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 .
1. Claims 1-22, 24-35, 37-43, and 45 have been cancelled. Claims 23, 36, 44, 46, 49, and 50-52 have been amended.
Claims 23, 36, 44, and 46-52 are pending and under examination.
2. All rejections pertaining to claims 24 and 37 are moot because the claims were cancelled with the reply filed on 11/07/2025.
The objections to claims 51 and 52 are withdrawn in response to the amendments filed on 11/07/2025.
Specification
3. The claim listing is objected to because the text of the cancelled claims 24 and 37 should not appear in the claim listing. Appropriate correction is required.
The following is a citation from MPEP:
714[Symbol font/0x5B]R-6[Symbol font/0x5D] - Amendments, Applicant’s Action
37 CFR 1.121. Manner of making amendments in application.
(c) (4) (i) No claim text shall be presented for any claim in the claim listing with the status of “cancelled” or “not entered”.
Claim Rejections - 35 USC § 103
4. 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.
5. Claims 23, 36, 44, 48, 49, and 51 are rejected under 35 U.S.C. 103 as being unpatentable over Fraga et al. (J. Control. Rel., 2015, 209: 37-46), in view of all Lee et al. (Biomaterials, 2005, 26: 2147-2156), Wolf et al. (Molecular Genetics and Metabolism, 2012, 106: 131-134), DeKelver et al. (PGPUB 2017/0202931),
and Sood et al. (Colloids and Surfaces B: Biointerfaces, 2014, 113: 330-337).
Fraga et al. teach a cationic nanoemulsion useful for the treatment of MPS I (i.e., a disease with central nervous system symptoms) comprising (1) a lipid phase of DOTAP/DOPE/DSPE-PEG/medium chain triglycerides and (2) an aqueous phase comprising glycerol and an IDUA-encoding plasmid; the cationic nanoemulsion has droplet diameter of about 200 nm and a DOTAP/plasmid ratio of 4/1; the IDUA-encoding plasmid is either adsorbed to or encapsulated by the nanoemulsion (claims 23, 48, and 49) (see Abstract; p. 37, paragraph bridging columns 1 and 2; p. 40, column 1, Table 1; p. 44, column 1, first paragraph). The cationic nanoemulsion comprises the adsorbed plasmid is prepared as recited in claim 44, except that Fraga et al. do not specifically teach hydrating the lipid film at 4º C and except that the aqueous phase comprising the plasmid does not comprise chitosan as recited claims 23 and 44 (see p. 38-39). While Fraga et al. do not teach chitosan, Lee et al. teach that using chitosan as a condensing agent enhances gene transfer mediated by cationic emulsions (see Abstract; p. 2148, column 2, last paragraph; p. 2149, column 1, second paragraph; paragraph bridging p. 2154 and 2155). Modifying Fraga et al. by further adding chitosan would have been obvious to one of skill in the art to achieve the predictable result of obtaining a composition mediating enhanced IDUA gene transfer. By doing so, one of skill in the art would have obtained the composition of claim 23 and would have practiced the method recited in claim 44. While Fraga et al. do not specifically teach hydrating the lipid film at 4º C, as per MPEP § 716.02, [a]ny differences between the claimed invention and the prior art may be expected to result in some differences in properties. The issue is whether the properties differ to such an extent that the difference is really unexpected. In re Merck & Co., 800 F.2d 1091, 231 USPQ 375 (Fed. Cir. 1986). In this case, there is no evidence that hydrating the lipid film at 4º C results in unexpected properties over the method taught by the prior art.
Fraga et al. teach that the intravenous administration of the cationic nanoemulsion to an IDUA-/- MPS I mouse model leads to significantly increased IDUA expression in diverse organs such as lungs, kidney, spleen, and liver; Fraga et al. teach the need for brain delivery to address the neurological complications of the disease and achieve efficient therapy (claims 36 and 51) (see Abstract; p. 37, paragraph bridging columns 1 and 2; p. 44, column 2). Wolf et al. teach that intranasal administration of IDUA to IDUA-/- MPS I mice results in IDUA delivery to the brain, suggesting delivery via the intranasal route as an effective treatment for lysosomal storage diseases (see Abstract; p. 131; paragraph bridging p. 131 and 132; p. 132, column 2, last paragraph). Based on these teachings, one of skill in the art would have found obvious to modify the method of Fraga et al. by using intranasal administration to achieve the predictable result of delivering IDUA to the brain of the IDUA-/- mouse.
Fraga et al., Lee et al., and Wolf et al. teach an IDUA-encoding plasmid. However, Fraga et al., Lee et al., and Wolf et al. do not teach a second plasmid encoding CRISPR/Cas9 (claim 23). DeKelver et al. using genome editing to introduce IDUA into the genome of the IDUA-/- mice to treat the diseases in these mice (see [0190]-[0193]; [0196]; [0232]; [0241]-[0245]). Although DeKelver et al. exemplify ZNF, they do teach that a vector-encoding CRISPR/Cas9 (such as a plasmid) could be used instead of ZNF; they also teach that the target tissue for IDUA expression could be the brain (see [0009]; [0016]-[0017]; [0019]; [0021]; [0023]; [0101]; [0113]; [0115]; [0136]; [0162]). Modifying Fraga et al., Lee et al., and Wolf et al. by further using a plasmid encoding CRISPR/Cas9 would have been obvious to one of skill in the art to achieve the predictable result of correcting for the defective IDUA gene in the IDUA-/- mice by integrating the functional IDUA into the genome of brain cells.
Fraga et al., Lee et al., Wolf et al., and DeKelver et al. do not teach a droplet diameter of 100-163 nm or the component concentrations recited in claims 23 and 48. Sood et al. teach optimizing the size of the nanoemulsions for intranasal delivery, with sizes of less than 200 nm being suitable for intranasal delivery; optimization entails varying the concentrations of the components to obtain droplets having diameters with desired sizes (see Abstract; paragraph bridging p. 220 and 331; p. 331, column 2, fourth full paragraph; p. 337, column 1, last paragraph). One of skill in the art would have found obvious to use routine experimentation and vary the concentrations of MCT, DOPE, DOTAP, DSPE-PEG, glycerol, chitosan, triglycerides, and nucleic acids with the reasonable expectation that doing so would identify the optimal formulations for intranasal delivery. Routine optimization is not considered inventive and no evidence has been presented that the selection the claimed sizes and concentrations was other than routine or that the results should be considered unexpected in any way over the teachings in the prior art (see MPEP 2144.05 II).
Thus, the claimed invention was prima facie obvious at the time of its effective filing date.
6. Claims 23, 36, 44, 47-49, and 51 are rejected under 35 U.S.C. 103 as being unpatentable over Fraga et al. taken with all Lee et al., Wolf et al., DeKelver et al., and Sood et al., in further view of Bruxel et al. (Int. J. Pharmaceutics, 2011, 416: 402-409).
The teachings of Fraga et al., Lee et al., Wolf et al., DeKelver et al., and Sood et al. are applied as above for claims 23, 36, 44, 48, 49, and 51. Fraga et al., Lee et al., Wolf et al., DeKelver et al., and Sood et al. do not teach water evaporation (claim 47). Bruxel et al. teach using evaporation under reduced pressure (i.e., between 0 and 1000 mbar) at 50º C to remove excess water from nanoemulsions to obtain the desired volume (see p. 403, column 1, last paragraph). Further using an evaporation step as taught by Bruxel et al. would have been obvious to one of skill in the art to achieve the predictable result of obtaining the desired nanoemulsion volume.
Thus, the claimed invention was prima facie obvious at the time of its effective filing date.
7. Claims 23, 36, 46, 48-50, and 52 are rejected under 35 U.S.C. 103 as being unpatentable over Fraga et al., in view of all Cramer et al. (Current Medicinal Chemistry, 2012, 19: 3163-3187), Woolf et al., DeKelver et al., and Sood et al.
Fraga et al. teach a cationic nanoemulsion useful for the treatment of MPS I (i.e., a disease with central nervous system symptoms) comprising (1) a lipid phase of DOTAP/DOPE/DSPE-PEG/medium chain triglycerides and (2) an aqueous phase comprising glycerol and an IDUA-encoding plasmid; the cationic nanoemulsion has droplet diameter of about 200 nm and a DOTAP/plasmid ratio of 4/1; the IDUA-encoding plasmid is either adsorbed to or encapsulated by the nanoemulsion (claims 23, 48, and 49) (see Abstract; p. 37, paragraph bridging columns 1 and 2; p. 40, column 1, Table 1; p. 44, column 1, first paragraph). The cationic nanoemulsion comprising the adsorbed plasmid is prepared by: (i) solubilizing DOTAP and the nucleic acids in a monophasic mixture of chloroform:methanol:water (1:2.1:1) at room temperature for 30 min; (ii) partitioning the monophasic mixture into a two-phase system by the addition of 1 ml of each chloroform and water, followed by vortexing and separation of the phases by centrifugation at 2000xg for 10 min; (iii) collecting the organic phase and adding TCM, DOPE, and DSPE-PEG; (iv) evaporating the organic solvent to form a lipid phase film; (v) adding glycerol dissolved in water to the lipid phase film; (vi) incubating overnight; (vii) sonicating the formulation for 15 min at 37 ºC; and (viii) homogenizing the formulation at 10 psi for 10 cycles (claims 46 and 50) (see p. 38-39).
Fraga et al. do not teach coating the nanoemulsion with chitosan (claim 46). However, coating the nanoemulsion with chitosan is suggested by the prior art. For example, Fraga et al. teach intravenously administering the cationic nanoemulsion to an IDUA-/- MPS I mouse model (claim 36). Fraga et al. teach that, since intravenous administration leads to significantly increased IDUA expression in diverse organs such as lungs, kidney, spleen, and liver, there is a need for brain delivery to address the neurological complications of the disease and achieve efficient therapy (see Abstract; p. 37, paragraph bridging columns 1 and 2; p. 44, column 2). Wolf et al. teach that intranasal administration of IDUA to IDUA-/- MPS I mice results in IDUA delivery to the brain, suggesting delivery via the intranasal route as an effective treatment for lysosomal storage diseases (see Abstract; p. 131; paragraph bridging p. 131 and 132; p. 132, column 2, last paragraph). Cramer et al. teach that coating nanoparticles with chitosan enhances delivery to the brain (see 3176; p. 3178, column 1). Based on these teachings, one of skill in the art would have found obvious to modify the method of Fraga et al. by coating the nanoemulsion with chitosan and further intranasally administer the resultant nanoemulsion to achieve the predictable result of delivering IDUA to the brain of the IDUA-/- mouse. By doing so, one of skill in the art would have practiced the method recited in claims 36, 46, and 52. While Fraga et al. do not specifically teach hydrating the lipid film at 4º C, as per MPEP § 716.02, [a]ny differences between the claimed invention and the prior art may be expected to result in some differences in properties. The issue is whether the properties differ to such an extent that the difference is really unexpected. In re Merck & Co., 800 F.2d 1091, 231 USPQ 375 (Fed. Cir. 1986). In this case, there is no evidence that hydrating the lipid film at 4º C results in unexpected properties over the method taught by the prior art. While Fraga et al. teach adding 1 and not 2 ml of chloroform and water, MPEP 2144.05 III A states that "[a] modification of a process parameter may be patentable if it ‘produce[s] a new and unexpected result which is different in kind and not merely in degree from the results of the prior art." (citing Aller, 220 F.2d 454, 456, 105 USPQ 233, 235 (CCPA 1955).” In this case, there is no evidence of a difference in kind or even degree when using 2 ml instead 1 ml chloroform/water.
Fraga et al., Wolf et al., and Cramer et al. teach an IDUA-encoding plasmid. However, Fraga et al., Wolf et al., and Cramer et al. do not teach a second plasmid encoding CRISPR/Cas9 (claim 23). DeKelver et al. using genome editing to introduce IDUA into the genome of the IDUA-/- mice to treat the diseases in these mice (see [0190]-[0193]; [0196]; [0232]; [0241]-[0245]). Although DeKelver et al. exemplify ZNF, they do teach that a vector-encoding CRISPR/Cas9 (such as a plasmid) could be used instead of ZNF; they also teach that the target tissue for IDUA expression could be the brain (see [0009]; [0016]-[0017]; [0019]; [0021]; [0023]; [0101]; [0113]; [0115]; [0136]; [0162]). Further using a plasmid encoding CRISPR/Cas9 would have been obvious to one of skill in the art to achieve the predictable result of correcting for the defective IDUA gene in the IDUA-/- mice by integrating the functional IDUA into the genome of brain cells.
Fraga et al., Lee et al., Wolf et al., and DeKelver et al. do not teach a droplet diameter of 100-163 nm or the component concentrations recited in claims 23, 46, and 50. Sood et al. teach optimizing the size of the nanoemulsions for intranasal delivery, with sizes of less than 200 nm being suitable for intranasal delivery; optimization entails varying the concentrations of the components to obtain droplets having diameters with desired sizes (see Abstract; paragraph bridging p. 330 and 331; p. 331, column 2, fourth full paragraph; p. 337, column 1, last paragraph). One of skill in the art would have found obvious to use routine experimentation and vary the concentrations of MCT, DOPE, DOTAP, DSPE-PEG, glycerol, chitosan, triglycerides, and nucleic acids with the reasonable expectation that doing so would identify the optimal formulations for intranasal delivery. Routine optimization is not considered inventive and no evidence has been presented that the selection the claimed sizes and concentrations was other than routine or that the results should be considered unexpected in any way over the teachings in the prior art (see MPEP 2144.05 II).
Thus, the claimed invention was prima facie obvious at the time of its effective filing date.
Response to Arguments
8. The applicant argues that it is unlikely that one of skill in the art would have even started with Fraga as a base reference.
This is not found persuasive because it is just an argument not supported by any evidence.
The applicant argues that the claimed composition is not the outcome at which one of skill in the art would arrive by looking at the cited references. This is because further experimentation, analysis, and conception to achieve the unexpected claimed solution.
This argument is not found persuasive. Unless it is undue, further experimentation is not evidence of non-obviousness. Fraga teaches a composition comprising a lipid phase as claimed (DOTAP/DOPE/DSPE-PEG/medium chain triglycerides) and an aqueous phase as claimed (glycerol/IDUA-encoding plasmid) and methods to make the composition, which are the same as the claimed methods.
The difference is that Fraga does not teach adding chitosan for intranasal delivery, a second plasmid encoding CRSPR/Cas9, and the recited size/component concentrations. However, the cited prior art provides the motivation to add chitosan for intranasal delivery and a plasmid encoding CRSPR/Cas9. Doing so would have only entailed routine experimentation. With respect to the size and component concentrations, the cited prior art teaches sizes of less than 200 nm are suitable for intranasal delivery; the prior art also teaches achieving the desired sizes by just using routine experimentation, which entails varying the concentrations of the components. Thus, the prior art evidences that arriving at the claimed invention would have only required routine experimentation. There is no evidence to the contrary of record.
Furthermore, analyzing the prior art is not evidence of non-obviousness either; this is what persons of skill in the art routinely do. With respect to the concept, the prior art provides all the elements, the motivation, and the reasonable expectation of success in arriving at the claimed invention. MPEP 2141.03 states:
"A person of ordinary skill in the art is also a person of ordinary creativity, not an automaton." KSR Int'l Co. v. Teleflex Inc., 550 U.S. 398, 421, 82 USPQ2d 1385, 1397 (2007). "[I]n many cases a person of ordinary skill will be able to fit the teachings of multiple patents together like pieces of a puzzle." Id. at 420, 82 USPQ2d 1397. Office personnel may also take into account "the inferences and creative steps that a person of ordinary skill in the art would employ." Id. at 418, 82 USPQ2d at 1396.
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The "hypothetical ‘person having ordinary skill in the art’ to which the claimed subject matter pertains would, of necessity have the capability of understanding the scientific and engineering principles applicable to the pertinent art." Ex parte Hiyamizu, 10 USPQ2d 1393, 1394 (Bd. Pat. App. & Inter. 1988).
The argument of lack of expectation for improvement when combining the cited references is not found persuasive. Fraga teaches that distributing the cationic nanoemulsion in blood via intravenous injection leads to increased IDUA expression in lung, kidney, spleen, and liver. While Fraga does not exemplify intranasal administration, the prior art teaches that intranasally administering nanoemulsions leads to distribution in both brain and blood; the addition of chitosan leads to higher concentrations in blood compared to the nanoemulsions without chitosan (Kumar, J. Drug Targeting, 2008, 16: 806-814; see p. 807, column 2, first full paragraph; p. 809, Fig. 1; p. 812, Table III). Furthermore, Comfort (Curr. Top. Med. Chem., 2015, 15: 256-368) teaches that blood distribution after intranasal administration leads to expression in organs such as lungs (see p. 13, last paragraph).
Thus, that intranasally administering Fraga’s nanoemulsions would result in IDUA brain expression as well as expression in lungs, kidney, spleen, and liver was reasonably expected from the teachings in the prior art. That adding chitosan would further increase IDUA expression in lungs, kidney, spleen, and liver was also reasonably expected from the teachings in the prior art.
For the reasons above, the following arguments are not found persuasive: (1) the cited references do not solve the problem solved by the invention; (2) the cited references do not teach the same composition, process of obtaining and using the composition, administration route, and biological effectiveness; and (3) unexpected results.
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).
Conclusion
9. The prior art made of record and not relied upon is considered pertinent to applicant's disclosure. Kumar (J. Drug Targeting, 2008, 16: 806-814) and Comfort (Curr. Top. Med. Chem., 2015, 15: 256-368) were cited in response to the argument of lack of expectation of success and unexpected results. The references provide evidence for reasonable expectation of success and also provide evidence that the results in the specification were reasonable expected from the teachings in the prior art.
10. THIS ACTION IS MADE FINAL. 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.
Any inquiry concerning this communication or earlier communications from the examiner should be directed to ILEANA POPA whose telephone number is (571)272-5546. The examiner can normally be reached 8:00 am to 4:30 pm.
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/ILEANA POPA/Primary Examiner, Art Unit 1633