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 .
Status of Application
Applicants' arguments/remarks filed 09/30/2025 are acknowledged. Claim 51 is currently amended. Claims 52-58 are newly added. Claims 1-2, 4, 7-9, 13, 16-18, 21, 24, 26-33, 35, 39, 43, 45-46, 48 and 51-58 are examined on the merits within and are currently pending.
Claim Rejections - 35 USC § 102
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.
(a)(2) the claimed invention was described in a patent issued under section 151, or in an application for patent published or deemed published under section 122(b), in which the patent or application, as the case may be, names another inventor and was effectively filed before the effective filing date of the claimed invention.
Claim(s) 1-2, 4, 7-9, 13, 16-18, 21, 24, 26-33, 35, 39, 43, 45-46, 48 and 51-58 is/are rejected under 35 U.S.C. 102(a)(1) as being anticipated by Haas et al. (CA 3078292 A1).
Claims 1, 2, 4,
Haas et al. teach a composition comprising RNA lipoplex particles. The RNA lipoplex particles comprise at least one cationic lipid and at least one additional lipid, sodium chloride at a concentration from 0 mM to about 40 mM, and a stabilizer. (pg. 102, Claim 68). The composition of any one of claims 64 to 68, wherein the composition further comprises a buffer. (pg. 103, Claim 69). The composition of any one of claims 64 to 74, wherein the concentration of stabilizer in the composition is from about 5 to about 35% w/v, or from about 12.5 to about 25 % w/v. (pg. 103, Claim 75). The composition of any one of claims 64 to 87, wherein the composition is in a liquid or frozen state. (pg. 105, Claim 88). The composition of any one of claims 57 to 109, which is formulated for systemic administration. (pg. 107, Claim 110). The composition of claim 110, wherein the systemic administration is by intravenous administration. (pg. 108, Claim 111).
With regard to claim 7,
In one embodiment, the stabilizer is a carbohydrate selected from a monosaccharide, a
disaccharide, a trisaccharide, a sugar alcohol, an oligosaccharide or its corresponding sugar
alcohol, and a straight chain polyalcohol. (pg. 14, lines 1-4).
With regard to claims 8-9,
In one embodiment, the stabilizer is sucrose at a concentration from about 5 to about 25 weight
by volume percent(% w/v). (pg. 16, lines 15-16).
With regard to claims 13 and 16,
In one embodiment, the buffer is 2-[4-(2-hydroxyethyl)piperazin-1-yl]ethanesulfonic acid
(HEPES), (pg. 16, lines 24-25) and dimethylarsinic acid, 2-morpholin-4-ylethanesulfonic acid (MES). (pg. 50, lines 9-10, 12).
With regard to claims 17-18 and 21,
In one embodiment, the composition has a pH from about 5.7 to about 6.7. (pg. 16, line 23).
In one embodiment, the HEPES is at a concentration from about 2.5 mM to about 10 mM. (pg. 16, line 26).
With regard to claims 24 and 26,
In one embodiment, the at least one cationic lipid comprises I ,2-di-O-octadecenyl-3-
trimethylammonium propane (DOTMA) and the at least one additional lipid comprises 1,2-di(
9Z-octadecenoy1)-sn-glycero-3-phosphoethanolamine (DOPE).
In one embodiment, the molar ratio of the at least one cationic lipid to the at least one additional
lipid is from about 10:0 to about 1 :9, from about 4: 1 to about 1 :2, from about 3: 1 to about 1:1, or about 2:1. (pg. 4, lines 11-16).
With regard to claims 27-29,
In one embodiment, the composition further comprises a chelating agent. (pg. 6, line 28).
In one embodiment, the chelating agent is ethylenediaminetetraacetic acid (EDTA).
In one embodiment, the EDTA is at a concentration from about 0.25 mM to about 5 mM, or to about 2.5 mM. (pg. 7, lines 23-25).
With regard to claim 30,
In one embodiment, the RNA encodes a peptide or protein comprising at least one epitope,
wherein the ratio of positive charges to negative charges in the RNA lipoplex particles is from
15 about 1:2 to about 1.9:2, or about 1.3:2.0. (pg. 6, lines 13-15).
Claim 31,
68. A composition comprising:
RNA lipoplex particles comprising:
RNA encoding a peptide or protein comprising at least one epitope,
at least one cationic lipid and at least one additional lipid,
wherein the ratio of positive charges to negative charges in the RNA lipoplex particles is
from about 1:2 to about 1.9:2, or about 1.3:2.0,
sodium chloride at a concentration from 0 mM to about 40 mM, and
a stabilizer. (Claim 68, pg. 102).
77. The composition of any one of claims 64 to 76, wherein the stabilizer is sucrose at a
concentration from about 5 to about 25 weight by volume percent (% w/v).
(Claim 77, pg. 103).
83. The composition of any one of claims 64 to 82, wherein the composition has a pH from
about 5.7 to about 6.7.
84. The composition of any one of claims 68 to 83, wherein the buffer is 2-[ 4-(2-
hydroxyethyl)piperazin-1-yl]ethanesulfonic acid (HEPES).
85. The composition of claim 84, wherein the HEPES is at a concentration from about 2.5
mM to about 10 mM.
(Claim 83-85, pg. 104).
In one embodiment, the composition further comprises a chelating agent. (pg. 6, line 28).
In one embodiment, the chelating agent is ethylenediaminetetraacetic acid (EDTA).
In one embodiment, the EDTA is at a concentration from about 0.25 mM to about 5 mM, or of about 2.5 mM. (pg. 7, lines 23-25).
In one embodiment, the at least one cationic lipid comprises I ,2-di-O-octadecenyl-3-
trimethylammonium propane (DOTMA) and the at least one additional lipid comprises 1,2-di(
9Z-octadecenoy1)-sn-glycero-3-phosphoethanolamine (DOPE).
In one embodiment, the molar ratio of the at least one cationic lipid to the at least one additional
lipid is from about 10:0 to about 1 :9, from about 4: 1 to about 1 :2, from about 3: 1 to about 1:1, or about 2:1. (pg. 4, lines 11-16).
With regard to claim 32,
In one embodiment, the RNA lipoplex particles have an average diameter that ranges from about
20 200 to about 800 nm, from about 250 to about 700 nm, from about 400 to about 600 nm, from
about 300 nm to about 500 nm, or from about 350 nm to about 400 nm. (pg. 10, line 19-21).
With regard to claim 33,
In one embodiment, the amount of RNA in the composition is from about 0.01 mg/mL to about 1
mg/mL, about 0.05 mg/mL to about 0.5 mg/mL, or about 0.05 mg/mL. (pg. 16, lines 1-2).
With regard to claim 35,
In one embodiment, the composition is in a liquid or frozen state. (pg. 17, line 10).
With regard to claim 39,
In one embodiment, the frozen composition is stable at a temperature from about -15°C to about -40°C for at least one month, for at least 6 months. (pg. 17, lines 11-12).
With regard to claims 43, 45-46,
The composition of any one of claims 64 to 87, wherein the composition is in a liquid or frozen state. (pg. 105, Claim 88). The composition of any one of claims 57 to 109, which is formulated for systemic administration. (pg. 107, Claim 110). The composition of claim 110, wherein the systemic administration is by intravenous administration. (pg. 108, Claim 111).
With regard to claim 48,
I. Methods for preparing RNA lipoplex particles, RNA Iipoplex particles and compositions
comprising RNA lipoplex particles. (pg. 2, lines 14-15).
In one embodiment, providing an aqueous composition comprising RNA 1ipop1ex partic1es and a stabilizer comprises providing an aqueous composition comprising RNA lipoplex particles and
adding the stabilizer to the aqueous composition comprising RNA lipoplex partic1es. (pg. 14, lines 5-7).
The RNA lipoplex compositions are frozen for storage, the compositions may be thawed and optionally the osmolality, ionic strength and/or the pH of the composition may be adjusted by adding an aqueous liquid. The resulting composition may be administered to a subject. (pg. 13, lines 15-18). The RNA lipoplex compositions are lyophilized or freeze-dried for storage, the compositions may be reconstituted by adding an aqueous liquid and optionally the osmolality, ionic strength and/or the pH of the composition may be adjusted by adding an aqueous liquid. The resulting composition may be administered to a subject. (pg. 13, lines 19-22).
With regard to claim 51,
The RNA integrity depends on the pH value of the formulation. The optimum pH range was identified to be in the range between pH 5.5 and 7.4. (pg. 85, lines 6-7). The pH of some of the RNA lipoplex formulations is adjusted to a value which is lower than the usual physiological range and the usual pH optimum for RNA storage in the bulk phase. A suitable range for the pH is between about 5.7 and about 6.7. (pg. 13, lines 10-13).
With regard to claims 52-54,
RNA lipoplex particles comprising: RNA encoding a peptide or protein comprising at least one epitope, at least one cationic lipid and at least one additional lipid, wherein the ratio of positive charges to negative charges in the RNA lipoplex particles is from about 1:2 to about 1.9:2, or about 1.3:2.0, sodium chloride at a concentration from 0 mM to about 40 mM, and a stabilizer. (pg. 15, lines 23-29), which includes 8.2 mM. In one embodiment, the stabilizer is sucrose at a concentration from about 5 to about 25 % (w/v). (pg. 16, lines 15-16), which includes 13% (w/v) and it overlapping with the range 12-14% (w/v).
With regard to claims 55-56,
The RNA integrity depends on the pH value of the formulation. The optimum pH range was identified to be in the range between pH 5.5. and 7.4. (pg. 85, lines 6-7). The composition of any one of claims 64 to 82, wherein the composition has a pH from about 5.7 to about 6.7. The composition of any one of claims 68 to 83, wherein the buffer is 2-[ 4-(2hydroxyethyl)piperazin-1-yl]ethanesulfonic acid (HEPES). 85. The composition of claim 84, wherein the HEPES is at a concentration from about 2.5 mM to about 10 mM, (Claims 83-85, pg. 104), which overlappes with the pH range 6.5-7.2, and includes the concentration 5mM at pH 6.7.
With regard to claims 57-58,
87. A composition comprising: RNA lipoplex particles comprising: RNA encoding a peptide or protein comprising at least one epitope at a concentration of about 0.05 mg/mL, and DOTMA and DOPE in a molar ratio of about 2: 1. (Claim 87, pg. 105).
Response to Arguments
II. Rejections under 35 U.S.C. § 102(a)(l)
Applicant argues that A. The Office fails to address each element of claim 1. without explanation, the Office appears to ignore the element in claim 1 that recites that the composition is formulated for direct administration to a human subject without dilution. The Office points to claim 110 of HAAS as mentioning "formulated for systemic administration," but the Office fails to address the entirety of the wherein clause in claim 1.
Applicant’s arguments have been fully considered but they are not persuasive since Hass does not teach that the formulation is needed to be diluted for administration. Even though Haas et al. teach The composition of any one of claims 64 to 87, wherein the composition can be in a liquid or frozen state. (pg. 105, Claim 88). With liquid formulations, Haas et al. teach the composition of any one of claims 57 to 109, which is formulated for systemic administration. (pg. 107, Claim 110) and The composition of claim 110, wherein the systemic administration is by intravenous administration. (pg. 108, Claim 111) and Haas et al. did not teach the formulations are needed to be diluted, which means they can be administered without dilution.
Applicant argues that B. The Office has not identified the claimed elements as arranged in the claims. While HAAS may mention some of the components recited in the pending independent
claims 1 and 31, it does not disclose the specifically claimed combination in either independent
claim. The Office identifies claim 68 of HAAS as reciting "sodium chloride at a concentration
from 0 mM to about 40 mM, and a stabilizer." Office Action, page 2. The Office then points to
claim 75 of HAAS as identifying the concentration of stabilizer in any one of claims 64 to 74 as
being "from about 5 to about 35 % w/v, or from about 12.5 to about 25 % w/v." Id. HAAS mentions combinations of various components such as salts, buffers, stabilizers, and other agents in amounts that differ from the present claims. The Office has not identified any specific formulation within HAAS that contains sodium chloride at a concentration of about 10 mM or less and a stabilizer at a concentration of more than about 10% weight by volume percent(% w/v) and less than about 15% weight by volume percent (% w/v) and is formulated for direct administration to a human subject without dilution (as recited in claim 1 ), let alone any specific formulation that contains the specific combination of elements recited in claim 31. Claim 31 differs from HAAS at least by:
• a specific combination of cationic lipid and additional lipid (DOTMA and DOPE) in a
specific molar ratio (about 2: 1 );
• a specific sodium chloride concentration (about 8.2 mM);
• a specific stabilizer at a specific concentration (sucrose at about 13%); and
• a specific buffer at a specific concentration and pH (HEPES at about 5 mM with pH of
about 6.7).
Applicant’s arguments have been fully considered but they are not persuasive since Hass teaches all elements of a composition of applicant’s claims 1 and 31. In the case where the claimed ranges "overlap or lie inside ranges disclosed by the prior art" a prima facie case of obviousness exists, as the rejection of independent claim 1 has been updated to the obvious 103 rejection, so do dependent claims, with respects to the amendments and arguments/remarks.
Applicant argue that C. The ranges identified by the Office do not provide sufficient specificity to anticipate the recited narrower ranges nor do they constitute disclosure of the recited specific points within such ranges. The Office relies on HAAS as allegedly teaching the following ranges:
• sodium chloride at a concentration from O mM to about 40 mM;
• stabilizer from about 5 to about 35 weight by volume percent (% w/v), or from about 12.5 to about 25 % w/v; and
• sucrose at a concentration from about 5 to about 25 % w/v. Pending claim 1 and its dependent claims recite different ranges:
• sodium chloride at a concentration of about 10 mM or less;
• a stabilizer at a concentration of more than about 10 % w/v) and less than about 15% % w/v; and
• sucrose at a concentration from about 12 to about 14% (w/v). Pending claim 31 and its dependent claims (and claims 4, 53, and 54) recite specific points:
• sodium chloride at a concentration of about 8.2 mM; and
• sucrose at a concentration of about 13% (w/v).
Applicant’s arguments have been fully considered but they are not persuasive since in the case where the claimed ranges "overlap or lie inside ranges disclosed by the prior art" a prima facie case of obviousness exists, as the rejection of independent claim 1 has been updated to the obvious 103 rejection, so do dependent claims, with respects to the amendments and arguments/remarks.
Conclusion
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.
Correspondence
No claim is allowed at this time.
Any inquiry concerning this communication or earlier communications from the examiner should be directed to NGOC-ANH THI NGUYEN whose telephone number is (571)270-0867. The examiner can normally be reached Monday - Friday 8:00 am.
Examiner interviews are available via telephone, in-person, and video conferencing using a USPTO supplied web-based collaboration tool. To schedule an interview, applicant is encouraged to use the USPTO Automated Interview Request (AIR) at http://www.uspto.gov/interviewpractice.
If attempts to reach the examiner by telephone are unsuccessful, the examiner’s supervisor, Robert A Wax can be reached at 571-272-0623. The fax phone number for the organization where this application or proceeding is assigned is 571-273-8300.
Information regarding the status of published or unpublished applications may be obtained from Patent Center. Unpublished application information in Patent Center is available to registered users. To file and manage patent submissions in Patent Center, visit: https://patentcenter.uspto.gov. Visit https://www.uspto.gov/patents/apply/patent-center for more information about Patent Center and https://www.uspto.gov/patents/docx for information about filing in DOCX format. For additional questions, contact the Electronic Business Center (EBC) at 866-217-9197 (toll-free). If you would like assistance from a USPTO Customer Service Representative, call 800-786-9199 (IN USA OR CANADA) or 571-272-1000.
/NGOC-ANH THI NGUYEN/Examiner, Art Unit 1615
/Robert A Wax/Supervisory Patent Examiner, Art Unit 1615