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 .
Claims 1-33 are pending.
Claims 4, 6, 11, and 20-33 are withdrawn.
Claims 15-16 and 18-19 have been amended.
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 1-3, 5, 7-9, and 14-18 are rejected under 35 U.S.C. 102(a)(1) as being anticipated by MOKHTARIEH (Asymmetric liposome particles with highly efficient encapsulation of siRNA and without nonspecific cell penetration suitable for target-specific delivery. Biochimica et Biophysica Acta. 2012.).
Regarding claim 1, MOKHTARIEH teaches an asymmetric liposome (abstract), which is a vesicle, comprising a bilayer of lipids. The inner layer of the lipids is cationic/positive and the surface/outer layer is negatively charged (abstract), which reads on wherein the inner layer of lipids and the outer layer of lipids are different, such as having an asymmetric charge distribution. The interior potion of the liposome is designed to encapsulate siRNA, which is a biomolecule (abstract).
Regarding claim 2 and 3, MOKHTARIEH teaches the inner layer of lipids, first net charge, has a positive net charge and the other layer of lipids, second net charge, has a negative charge (abstract).
Regarding claim 5 and 9, MOKHTARIEH teaches the biomolecule encapsulated is siRNA (abstract), which is negatively charged.
Regarding claim 7, MOKHTARIEH teaches the inner layer is positive and the siRNA, which is used as a therapeutic drug, is negative (abstract). Note, since the prior art teaches the same charges of the inner layer and drug, it would inherently reduce the leakage of the drug compared to a non-charged vesicle comprising the same drug.
Regarding claim 8, the liposomes are made using an aqueous medium, which will remain on the interior portion of the liposome (fig 1).
Regarding claim 14 and 15, both the inner and outer layer of lipids comprise a plurality of lipids (abstract). The inner comprises 1,2-dioleoyl-3-dimethylammonium-propane (DODAP), which is cationic and 1,2-dioleoyl-sn-glycero-3-phosphoethanolamine (DOPE), which is zwitterionic. The outer layer comprises 1,2-distearoyl-sn-glycero-3-phosphocholine (DSPC), which is zwitterionic, DOPE, which is uncharged, polyethylene glycol- 1,2-distearoyl-sn-glycero-3-phosphatidylethanolamine (PEG-PE), which is anionic, and cholesterol (abstract).
Regarding claim 16, MOKHTARIEH teaches that the outer layer comprises cholesterol (abstract) and the inner layer comprises DODAP, which is a zwitterionic lipid.
Regarding claim 17, MOKHTARIEH teaches that phosphatidylcholine can be used in the liposome (page 1636, paragraph 5).
Regarding claim 18, MOKHTARIEH teaches the cationic lipid used for the inner layer is dioleoyl-3-dimethylammonium-propane (page 1634, Figure 1).
Additional disclosures: MOKHTARIEH teaches that the positive charge on the inner layer increased the encapsulation of the siRNA (page 1636, paragraph 4) and the negative charge on the outer layer prevented aggregation and increased circulation in the blood (page 1637, paragraph 3).
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 1-3, 5, 7-10, and 12-19 are rejected under 35 U.S.C. 103 as being unpatentable over MOKHTARIEH (Asymmetric liposome particles with highly efficient encapsulation of siRNA and without nonspecific cell penetration suitable for target-specific delivery. Biochimica et Biophysica Acta. 2012.) in view of ZHIGALTSEV (US 7,273,620).
MOKHTARIEH teaches Applicant’s invention as discussed above.
MOKHTARIEH does not teach encapsulating doxorubicin, having cholesterol in the inner layer or incorporating phosphatidylglycerol.
Regarding claim 10, ZHIGALTSEV teaches charged liposomes (abstract) can be used to deliver RNA or drugs (column 4, paragraph 3), such as doxorubicin (column 14, paragraph 3).
Regarding claim 13, ZHIGALTSEV teaches that having cholesterol within the bilayer allows for rapid release of the active agent (column 14, paragraph 3).
Regarding claim 19, ZHIGALTSEV teaches a charged liposome created with a layer of DSPC, DOPE, a charged lipid, and cholesterol (figure 3). The charged lipid can be the anionic phospholipid phosphatidylglycerol (column 6, paragraph 4).
It would have been obvious to the person of ordinary skill in the art at the time the invention was made to incorporate doxorubicin. The person of ordinary skill in the art would have been motivated to make those modifications and reasonably would have expected success because doxorubicin and RNA are functional equivalents of active agents that can be encapsulated by a liposome.
It would have been obvious to the person of ordinary skill in the art at the time the invention was made to incorporate phosphatidylglycerol. The person of ordinary skill in the art would have been motivated to make those modifications, because it is an alternate way to achieve a negatively charged outer surface, and reasonably would have expected success because it utilizes the same components as the outer layer of the liposome in MOKHTARIEH; DSPC, DOPE and cholesterol.
It would have been obvious to the person of ordinary skill in the art at the time the invention was made to incorporate adding cholesterol to the inner layer of the liposome. The person of ordinary skill in the art would have been motivated to make those modifications, because it allows for rapid release of the active agent, and reasonably would have expected success because the references are in the same field of endeavor such as liposomes involving DSPC, DOPE and cholesterol.
Regarding claim 12, the reference does not specifically teach the percentage of charged phospholipids used in each layer of lipids as claimed by the Applicant. The percentage of charged phospholipids used in each layer of lipids is clearly a result effective parameter that a person of ordinary skill in the art would routinely optimize. Optimization of parameters is a routine practice that would be obvious for a person of ordinary skill in the art to employ and reasonably would expect success. It would have been customary for an artisan of the ordinary skill to determine the optimal percentage of charged phospholipids used in each layer of lipids in order to best achieve desired results, such as having the desired charge for each layer to achieve the asymmetric charge distribution and the benefits that come with it, such as increased siRNA encapsulation and improved circulation within the blood. Thus, absent of some demonstration of unexpected results from the claimed parameters, this optimization of the percentage of charged phospholipids used each layer of lipids would have been obvious at the time of Applicant’s invention.
Response to Arguments
Applicant argues, Mokhtarieh does not expressly disclose that the vesicles prepared therein possess confirmed leaflet-specific compositional asymmetry. Nowhere does Mokhtarieh provide analytical evidence demonstrating that the designated "inner'' lipids formed exclusively or preferentially the inner leaflet, or that the designated "outer" lipids formed the outer leaflet. No leaflet specific
compositional analysis (e.g., enzymatic probing, fluorescence quenching, NMR, or other established asymmetry-confirmation techniques) was reported. At most, Mokhtarieh suggests that the resulting particles "may have asymmetric inside and outside distributions of lipids."
Examiner does not find the argument persuasive because in response to applicant's argument that the references fail to show certain features of the invention, it is noted that the features upon which applicant relies (i.e., leaflet, specifically leaflet specific compositional analysis leaflet specific compositional analysis (e.g., enzymatic probing, fluorescence quenching, NMR, or other established asymmetry-confirmation techniques)) are not recited in the rejected claim(s). Although the claims are interpreted in light of the specification, limitations from the specification are not read into the claims. See In re Van Geuns, 988 F.2d 1181, 26 USPQ2d 1057 (Fed. Cir. 1993).
Furthermore, MOKHHTARIEH teaches asymmetric liposome particles where the inner and outer layers are different (abstract). The inner layer comprises 1,2-dioleoyl-3-dimethylammonium-propane (DODAP), which is cationic/positive and 1,2-dioleoyl-sn-glycero-3-phosphoethanolamine (DOPE), which is zwitterionic, which gives a positive charge. The outer layer comprises 1,2-distearoyl-sn-glycero-3-phosphocholine (DSPC), which is zwitterionic, DOPE, which is uncharged, polyethylene glycol- 1,2-distearoyl-sn-glycero-3-phosphatidylethanolamine (PEG-PE), which is anionic, and cholesterol (abstract), which gives a negative charge. This reads on applicant claim of the outer layer of lipids is different and there is an asymmetric charge distribution.
Applicant argues, The cited art is silent regarding any comparative leakage reduction attributable to leaflet-specific electrostatic interaction. The claimed functional limitation is not an inherent result of merely using charged lipids, rather, it arises from the specific asymmetric charge architecture recited in the claims.
The Examiner does not find the argument persuasive because as discussed above, MOKHTARIEH teaches the inner layer is positive and the siRNA, which is used as a therapeutic drug, is negative (abstract). Note, since the prior art teaches the same charges of the inner layer and drug, it would inherently reduce the leakage of the drug compared to a non-charged vesicle comprising the same drug. Furthermore, the composition recited in claim 1 is also taught by the reference as discussed above and would have the same inherent chemical/physical properties.
Conclusion
No claims are allowable.
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.
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/S.L.M./Examiner, Art Unit 1618 /JAKE M VU/Primary Examiner, Art Unit 1618
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