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 .
Continued Examination Under 37 CFR 1.114
A request for continued examination under 37 CFR 1.114, including the fee set forth in 37 CFR 1.17(e), was filed in this application after final rejection. Since this application is eligible for continued examination under 37 CFR 1.114, and the fee set forth in 37 CFR 1.17(e) has been timely paid, the finality of the previous Office action has been withdrawn pursuant to 37 CFR 1.114. Applicant's submission filed on 08/04/2025 has been entered.
Election/Restrictions
Claims 1, 3, 7, 9, 10, 21-25 are pending.
Claims 1, 3, 7, 9, 10, 21, 22, and 24 and species of CCL5 specific targeting ligand and HIV-1 disease are examined in this action. Claim 23 and 25 stand withdrawn from further consideration pursuant to 37 CFR 1.142(b) as being drawn to a nonelected invention, there being no allowable generic or linking claim.
Priority
It is recognized that the application claims benefit of the Provisional Application 62/896481 filed on 9/5/2019. All examined claims enjoy the benefit of ‘481 filing.
Claim Objections
Objection to claim 1 is withdrawn; the periods in the middle of the claim are removed and limitation f is canceled.
Claim 24 is objected to under 37 CFR 1.75 as being a substantial duplicate of claim 3. Claim 24 recites “wherein CCL5, a ligand for CCR5 receptor, is on the surface of the nanosomes,” with amendment of cl. 1 (reciting targeting CCR5) and cl. 3, reciting “CCL5, a ligand CCR5 receptor, is on the surface of the nanosomes,” the limitation of cl. 24 is substantially duplicative. When two claims in an application are duplicates or else are so close in content that they both cover the same thing, despite a slight difference in wording, it is proper after allowing one claim to object to the other as being a substantial duplicate of the allowed claim. See MPEP § 608.01(m).
Claim Interpretation
Claim interpretation of cl. 2 and 3 is deleted since claim 2 is canceled, while claim 3 is rejected under 112(b) below due to amendment to claim 1.
However, nanosome is interpreted as a nanoparticle and the terms are used interchangeably in this action. Change in the interpretation will result in introducing new matter and thus change of priority date.
Response to Arguments
The Remarks attempt to distinguish between nanosome and nanoparticle by using an uncited, illegible figure (pg. 2-3). The argument is not persuasive. As noted in prior actions, the specification uses the term nanoparticle and nanosomes interchangeably: E.g., both the original and the amended Brief Description of the Drawings of Fig. 1 of 07/24/2023 note the following “Fig. 1 depicts CNAPTM nanoparticles (aka nanosomes).”
Claim Rejections - 35 USC § 112
35 U.S.C. 112(b)
Rejection of claim 21 under 112(b) is withdrawn. Claim 21 recites “the aqueous core.” Although cl. 10 has been amended to overcome 112(b) rejection, its rejection is maintained due to amendment to cl. 1.
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, 10 and their dependent claims 7, 9, 21-22, 24 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 1 is rejected for several reasons:
Claim 1 is rejected since the method claim of making nanosomes fails to recite adequate corresponding recitations of steps that achieve those results. E.g., for the ligand (and CCL5 specifically), the specification provides the following:
Coating CCL5 on nanosomes will be achieved by incorporating phosphatidylethanolamine into the lipid bilayer during synthesis of the nanosomes. The ethanolamine on the surface of the nanosomes will then be cross-linked to the lysine residues in the RANTES protein by glutaraldehyde or other amine cross-linking chemistries. (pg. 3).
Here, the claims do not recite the specific steps in making nanosomes with the ligand, as discussed in the specification, thus it is not clear whether the claim is limited to the additional, unrecited conditions that appear to contribute to achieving the claimed results.
E.g., for the nanosomes, the specification discusses the following:
SuperFluids™ (SFS) technology can be used to manufacture and deliver highly pure Critical Fluid Nanosomes (CFN™) in the particle size range of 100 nm to 200 nm (pg. 7).
The selection of SuperFluids™ will depend on the solubility of the bilayer forming lipids and the hydrophobic active ingredient, Maraviroc. Based on our experience with similar molecules, we plan to use SFS propane and 20% ethanol at 3,000 psig and 40° C unless suggested otherwise by thermodynamic, solubility and stability studies (pg. 13).
So in addition to failing to disclose adequate corresponding recitations of steps that achieve those results, the specification, quoted above, notes that the condition may also be optimized. Further the nanosome production also requires the phospholipid raw material (noted on pg. 13 and Table 1). None of the factors, including lipids, discussed in making the nanosomes are noted in the claims, thus it is not clear whether the claim is limited to the additional, unrecited conditions that contribute to achieving the claimed results.
E.g., for the recited size of 100 nm-200 nm, the specification notes:
Several operational conditions have been identified including temperature, nozzle size and rate of decompression that strongly influence nanosomes size distribution. Other parameters include phospholipid type (synthetic PEGylated or unpegylated), nanosomes composition and load, NA-Protein (cocktail) to lipid ratios. Effects of these parameters on nanosomes physical characteristics and stability in biological fluids are determined by constructing CNAP in nanosomes of different sizes ranging from 100 nm to 200 nm using various lipid materials (phosphatidylcholine and cholesterol), suspended and sterilized through 0.22 μm filters (pg. 15).
Based on the specification, the size can be optimized based on the conditions noted, which are not clearly defined, but nevertheless are a few of the factors that control the size of the nanosomes.
There are other resulting, specific structural properties noted in the claims (NA, NA-protein Cas9/gRNA complex) but the “making,” steps reciting the encapsulation of those structures within the nanosomes, are not adequately recited.
Claim 1 recites “a method of making nanosomes for delivering NA therapeutics,” then adds limitation of the nucleic acid in the aqueous nanosome core, which “encapsulates and co-delivers an RNA-protein hybrid therapeutic,” and then adds the transitional term “comprising” followed by steps a) through e):
First, it is unclear what limitation “comprising” the steps a) through e) is referring to; from previous amendments, it is understood that the steps a) through e) are limitations of making of the nanosomes for delivering NA.
Second, in the steps a) through e) there is no recitation of “RNA-protein hybrid,” where the nanosome core further comprises the “RNA-protein hybrid.” Thus, the making of the nanosome limitations and content of the aqueous core limitation are a bit different and would lead to confusion.
Claim 3 recites “NA-protein hybrids CCR5-CRISPR/Cas9” (line 1) the “NA-protein” lacks sufficient antecedent basis. Amended claim 1 recites RNA-protein hybrid and NA is understood to be broader in scope, including DNA or other nucleic acid monomers. In the interest of compact prosecution, The “NA-protein hybrids” will be interpreted as “RNA-protein hybrids.” And again the term “CRISPR” will be interpreted to be deleted, and will be interpreted as Cas9 and the guide RNA comprises a sequence that targets CCR5 (as of claim 1).
It would be simpler to recite “The method of claim 1, the targeting ligand is CCL5, a ligand for CCR5 receptor.” Claim 1 recites “PEGylated targeting ligands on the outer surface.”
Claim 10 recites “the PEGylated NA-protein” and “the genome-specific RNA molecule,” both limitations lack sufficient antecedent basis. Further cl. 1 specifically recites “specifically target HIV co-receptor CCR5,” which is interpreted as guide RNA targeting CCR5. “RNA-protein” is recited in claim 1, “NA-protein” is not
In the interest of compact prosecution, “the genome-specific RNA molecule” will be interpreted as “the guide RNA targeting CCR5.” “[T]he PEGylated NA-protein,” will be interpreted as further limitation of Cas9/guide RNA complex of cl. 1 through pegylation.
35 U.S.C. 112(d):
The following is a quotation of 35 U.S.C. 112(d):
(d) REFERENCE IN DEPENDENT FORMS.—Subject to subsection (e), a claim in dependent form shall contain a reference to a claim previously set forth and then specify a further limitation of the subject matter claimed. A claim in dependent form shall be construed to incorporate by reference all the limitations of the claim to which it refers.
The following is a quotation of pre-AIA 35 U.S.C. 112, fourth paragraph:
Subject to the following paragraph [i.e., the fifth paragraph of pre-AIA 35 U.S.C. 112], a claim in dependent form shall contain a reference to a claim previously set forth and then specify a further limitation of the subject matter claimed. A claim in dependent form shall be construed to incorporate by reference all the limitations of the claim to which it refers.
Claims 21, 22 are rejected under 35 U.S.C. 112(d) or pre-AIA 35 U.S.C. 112, 4th paragraph, as being of improper dependent form for failing to further limit the subject matter of the claim upon which it depends, or for failing to include all the limitations of the claim upon which it depends.
Claim 21 does not further limit 1c), which recites “said nanosomes having a membrane layer surrounding the aqueous core.”
Claim 22 recites “contains nucleic acid RNA specific for the treatment of HIV-1” and does not further limit the “CRISPR/Cas9 proteins to specifically target HIV co-receptor CCR5” of claim 1. Only “RNA” currently recited in claim 1 is the “guide RNA”, thus it is interpreted that RNA is referring to the guide RNA; and thus can be any guide RNA, when claim 1 is limited to “specifically target HIV co-receptor CCR5.”
Applicant may cancel the claim(s), amend the claim(s) to place the claim(s) in proper dependent form, rewrite the claim(s) in independent form, or present a sufficient showing that the dependent claim(s) complies with the statutory requirements.
Claim Rejections - 35 USC § 103
Rejection of claim 3 is maintained under 103 as noted below, along with rejection of remaining claims.
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 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.
Claims 1, 7, 21, and 22 are rejected under 35 U.S.C. 103 as being unpatentable over Castor (2005, Current Drug Delivery, 2, pg. 1-12, referred as “Castor 2005”) and Castor (WO2016191363A1, pub. 12/01/2016, referred as “’363A1”) and Mandal et al. (2014, Cell Stem Cell, 15, 643-652, referred as Mandal) and Givens et al. (2018, AAPS Journal, 20, 1-22, referred as Givens).
Castor 2005 discloses making uniform phospholipid nanosomes by using supercritical fluid technologies (abstract). Castor 2005 discloses that the size of the nanosomes can be controlled by various factors, such as size and design of nozzle, type of supercritical fluid (also termed “SuperFluidsTM”, SFS, pg. 2) and co-solvent (pg. 5-6), and provides a 120 nm size nanosome (see Table 2, pg. 6) that are stable (pg. 6, “SFS CO2 phospholipid nanosomes demonstrate excellent stability at a storage temperature of 4oC over a six-month period”; relevant to instant cl. 1a). Castor 2005 notes that “SFS-CFN [SuperFluidsTM phospholipid nanosomes] technique, the phospholipids and the target compound are solvated simultaneously in a SFS ‘cocktail,’ which is dispersed continuously” and this technique “is ideally suited for encapsulation of recombinant proteins for enhanced drug delivery, DNA used in gene therapy, RNAi delivery [RNAi is understood to be a canonical double stranded siRNA molecule and is a nucleic acid, relevant to instant 1a, 1e], and other hydrophilic therapeutics,” and notes the hydrophilic therapeutic compounds is encapsulated in the aqueous core (pg. 1, 2, relevant to instant cl. 1a,b). Castor 2005 demonstrated the use of the nanosomes in vitro and in vivo (pg. 8, a study demonstrated nanosomes encapsulated with betulinic acid inhibited expression of a HIV marker at lower concentrations than betulinic acid alone, pg. 11, see Fig. 13).
Castor 2005 does not disclose pegylated targeting ligand on the outer surface or co-encapsulating a guide RNA in the aqueous core.
‘363A1 discloses making immunonanosomes that comprise ligands and PEG moieties on the outer surface (see Fig. 1, which is provided below, see “PEG” on outer surface, relevant to claim 1d, 7). The bNab, broadly neutralizing antibody, is a ligand; and ‘363A1 discloses the head groups (denoted 31 in figure below) of the phospholipids attached to a ligand (denoted 23, pg. 8)). Note an inner membrane or a membrane surrounding the aqueous core carrying a HIV therapeutic HDAC (histone deacetylase) inhibitor (relevant to instant cl. 1b, 1c, 21). ‘363A1 discloses the purpose of the ligand for targeting the nanosome to a desired cell, such as immune cells, to combat target latent HIV virus (CD4+ T-cells, pg. 8, pg. 12). Further ‘363A1 discloses coating with polyethylene glycol (PEG) prevents the nanosome from being removed from the circulation and thus PEG increases residence time (pg. 12-13, relevant to claim 7).
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Neither Castor 2005 and ‘363A1 discloses guide RNA.
Mandal discloses the use of Cas9 encoding plasmid along with both single and dual CCR5 gRNA encoding plasmids to ablate CCR5 gene in primary human CD4+ T cells hematopoietic stem and progenitor cells (HSPCs) (abstract, pg. 650, in experimental procedure of transfection of cells, relevant to instant cl. 1e). Mandal discloses designing and the use of CCR5 gRNA to target CCR5 gene (pg. 644, relevant to instant cl. 1e, 22). Mandal discloses CCR5 is “the main co-receptor used by CCR5-tropic strains of HIV-1 and a validated target for gene ablation, as mutations resulting in loss of protein expression or haploinsufficiency protect against HIV infection” (pg. 644).
Castor 2005, ‘363A1 and Mandal do not disclose a nanosome encapsulated with nucleic acid-protein and genome specific RNA molecules (interpreted as gRNA) for treatment of HIV-1 (cl. 10).
Givens, a review article, discloses various types of nanoparticles used to deliver Cas9/gRNA complexes in various forms, i.e. 1) Cas9 endonuclease protein with gRNA , 2) a plasmid-encoded or other nucleic acid encoded Cas9/gRNA, 3) a Cas9/gRNA complex, called a ribonucleoprotein (RNP) (pg. 2, relevant to instant cl. 1, 22). Givens suggests considering various factors during formulation: for translational therapies, Cas9/gRNA RNP complex is ideal to avoid nucleic acid molecule “outstaying its welcome” and the RNP complex does not require additional cellular machinery to produce the protein/gRNA products (pg. 2). Givens discloses that nanoparticles are ideally suited for delivering CRISPR/Cas9 elements since they can be engineered to bind to specific cells/tissues, protect cargo from degradation until they reach the target site, can deliver variable size cargos, from plasmids to large proteins, and generally are safe eliciting minimal immune response (pg. 2) and can be purchased commercially or produce in a lab (pg. 5). The review provides numerous examples of RNP complex being successfully delivered to cells and editing the targeted genome site (see Table 1, pg. 6-7). Givens discloses a Ramakrishna study demonstrating use of Cas9 nuclease/CCR5 gRNA, pg. 11 (relevant to instant cl. 1, 1e). As noted above Mandal discloses the ablation of CCR5 gene to reduce HIV infection by use of Cas9/gRNA targeted to CCR5 (relevant to instant cl. 22).
One of the KSR rationale that may be used to support a conclusion of obviousness is that there is some teaching, suggestion, or motivation in the prior art that would have led one of ordinary skill to modify the prior art reference or to combine prior art reference teachings to arrive at the claimed invention. Therefore, it would have been prima facie obvious for one of ordinary skill in the art before the filing date of the claimed invention to have modified the process of making a nanosome of Castor 2005 in view of ‘363A1 and arrive at the claimed invention with a reasonable expectation of success. Based on Castor 2005 making and demonstrating the use of its nanosome, and ‘363A1 making and demonstrating the use of immunonanosome, which comprises a ligand on its surface for cell-targeting purpose and coating the outer surface with PEG molecules, a skilled artisan would reasonably expect success in combining the processes of Castor 2005 and ‘363A1 in modifying the nanosome of Castor 2005 with ligands and coating the outer surface with PEG molecule as taught by ‘363A1 for targeting immune cells and to increase residence time, respectively.
Although Mandal discloses the use of a plasmid to encode a gRNA, it’s the expressed gRNA that eventually targets the genome, as taught by Givens. Thus, the plasmid encoding and eventually expressing a CCR5 gRNA, whose function and structure are equivalent to a gRNA as of Givens or a gRNA generally, is not distinct from a gRNA.
Further, it would have been prima facie obvious for one of ordinary skill in the art before the filing date of the claimed invention to have modified the process of making a nanosome of Castor 2005 and ‘363A1 in view of Mandal and arrive at the claimed invention with a reasonable expectation of success. One of ordinary skill in the art would have been motivated to modify the process of making a nanosome with nucleic acid of Castor 2005 and the process of making an pegylated-immunonanosome comprising ligands to target cells to combat latent HIV virus of ‘363A1 by incorporating in the mixing process a plasmid DNA encoding Cas9 and CCR5 gRNA nucleic acid as taught by Mandal to prevent or reduce HIV infection. Or alternatively, a skilled artisan would reasonably expect success in substituting the therapeutics in SFS generated pegylated nanosome of Castor 2005/‘363A1 with the Cas9/CCR-5 gRNA RNP complex as a therapeutic as taught by Givens to modify a CCR5 gene to combat HIV infection as taught by Mandal. Thus, claims 1, 7, 21 and 22 are obvious.
Claims 3, 9 and 24 are rejected under 35 U.S.C. 103 as being unpatentable over Castor (2005, Current Drug Delivery, 2, pg. 1-12, referred as “Castor 2005”) and Castor (WO2016191363A1, pub. 12/01/2016, referred as “’363A1”) and Mandal et al. (2014, Cell Stem Cell, 15, 643-652, referred as Mandal) and Givens et al. (2018, AAPS Journal, 20, 1-22, referred as Givens) as applied to claims 1, 7, 21, and 22 above, and further in view of Ramana et al. (Journal of Controlled Release, 2014, 192, pg. 271-283, of record).
Rejection of claims 1, 7, 21 and 22 is noted above.
Castor 2005, ‘363A1, Mandal, and Givens do not disclose CCL5, a ligand for CCR5 receptor (cl. 3, 24) and a ligand coating the surface specific for targeted cells (cl. 9).
Ramana’s review article discloses suggestion of targeting strategies for delivery of anti-HIV drugs (title) and suggests mimicking the strategy used by HIV to infect cells to design nanoparticles conjugated with targeting moieties (abstract, pg. 272-273, section 4.1). One suggested strategy is “the natural ligand for CCR5 [is] chemokine C-C ligand 5 (CCL5) also referred to a RANTES . . . can also be used to deliver the therapeutics moieties to HIV infected cells” (pg. 276, relevant to instant cl. 3, 9, 24). Ramana teaches that CCL5 is a natural ligand for CCR5.
One of the KSR rationale that may be used to support a conclusion of obviousness is that there is some teaching, suggestion, or motivation in the prior art that would have led one of ordinary skill to modify the prior art reference or to combine prior art reference teachings to arrive at the claimed invention. Therefore, it would have been prima facie obvious for one of ordinary skill in the art before the filing date of the claimed invention to have modified the nanosomes comprising ligand on the surface of ‘363A1 in view of Ramana and arrive at the claimed invention with a reasonable expectation of success. Based on the use of ligand on the surface of nanosomes to target specific cells as taught by ‘363A1 and Ramana teaching that CCL5 is a natural ligand of CCR5, a skilled artisan would reasonably expect success by substituting the ligand on the surface of nanosomes of ‘363A1 with CCL5 ligand of Ramana to effectively deliver therapeutics to target HIV infected cells. Thus, cl. 3, 9, 24 are obvious.
Claim 10 is rejected under 35 U.S.C. 103 as being unpatentable over Castor (2005, Current Drug Delivery, 2, pg. 1-12, referred as “Castor 2005”) and Castor (WO2016191363A1, pub. 12/01/2016, referred as “’363A1”) and Mandal et al. (2014, Cell Stem Cell, 15, 643-652, referred as Mandal) and Givens et al. (2018, AAPS Journal, 20, 1-22, referred as Givens) as applied to claims 1, 7, 21, and 22 above, and further in view of Zhen et al. (2016, Oncotarget, 8, 9375-9387, referred as Zhen).
Rejection of claim 1, 7, 21 and 22 is noted above. Again, ‘363A1 discloses coating with polyethylene glycol (PEG) prevents the nanosome from being removed from the circulation and thus PEG increases residence time (pg. 12-13, relevant to claim 7).
Castor 2005, ‘363A1, Mandal and Givens do not disclose PEGylated RNA-protein hybrid therapeutic.
Similar to teaching of ‘363A1, Zhen discloses that “terminal modification of RNAs with PEG increases the half-life of many oligonucleotide-based therapies” (pg. 9382). Although Zhen targets a different type of RNA, i.e. an aptamer, for PEG modification, the teaching that PEGylation extends the half-lives of bio-molecules, including RNA and lipids, is well known in the art.
One of the KSR rationale that may be used to support a conclusion of obviousness is that there is some teaching, suggestion, or motivation in the prior art that would have led one of ordinary skill to modify the prior art reference or to combine prior art reference teachings to arrive at the claimed invention. Therefore, it would have been prima facie obvious for one of ordinary skill in the art before the filing date of the claimed invention to have modified the gRNA of a gRNA-Cas9 complex in view of Zhen and arrive at the claimed invention with a reasonable expectation of success. Based on Zhen’s teaching that PEG-modified RNA have a longer half-lifer, a skilled artisan would reasonably expect success of modifying the gRNA with PEG to improve its half-life thus increase the therapeutic potential of gRNA/Cas9 complex. Thus, cl. 10 is obvious.
Response to Arguments
Applicant's arguments filed 08/04/2025 (“the Remarks”) have been fully considered but they are not persuasive.
The Remarks argue the following:
To combine references, there “must be a basis in the references” when there are many alternatives and suggest that there is lack of motivation to combine or modify the references (pg. 6). The Remarks insist that “Mandal article does not teach or contemplate a mechanism for delivering any therapeutics to diseased target cells. There is no mention of nanoparticles or nanosomes or any other method of delivery of any type” and suggest that Mandal’s use is “classic hindsight reconstruction” and that the somehow conclusion for obviousness cannot derive from applicant’s specification (pg. 6-7).
Regarding rejection of cl. 3, 9, and 24, the Remarks quote Ramana that conjugation of large antibodies to the surface of the nanoparticles is problematic and thus would be considered “teaching away” since it is disadvantageous to associate antibodies on the surface of nanoparticles(pg. 8). Again due to the many alternatives suggested by Ramana, the rejection is based on improper hindsight reconstruction based on instant claims/specification (pg. 8).
Regarding rejection of cl. 10, the Remarks insist that Examiner fails to show a reasonable motivation to combine or modify Givens, Givens does not include limitations of instant cl. 10, specifically “delivering complex drug formulations” (pg. 9).
Then notes that “this approach to applying these references to the present invention improperly disregards the “as a whole” statutory mandate of MPEP 2141.02: to pick and choose from any one reference only so much of it as will support a given position, to the exclusion of other parts . . .” (pg. 9-10).
The argument is not persuasive.
First, dealing with improper use of hindsight reasoning. In response to applicant's argument that the examiner's conclusion of obviousness is based upon improper hindsight reasoning, it must be recognized that any judgment on obviousness is in a sense necessarily a reconstruction based upon hindsight reasoning. But so long as it takes into account only knowledge which was within the level of ordinary skill at the time the claimed invention was made, and does not include knowledge gleaned only from the applicant's disclosure, such a reconstruction is proper. See In re McLaughlin, 443 F.2d 1392, 170 USPQ 209 (CCPA 1971). Here, all the references combined teach the claimed invention and are disclosed before the filing before instant application.
The concept of claimed invention is not novel since HIV is a very serious and infectious disease, and latent infected cells remain a permanent source of viral reactivation (‘363A1, pg. 5). Based on this motivation to treat HIV, the references combined make the claimed invention obvious. Castor 2005 teaches the nanosome delivery vehicle that can deliver various types of cargo, including protein and RNA; 363A1 titled “Combination HIV Therapeutic” teaches PEG and ligand on the outer surface of the nanosomes and also teaches other HIV therapeutic inhibitor within its core to combat latent HIV virus, and other cited references teach elements of claimed invention, and thus the combination of the teachings of the cited references make the claimed invention obvious.
Addressing argument 1, Mandal reference provides an excellent basis and demonstrates the purpose of targeting CCR5, CCR is the main co-receptor used by CCR5-tropic strains of HIV-1 and its ablation protects against HIV infection (see prior action, pg. 8). Further, others have also demonstrated a similar approach of targeting CCR5 with use of gRNA targeting CCR5 with Cas9 endonuclease (see Hillman above). Thus a skilled artisan would reasonably expect success in use of gRNA to target CCR5 and Cas9 to cleave the target genome to protect against HIV infection. Further, since the Remarks fail to specifically note the “many alternatives,” those are not addressed here; regardless, regarding nucleases, Mandal provides motivation for why Cas9 nuclease should be used instead of the alternatives. Further, Mandal is used along with other references for an obviousness rejection, thus its silence on nanoparticles/nanosomes is not a setback.
Addressing argument 2, in response to applicant's arguments against the references individually, one cannot show nonobviousness by attacking references individually where the rejections are based on combinations of references. See In re Keller, 642 F.2d 413, 208 USPQ 871 (CCPA 1981); In re Merck & Co., 800 F.2d 1091, 231 USPQ 375 (Fed. Cir. 1986). First, the argument that Ramana teaches away does not apply here, since here the claims are not toward antibodies on nanoparticles but rather ligand, i.e. the CCL5 ligand, which a skilled artisan understands are smaller than large antibodies. Second, ‘363A1, Applicant’s own prior work, specifically teaches the use of ligands, which include antibodies (see bNAb in Fig. on pg. 10 above), for targeting purposes. Thus, the teachings of the combination of the references make the invention obvious.
Addressing argument 3 that Givens does not teach limitation of instant cl. 10, specifically delivering “complex drug formulations” (pg. 9). The title of Givens is “Nanoparticles-based delivery of CRISPR/Cas9 genome editing therapeutics” and discusses the use of nanoparticle to deliver drugs. Since Givens discusses the use of nanoparticles to deliver the same drug formulation (Cas9/gRNA or NA) as instant claimed invention, it teaches the concept of delivering the recited “drug formulation”. However, Givens is not the sole reference for the purpose of delivery of Cas9 and guide RNA, both Castor 2005 and ‘363A1 are used to show nanosomes are used to deliver “complex” drug formulation. Thus, again, nanoparticles/nanosomes as delivery vehicles are noted in prior art references cited.
Addressing argument 4, the Remarks argue that the action “picks and chooses” from any one of references. The references are considered as a whole. E.g., Castor 2005 specifically notes that, as noted in the action, “SFS-CFN injection technique is ideally suited for the nanosomal encapsulation of recombinant proteins for enhanced drug delivery, DNA used in gene therapy, RNAi delivery, and other hydrophilic therapeutics” (pg. 2). Thus, the broad reading of the Castor 2005 allows a skilled artisan to incorporate Cas9 enzyme or NA encoding Cas9 and gRNA of their choosing in the Castor 2005’s nanosomes due to the advantages noted in the action, including uniformity of the nanosomes. And a skilled artisan reasonably expects success in delivering various types of therapeutic drug formulation to targeted cells using Castor 2005 and ‘363A1 nanosomes. The Remarks fail to provide evidence why the combination would not work.
Thus, the rejection of examined claims is maintained.
Relevant Art, but not relied upon
Hillman (Jul., 2019, Europe PMC, v1, pg. 1-8).
Allowable Subject Matter
No claim allowed.
Conclusion
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/KEYUR A VYAS/Examiner, Art Unit 1637
/Soren Harward/Primary Examiner, TC 1600