 18, and 22 above, and further in view of Schlick et. al. (Bioorganic and Medicinal Chemistry Letters, pg. 5078-5083, publication year: 2011, cited in the IDS filed 8/26/2024), as evidenced by Israelachvili (Proc. Natl. Acad. Sci., pg. 8378-8379, publication year: 1997).
Determination of the scope and the content of the prior art
(MPEP §2141.01)
Hammond teaches the relevant limitations as described above.
Ascertainment of the Difference Between Scope of the Prior Art and the Claims
(MPEP §2141.02)
Hammond does not teach the inclusion of a glycoside moiety as the hydrophilic mask domain. However, this deficiency is cured by Schlick.
Schlick teaches that glycoside clusters may be attached to PAMAM dendrimers (pg. 1, Abstract). The tris-mannoside clustering allows for a redistribution of the dendrimers’ surface functionalities. From this chemistry one can obtain patterned dendrimers that incorporate solubilizing groups, or groups to alter immunogenicity, imaging agents, prodrugs, and targeting ligands all on the same dendrimer. This suggests an effective way to cluster the targeting carbohydrate groups so that additional groups can be added without loss of binding specificity or selectivity for the targeted lectin-carbohydrate interaction (pg. 5, Conclusion).
Finding of a Prima Facie Obviousness Rationale and Motivation
(MPEP §2142-2143)
It would have been prima facie obvious to one of ordinary skill in the art of filing to utilize a glycoside moiety as part of the hydrophilic mask domain of the dendrimer taught by Hammond. One would have understood in view of Schlick that a PAMAM dendrimer comprising a tris-mannoside glycoside functionalization allows for clustering of the targeting carbohydrate groups to allow additional functionalization of the dendrimer. One of ordinary skill in the art would have been capable of applying the known technique (tris-mannoside glycoside functionalization of PAMAM dendrimers) to a known device (the PAMAM dendrimer of Hammond) that was ready for improvement and the results would have been predictable (creation of more sites for functionalization of the dendrimer). The artisan of ordinary skill in the art would have had reasonable expectation for success because Schlick teaches that PAMAM dendrimers may be modified with glycoside functionalization. See MPEP 2143 (I)(D).
Claim 9 is rejected under 35 U.S.C. 103 as being unpatentable over Hammond (U.S. Patent Application Publication No. 2020/0155692, publication year: 2020, cited in the IDS filed 8/26/2024) as applied to claims 1, 4, 6, 8, 10-14, 18, and 22 above, and further in view of Gao (U.S. Patent No. 8,678,686, issue year: 2014), as evidenced by Israelachvili (Proc. Natl. Acad. Sci., pg. 8378-8379, publication year: 1997).
Determination of the scope and the content of the prior art
(MPEP §2141.01)
Hammond teaches that the charge-shielding group may comprise a fatty acid or phospholipid [0058].
Ascertainment of the Difference Between Scope of the Prior Art and the Claims
(MPEP §2141.02)
Hammond does not teach a number of carbons that may be present in the fatty acid. However, this deficiency is cured by Gao.
Gao teaches a lipopolyamine comprising a polyamine dendrimer such as a PAMAM (col. 5 line 19) coupled with a lipid moiety. The lipids may include a saturated or solid chain of C4 to C40 in length (col. 4 line 62) and may be a fatty acid such as oleic acid (col. 4 line 58). When co-formulated with DOPE, the lipopolyamines
Finding of a Prima Facie Obviousness Rationale and Motivation
(MPEP §2142-2143)
The idea for combining compounds each of which is known to be useful for the same purpose, in order to form a composition which is to be used for the same purpose, flows logically from their having been used individually in the prior art. See In re Kerkhoven 626 F.2d 846, 850, 205 USPQ 1069, 1072 (CCPA 1980). As shown by the recited teachings, the instant claims define nothing more than the concomitant use of conventional long-chain fatty acids used in modifying PAMAM dendrimers. It would follow that the recited claims define prima facie obvious subject matter. See MPEP 2144.06.
Claims 15-17 and 21 are rejected under 35 U.S.C. 103 as being unpatentable over Hammond (U.S. Patent Application Publication No. 2020/0155692, publication year: 2020, cited in the IDS filed 8/26/2024) as applied to claims 1, 4, 6, 8, 13-14, 18, and 22 above, and further in view of Pungente (WO2014/071072, publication year: 2014, cited in the IDS filed 8/26/2024), as evidenced by Israelachvili (Proc. Natl. Acad. Sci., pg. 8378-8379, publication year: 1997).
Determination of the scope and the content of the prior art
(MPEP §2141.01)
Regarding claims 15-17 and 21, Hammond teaches the relevant limitations as described above. Hammond also teaches that each end group includes an amine moiety [0006].
Ascertainment of the Difference Between Scope of the Prior Art and the Claims
(MPEP §2141.02)
Regarding claims 15-17 and 21, Hammond does not teach the inclusion of a cationic charge domain comprising the species recited by claim 15, a quaternary amine, or spermine or spermidine. However, this deficiency is cured by Pungente.
Pungente teaches that nucleic acid binding by a cationic lipid vector calls for a headgroup that can sustain a positive charge at physiological pH. Typical headgroup moieties include primary, secondary, or tertiary amines, quaternary ammonium salts, guanidine, imidazole, and polyamines such as spermine and spermidine (pg. 2 lines 8-13).
Finding of a Prima Facie Obviousness Rationale and Motivation
(MPEP §2142-2143)
The idea for combining compounds each of which is known to be useful for the same purpose, in order to form a composition which is to be used for the same purpose, flows logically from their having been used individually in the prior art. See In re Kerkhoven 626 F.2d 846, 850, 205 USPQ 1069, 1072 (CCPA 1980). As shown by the recited teachings, the instant claims define nothing more than the concomitant use of conventional amine head groups used in complexes intended to sustain a cationic charge at physiological pH. It would follow that the recited claims define prima facie obvious subject matter. See MPEP 2144.06).
Claim 25 and 28 are rejected under 35 U.S.C. 103 as being unpatentable over Hammond (U.S. Patent Application Publication No. 2020/0155692, publication year: 2020, cited in the IDS filed 8/26/2024) as applied to claims 1, 4, 6, 8, 10-14, 18, and 22 above, and further in view of Murthy (U.S. Patent Application Publication No. 2020/0368206, publication year: 2020), as evidenced by Israelachvili (Proc. Natl. Acad. Sci., pg. 8378-8379, publication year: 1997).
Determination of the scope and the content of the prior art
(MPEP §2141.01)
Regarding claims 25 and 28, Hammond teaches the relevant limitations as described above.
Ascertainment of the Difference Between Scope of the Prior Art and the Claims
(MPEP §2141.02)
Regarding claims 25 and 28, Hammond does not teach that the hydrophilic masking groups are configured to be removed. However, this deficiency is cured by Murthy.
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Murthy teaches an endosomal disrupter of the formula (I):
wherein M is a hydrophilic masking group, Z is a cleavable linker capable of cleavage with an endosome to release M and produce and an endosomal disrupting surfactant. A is a masked hydrophobic group comprising a cyclic group selected from an aryl, a substituted aryl, a heteroaryl, a substituted heteroaryl, a saturated carbocycle, a substituted carbocycle, a heterocycle, and a substituted heterocycle, and a hydrophobic chain. T is a hydrophilic tail group [0462]. The hydrophobic chain includes a linear or branches alkyl chain [0123]. The masking moiety masks the endosomal disrupting surfactant. Upon entering the endosomal compartment, the acid-labile linking group is hydrolyzed, thereby freeing and unmasking the endosomal disrupting surfactant. The released endosomal disrupting surfactant trippers endosomal disruption, allowing release of any co-delivered macromolecule into the cytoplasm [0122].
Finding of a Prima Facie Obviousness Rationale and Motivation
(MPEP §2142-2143)
It would have been prima facie obvious to one of ordinary skill in the art of filing to include an acid-labile linking group in the dendrimer composition of Hammond. One would have understood in view of Murthy that a cleavable linker group may be included between a masked hydrophobic group and a hydrophilic masking group to facilitate release of the masking group upon entering the endosomal compartment, thereby facilitating release of the cargo into the cytoplasm. It would have been obvious to include such a cleavable linker in the dendrimer of Hammond. One of ordinary skill in the art of filing would have been motivated to include such an acid-labile linking group between the hydrophobic domain and hydrophilic masking group of Hammond in order to facilitate endosomal removal of the masking group and release of the cargo into the cytoplasm of the cell. The artisan of ordinary skill would have had reasonable expectation of success because Murthy teaches that an acid-labile linking group may be used to link a hydrophilic masking group to a hydrophobic group in an endosomal-disruption composition.
Claim 46 is rejected under 35 U.S.C. 103 as being unpatentable over Guild (U.S. Patent Application Publication No. 2020/0237671, publication year: 2020).
Determination of the scope and the content of the prior art
(MPEP §2141.01)
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Guild teaches compounds that are cationic or ionizable lipids that may be used as a liposomal composition to facilitate or enhance the delivery and release of encapsulated materials to one or more target cells [0017]. The liposomal composition may comprise a compound such as HGT4003 (formula VI), HGT4004 (formula VII), or HGT4005 (formula VIII):
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In certain embodiments, the one or more cleavable functional groups (e.g., a disulfide) that comprise such compounds allow, for example, a hydrophilic functional head group to dissociate from a lipophilic functional tail-group of the compound, thereby facilitating a phase transition in the lipid bilayer of the one or more target cells. The phase transition in the lipid bilayer of the one or more target cells facilitates the delivery of the encapsulated materials in the one or more target cells [0006]. The imidazole-based compounds such as HGT4001 and HGT4004 are related to the endosomal disruption properties which promote osmotic swelling and the disruption of the liposomal membrane, followed by the transfection or intracellular release of the polynucleotide materials loaded or encapsulated therein into the target cell [0043].
Ascertainment of the Difference Between Scope of the Prior Art and the Claims
(MPEP §2141.02)
Guild does not teach a single embodiment or example meeting all limitation of the invention of claim 46.
Finding of a Prima Facie Obviousness Rationale and Motivation
(MPEP §2142-2143)
Within the broader scope of Guild all of the limitations of the invention of claim 46 are met. It would have been prima facie obvious for one having ordinary skill in the art to choose the limitations in the instant claims from those disclosed by Guild and arrive at this conclusion because such was contemplated by Guild.
Conclusion
No claims are allowed.
Any inquiry concerning this communication or earlier communications from the examiner should be directed to ELIZABETH ANNE MEYERS whose telephone number is (571)272-2271. The examiner can normally be reached Monday-Friday 8am-5pm ET.
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ELIZABETH ANNE MEYERSExaminer, Art Unit 1617
/ALI SOROUSH/Supervisory Patent Examiner, Art Unit 1614
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