DETAILED ACTION
The present application, filed on or after March 16, 2013, is being examined under the first inventor to file provisions of the AIA .
This Office action is in response to the communications filed 4-30-26.
Claims 1, 57-71 are pending in the instant application.
Election/Restrictions
Claims 2-56 are withdrawn from further consideration pursuant to 37 CFR 1.142(b) or hereby canceled, as being drawn to a nonelected invention or species, there being no allowable generic or linking claim. Election was made without traverse in the reply filed on 4-30-26.
Applicant’s election without traverse of Group I, 14:0 TAP as the single SORT lipid, and the ionizable cationic lipid 5A2-SC8, claims 1, 57-71, in the reply filed on 4-30-26 is acknowledged.
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.
Claim 65 is 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.
In claim 65, (1), the claim recites a size of “100 nanometers (nm) or less.” The metes and bounds of the claim cannot be determined.
Appropriate clarification is required.
The following is a quotation of the first paragraph of 35 U.S.C. 112(a):
IN GENERAL.—The specification shall contain a written description of the invention, and of the manner and process of making and using it, in such full, clear, concise, and exact terms as to enable any person skilled in the art to which it pertains, or with which it is most nearly connected, to make and use the same, and shall set forth the best mode contemplated by the inventor or joint inventor of carrying out the invention.
The following is a quotation of the first paragraph of pre-AIA 35 U.S.C. 112:
The specification shall contain a written description of the invention, and of the manner and process of making and using it, in such full, clear, concise, and exact terms as to enable any person skilled in the art to which it pertains, or with which it is most nearly connected, to make and use the same, and shall set forth the best mode contemplated by the inventor of carrying out his invention.
Claims 1, 57-66, 70 and 71 are rejected under 35 U.S.C. 112(a) or 35 U.S.C. 112 (pre-AIA ), first paragraph, as failing to comply with the written description requirement. The claim(s) contains subject matter which was not described in the specification in such a way as to reasonably convey to one skilled in the relevant art that the inventor or a joint inventor, or for pre-AIA the inventor(s), at the time the application was filed, had possession of the claimed invention.
The breadth of the claims:
The claims are drawn to compositions formulated for systemic administration comprising a therapeutic agent assembled with a lipid composition comprising (i) any ionizable cationic lipid at a molar percentage from 5% to 30%; (ii) any polymer-conjugated lipid at a molar percentage from 0.5% to 10%;(iii) any phospholipid at a molar percentage from 8% to 23%; (iv) any steroid or steroid derivative at a molar percentage from 15% to 46%; and (v) any selective organ targeting (SORT) lipid separate from the ionizable cationic lipid at a molar percentage of 20% to 65%, wherein the SORT lipid is a trimethylammonium-propane (TAP) lipid selected from a group consisting of 14:0 TAP, 16:0 TAP, 18:0 TAP, and 18:1 TAP, which ionizable cationic lipid is at a molar percentage from 12% to 16%; (ii) the polymer-conjugated lipid is at a molar percentage from 2% to 4%; (iii) the phospholipid is at a molar percentage from 12% to 18%; (iv) the steroid or steroid derivative is at a molar percentage from 25% to 30%; and (v) the SORT lipid is at a molar percentage from 35% to 45%, or which ionizable cationic lipid is at a molar percentage of 14.3%; (ii) the polymer-conjugated lipid is at a molar percentage of 2.8%; (iii) the phospholipid is at a molar percentage of 14.3%; (iv) the steroid or steroid derivative is at a molar percentage of 28.6%; and(v) the SORT lipid is at a molar percentage of 40%, or which ionizable cationic lipid is selected from those set forth in Table 4 or Table 5, which therapeutic agent is a polynucleotide; and which molar ratio of the therapeutic agent to total lipids of said lipid composition is optionally no more than about 1:1, 1:10, 1:50, or 1:100.
Teachings in the specification:
The specification teaches the following lipid compositions:
For preparation of the LNP formulation, a dendrimer or dendron lipid, DOPE, Cholesterol and DMG-PEG were dissolved in ethanol at desired molar ratios. The mRNA was dissolved in citrate buffer (10 mM, pH 4.0). The mRNA was then diluted into the lipids solution to achieve a weight ratio of 40:1 (total lipids: mRNA) by rapidly mixing the mRNA into the lipid solution at a volume ratio of 3:1 (mRNA: lipids, v/v). This solution was then incubated for 10 min at room temperature. For formation of DOTAP modified LNP formulations, mRNA was dissolved in 1 X PBS or citrate buffer (10 mM, pH 4.0), and mixed rapidly into ethanol containing 5A2-SC8, DOPE, Cholesterol, DMG-PEG and DOTAP, fixing the weight ratio of 40:1 (total lipids:mRNA) and volume ratio of 3:1 (mRNA:lipids).
Formulations are named X% DOTAP Y (or X%DODAP Y) where X represents the DOTAP (or DODAP) molar percentage in total lipids, and Y represents the type of dendrimer or dendron lipid. Alternatively, formulation may be named Y X%DOTAP or Y X%DODAP where X represents the DOTAP (or DODAP) molar percentage in total lipids, and Y represents the type of dendrimer or dendron lipid.
Example 2: SORT LNP Stability:
[00337] Example lipid compositions as described herein were generated using either a microfluidic mixing method or a cross/tee mixing method and tested for stability. The physical characteristics including size, polydispersity index (PDI) and zeta-potential were characterized by dynamic light scattering (DLS) from various example lipid (LNP) compositions (3 separate measurements for each formulation) and illustrated in Table 7.
[00338] The encapsulation efficiency was tested using a Ribogreen RNA assay (Zhao et al., 2016). Briefly, mRNA was encapsulated with > 95% efficiency in LNPs when the nRNA was dissolved in acidic buffer (10 mM citrate, pH 4). The characteristics were observed over 28 days for the two types of LNPs (5A2-SC8 with 20% DODAP ("Liver-SORT) and 5A2-SC8 with 50% DOTAP ("Lung-SORT")).
FIG. 3 illustrates changes in the physical characteristics of the lipid compositions over a duration of 28 days.
Table 7: SORT LNP characteristics Example 3: Lung-SORT IV Study
[00339] This example compiles several studies of administration of Lung-SORTs intravenously and systemically to multiple species (e.g., mice, rats, dogs, and non-human primate (NHP) (e.g., Rhesus macaques, Cynomolgus macaques)).
Summary [00340] Most of the test subjects were administered a single dose of luciferase mRNA encapsulated in a Lung-SORT LNP (5A2-SC8 with 50% DOTAP). Some of the test subjected were administered two doses. The low doses administered to dogs and NHP ware translated from mice studies.
The specification, prior art and claims do not adequately describe the genus of formulations claimed. The examples taught in the specification, of compositions comprising LNPs 5A2-SC8 with 20% DODAP ("Liver-SORT) and 5A2-SC8 with 50% DOTAP ("Lung-SORT"), of luciferase mRNA encapsulated in a Lung-SORT LNP (5A2-SC8 with 50% DOTAP), and of mRNA placed into a lipid solution at a volume ratio of 3:1 (mRNA: lipids, v/v), which solution was then incubated for 10 min at room temperature. For formation of DOTAP modified LNP formulations, mRNA was dissolved in 1 X PBS or citrate buffer (10 mM, pH 4.0), and mixed rapidly into ethanol containing 5A2-SC8, DOPE, Cholesterol, DMG-PEG and DOTAP, fixing the weight ratio of 40:1 (total lipids:mRNA) and a volume ratio of 3:1 (mRNA:lipids), are not representative of the genus of formulations claimed. The specification fails to provide a representative number of species, and does not indicate what distinguishing attributes are concisely shared by the members of this broad genus.
For the reasons stated above, the instant rejection for lacking adequate written description is proper.
Allowable Subject Matter
Claims 67-69 are objected to as being dependent upon a rejected base claim, but would be allowable if rewritten in independent form including all of the limitations of the base claim and any intervening claims.
Conclusion
Certain papers related to this application may be submitted to Art Unit 1637 by facsimile transmission. The faxing of such papers must conform with the notices published in the Official Gazette, 1156 OG 61 (November 16, 1993) and 1157 OG 94 (December 28, 1993) (see 37 C.F.R. ' 1.6(d)). The official fax telephone number for the Group is 571-273-8300. NOTE: If Applicant does submit a paper by fax, the original signed copy should be retained by applicant or applicant's representative. NO DUPLICATE COPIES SHOULD BE SUBMITTED so as to avoid the processing of duplicate papers in the Office.
Any inquiry concerning this communication or earlier communications from the examiner should be directed to Jane Zara whose telephone number is (571) 272-0765. The examiner’s office hours are generally Monday-Friday, 10:30am - 7pm. If attempts to reach the examiner by telephone are unsuccessful, the examiner's supervisor, Jennifer Dunston, can be reached on (571)-272-2916. Any inquiry of a general nature or relating to the status of this application should be directed to the Group receptionist whose telephone number is (703) 308-0196.
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Jane Zara
6-16-26
/JANE J ZARA/Primary Examiner, Art Unit 1637
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