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 .
Application Status
The preliminary amendment filed February 1, 2024 is acknowledged. Claims 48-49, 53, 56-64, 66, 69-71, 77-79 and 84 are pending and under examination.
The application claims priority to two provisional applications, 63/229496 filed 08/04/2021 and 63/164518 filed 03/22/2021, that provide support for the claimed invention. The effective filing date of the claimed invention is March 22, 2021.
Drawings
The drawings are objected to because:
1) The chemical structures in FIG. 2 are blurry and the Y-axis text in FIG. 8 is blurry. Rule 37 C.F.R. 1.84(l) requires that “all drawings be made by a process which will give them satisfactory reproduction characteristics. Every line, number, and letter must be durable, clean, black (except for color drawings), sufficiently dense and dark, and uniformly thick and well-defined.”
2) The reference character “FIG. 8” is not oriented in the same direction as the rest of the text and figure legends in the Figure. Rule 37 C.F.R. 1.84(p)(1) indicates that reference characters must be oriented in the same direction as the view so as to avoid having to rotate the sheet.
Corrected drawing sheets in compliance with 37 CFR 1.121(d) are required in reply to the Office action to avoid abandonment of the application. Any amended replacement drawing sheet should include all of the figures appearing on the immediate prior version of the sheet, even if only one figure is being amended. The figure or figure number of an amended drawing should not be labeled as “amended.” If a drawing figure is to be canceled, the appropriate figure must be removed from the replacement sheet, and where necessary, the remaining figures must be renumbered and appropriate changes made to the brief description of the several views of the drawings for consistency. Additional replacement sheets may be necessary to show the renumbering of the remaining figures. Each drawing sheet submitted after the filing date of an application must be labeled in the top margin as either “Replacement Sheet” or “New Sheet” pursuant to 37 CFR 1.121(d). If the changes are not accepted by the examiner, the applicant will be notified and informed of any required corrective action in the next Office action. The objection to the drawings will not be held in abeyance.
Claim Objections
Claims 48, 57, 58 and 69 are objected to because of the following informalities:
The chemical structures depicted in each of the above claims is blurry and do not have satisfactory reproduction characteristics.
Appropriate correction is required.
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.
Claims 48, 60-62, 69 and 77-78 are rejected under 35 U.S.C. 102(a)(1) as being anticipated by Lockhart (US 20190117796 A1, published April 25, 2019).
Regarding claim 48, Lockhart teaches a method for treating primary ciliary dyskinesia (PCD) by administering a polyribonucleotide (i.e. RNA, a heterologous polynucleotide) encoding dynein axonemal intermediate chain 1 (DNAI1) ([0061]-[0062], Abstract). Lockhart teaches the polynucleotide encoding DNAI1 has SEQ ID NO 15 (Table 2), which is 100% identical to SEQ ID NO 15 of the examined application. Lockhart teaches that the DNAI1 mRNA is sufficient for expression of the DNAI1 protein with cells of a patient ([0271]). Lockhart teaches delivering the RNA with lipids having formula (IV) ([0172]-[0178]), which is identical to the claimed cationic lipid having structural formula (I’).
Regarding claim 60, Lockhart teaches treating subjects having a mutation in the DNAI1 gene that results in the absence of the DNAI1 protein causing cilia to be nonfunctional ([0062]).
Regarding claim 61, Lockhart teaches the subjects having PCD are human ([0094]).
Regarding claim 62, Lockhart teaches delivering the polyribonucleotides to the lungs of the subject (Abstract).
Regarding claim 69, the teachings of Lockhart are recited above as for claim 48. Briefly, Lockhart teaches delivering RNA encoding DNAI1 having 100% identity to SEQ ID NO 15 in a lipid composition wherein the lipids have the generic structure recited in Formula (I’). Lockhart also teaches the method is to enhance the expression of DNAI1 in the cells that do not produce DNAI1 ([0061]-[0062]).
Regarding claim 77, Lockhart teaches delivering the DNAI1-encoding RNA in lipid formulations to individuals/cells having mutations in DNAI1 ([0062]).
Regarding claim 78, Lockhart teaches delivering the polyribonucleotides to the lungs of the subject (i.e., contacting a plurality of cells) (Abstract).
Claim Rejections - 35 USC § 103
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.
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 49, 53, 56-59, 63-64, 66, 70-71, 79 and 84 are rejected under 35 U.S.C. 103 as being unpatentable over Lockhart (US 20190117796 A1, published April 25, 2019) as applied to claims 48, 60-62, 69 and 77-78 above, and further in view of Rudolph (WO 2020165352 A1, published August 20, 2020).
The teachings of Lockhart are recited above as for claims 48, 60-62, 69 and 77-78 and incorporated here. Regarding claims 63-64, 66 and 78, Lockhart also teaches a working example of contacting undifferentiated and differentiated human airway epithelial cells in vitro with mRNA encoding DNAI1 using a different lipid formulation ([0271]).
Lockhart does not teach the specific chemical structures claimed in claims 49 and 53, 56-58. Lockhart does not teach administering by nebulization with the generic formula (IV). Lockhart does not teach timing effects between delivery of mRNA and expression of the encoded protein.
Regarding claims 49, 53, 56-58, Rudolph teaches methods of treating a ciliopathy in a subject by delivering a polyribonucleotide (i.e., mRNA) in pharmaceutical compositions to the respiratory systems (Abstract). Rudolph teaches in preferred embodiments the mRNA encodes for a functional version of DNAI1 (page 17, ¶3). Rudolph teaches oligo(alkyene amine) lipidoid moieties for use as agents for introducing RNA into cells (page 23, last ¶ through page 36). Rudolph specifically teaches Formulas (V) and (VI) for delivering mRNAs to cells (pages 35 and 36), which are the formulas recited in claims 57 and 58, and are encompassed by the functional groups and parameters reicted in claims 49, 53 and 56. Rudolph teaches delivering to patient-derived airway epithelial cells mRNA-encoding CCDC40 in lipid formulation 92 (LF92) (page 74), which comprises the R-isomer of C12-(2-3-2) (formula VI) is formulated with the lipids DPPC and cholesterol and PEG-lipid DMG-PEG2000 (page 37). Therefore, Rudolph discloses a working example of delivering mRNA to patient-derived airway cells in a lipid composition comprising the claimed lipids. Rudolph teaches expression of the protein encoded by the delivered mRNA (page 74).
It would have been obvious to one skilled in the art to have delivered Lockhart’s DNAI1 mRNA in a Rudolph’s LF92 lipid formulation in Lockhart’s method of treating PCD. It would have amounted to the simple combination of known elements by know means to yield predictable results. The skilled artisan would have specifically chosen the claimed lipidoid structures because Rudolph demonstrates successful mRNA delivery and protein expression in ciliated airway cells. The skilled artisan would have been motivated to use the C12-(2-3-2) (i.e., formula I’ lipid) because 1) Rudolph suggests using it when delivering mRNA DNAI1 to cells, and 2) demonstrates successful gene delivery to the cells that Lockhart’s method targets.
Regarding claim 59, Lockhart teaches pharmaceutical compositions delivered in the form of an aerosol spray from a nebulizer ([0231]). Lockhart teaches delivering the DNAI1 mRNA formulation for administration by nebulizing ([0245]). Rudolph teaches the pharmaceutical composition is in a form which allows administration to the respiratory system e.g. via nebulization, which is advantageous for the patients as an administration using a nebulizer can easily be done by the patient, is comfortable to transport, and thus, easily available for the patient without restricting any freedom of action.
It would have been obvious to one skilled in the art before the effective filing date of the claimed invention to have delivered the mRNA/LF92 composition rendered obvious above by nebulization because both Lockhart and Rudolph teach that the pharmaceutical formulations can be delivered as such using known methods in the art. One would have been motivated to do so because Rudolph teaches nebulization is easily done by the patient.
Regarding claim 63, 64, 66, either or both Lockhart and Rudolph teach delivering mRNA in lipid formulations to ciliated epithelial cells and undifferentiated cells as indicated above. In addition, Rudolph teaches the formulations can be delivered to respiratory organs and tissues including the lungs (page 16)
It would have been obvious to one skilled in the art before the effective filing date of the claimed invention to have delivered the mRNA/LF92 composition rendered obvious above to ciliated epithelial cells and undifferentiated cells in the lung because the skilled artisan would understand that in order to treat the patient with PCD, the mRNA-encoding DNAI1 will need to be delivered to the affected cells in vivo. In addition, Rudolph teaches the formulations can be delivered to cells of the lung.
Regarding claims 70, 71, 79 and 84, Rudolph teaches delivering mRNA to HEK cells and detecting peak translation efficiency at 6 hours post-transfection in vitro (page 74, ¶1). Rudolph teaches repeated transfection of patient-derived cells with LP92/mRNA formulation (page 74, ¶3-4). Rudolph teaches LP92/mRNA formulations delivered to patient-derived cells and detecting ciliary movement (i.e., effective activity of functional protein) at 6, 12 and 18 days post transfection (Figure 3).
It would have been obvious to one skilled in the art before the effective filing date of the claimed invention to have delivered the DNAI1 mRNA/LF92 composition rendered obvious above to in vitro and ex vivo cells with repeated transfections with the predictable results of protein expression detectable by about 6 hours and activity in about 6 days. It would have amounted to the simple combination of known transfection methods with the obvious formulation by known means to yield predictable results. The skilled artisan would have predicted that a DNAI1 mRNA/LF92 formulation would have similar expression dynamics as the Rudolph’s CCDC39 mRNA because both constructs are delivered as mRNA and the underlying translational machinery in the cells of interest is the same. The skilled artisan would have been motivated to make repeated transfections since Rudolph demonstrates successful rescue of ciliary movements using the formulation and protocol.
Conclusion
No claims are allowable.
Any inquiry concerning this communication or earlier communications from the examiner should be directed to CATHERINE KONOPKA whose telephone number is (571)272-0330. The examiner can normally be reached Mon - Fri 7- 4.
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If attempts to reach the examiner by telephone are unsuccessful, the examiner’s supervisor, Ram Shukla can be reached at (571)272-0735. The fax phone number for the organization where this application or proceeding is assigned is 571-273-8300.
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/CATHERINE KONOPKA/Primary Examiner, Art Unit 1635
