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 .
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 5 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.
Claim 5 recites: The suspension formulation in accordance with any of claim 1, wherein the nanoparticles comprise: 30 to 65 mol% of the ionizable lipid or ionizable lipidoid (b), and one or more of the following components: 10 to 50 mol% of the lipid having a sterol structure (c1),4 to 50 mol% of the phosphoglyceride lipid (c2), 0.5 to 10 mol% of one of the PEG-conjugated lipid (c3), the polysarcosine-conjugated lipid (c4) and the PASylated lipid (c5), or of any combination thereof, 0.5 to 10 mol% of the cationic polymer (c6), such that the sum of (b) and (c1) to (c6) amounts to 100 mol%.
The claim requires 30 to 65 mol% of the ionizable lipid or ionizable lipidoid in combination with one or more of the listed components, but the sum of the amounts is 100 mol%. The claim encompasses any one of the parts listed in combination with the 30 to 65 mol% of the ionizable lipid or ionizable lipidoid, although each would not be able to meet the sum requirement of 100 mol%.
The following is a quotation of the first paragraph of 35 U.S.C. 112(a):
(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 15-17 are rejected under 35 U.S.C. 112(a) or 35 U.S.C. 112 (pre-AIA ), first paragraph, because the specification, while being enabling for a method of delivering the suspension formulation of claim 1, does not reasonably provide enablement for a method of treating or preventing any disease via delivery of the suspension formulation of claim 1 alone. The specification does not enable any person skilled in the art to which it pertains, or with which it is most nearly connected, to make and/or use the invention commensurate in scope with these claims.
Factors to be considered in a determination of lack of enablement include, but are not limited to:
(A) The breadth of the claims;
(B) The nature of the invention;
(C) The state of the prior art;
(D) The level of one of ordinary skill;
(E) The level of predictability in the art;
(F) The amount of direction provided by the inventor;
(G) The existence of working examples; and
(H) The quantity of experimentation needed to make or use the invention based on the content of the disclosure.
In re Wands, 858 F.2d 731, 737, 8 USPQ2d 1400, 1404 (Fed. Cir. 1988)
The claims are directed to a method a method of treating or preventing any disease via delivery of the suspension formulation of claim 1 alone.
The specification does not draw an adequate nexus between aerosol delivery of the instant genus of compositions in combination with any possible nucleic acid and the predictable outcome of treatment of any possible disease, which encompasses an enormous genus of diseases that have not been shown to be reliant upon the expression of any nucleic acid alone.
The claims are not limited to any specific composition, but rather encompass any lipid or lipidoid nanoparticles that comprise any possible nucleic acid wherein the aqueous vehicle solution comprises a triblock copolymer which contains one poly(propylene oxide) block and two poly(ethylene oxide) blocks. The specification does not demonstrate delivery of nucleic acids from such a broad possible genus of lipids or lipidoids.
The specification demonstrates nebulization of the instant nanoparticle preparation comprising MC3 for mRNA delivery, Dlin-MC3-DMA, DSPC, cholesterol, and CMPE-PEG2k at the molar ratios of 50/10/38.5/1, respectively. The specification discloses that incorporation of Poloxamer was n3ecessary to prevent aggregation. The instant claims are not limited to this formulation and the specification did not demonstrate treatment or prevention of even a single species of diseases via delivery of the mRNA.
Additionally, even with regards of the single species of composition of the specification that is not commensurate in scope with the entire claimed genus, the specification does not draw an adequate nexus between delivery of this composition comprising any possible nucleic acid and the predictable outcome of treatment or absolute prevention of any disease or any pulmonary disease. The claims encompass delivery of an enormous possible genus of nucleic acids that would not predictably result in the treatment or absolute prevention of any disease or any pulmonary disease. Additionally, certainly not any disease can be treated or prevented via aerosol delivery of the nanoparticle formulation.
With regards to siRNAs, a single species of the instant nucleic acids, the instant siRNAs are not required to have any specific structural relationship with any specific target sequence. It was known that the siRNA must have a strand that is complementary to a specific target sequence and that different disease states require different modes of delivery.
For example, Elbashir et al. (The EMBO Journal, Vol. 20, No. 23, pages 6877-6888, 2001) teaches that duplexes of 21-23 nt RNAs are the sequence specific mediators of RNAi and that even single mismatches between the siRNA duplex and the target mRNA abolish interference (abstract and page 6888).
Fujita et al. (Int. J. Mol. Sci. 2015, 16, 5254-5270) teach that two types of small RNA molecules, small interfering RNAs (siRNAs) and microRNAs (miRNAs), have a central function in RNAi technology. The success of RNAi-based therapeutic delivery may be dependent upon uncovering a delivery route, sophisticated delivery carriers, and nucleic acid modifications (page 5254). Fujita et al. teach that the success of an RNAi-based therapy in clinical trials rests on careful selection of target genes and miRNAs. Moreover, we suggest that a delivery route, sophisticated delivery carriers, chemical modification, and modified RNAi platforms are needed to enhance RNAi effects in cancer cells (pages 5262-5263).
Umansky et al. (WO 2011/057003 A2) teaches a method of diagnosing Parkinson's disease comprising determining the expression level of miRNAs (pages 6-10, for example). Umansky et al. demonstrates that specific miRNAs are up regulated and specific miRNAs are down regulated in a specific disease state. Therefore, delivery of a miRNA in a disease state wherein the miRNA is already upregulated, for example, would not likely result in treatment or prevention of that disease state. The instant claims encompass delivery of such a nucleic acid.
As outlined above, it is well known that there is a high level of unpredictability in the RNAi art (a single species of the claimed nucleic acids) for therapeutic in vivo applications and design. The scope of the claims in view of the specification as filed together do not reconcile the unpredictability in the art to enable one of skill in the art to make and/or use the claimed invention, namely a broad method of delivering any possible nucleic acid to treat any possible disease via aerosol delivery encompassing in vivo effects.
MPEP 2164.01
Any analysis of whether a particular claim is supported by the disclosure in an application requires a determination of whether that disclosure, when filed, contained sufficient information regarding the subject matter of the claims as to enable one skilled in the pertinent art to make and use the claimed invention.
Also, MPEP 2164.01(a)
A conclusion of lack of enablement means that, based on the evidence regarding each of the above factors, the specification, at the time the application was filed, would not have taught one skilled in the art how to make and/or use the full scope of the claimed invention without undue experimentation. In re Wright, 999 F.2d 1557,1562, 27 USPQ2d 1510, 1513 (Fed. Cir. 1993).
Given the teachings of the specification as discussed above, one skilled in the art could not predict a priori whether introduction of any nucleic acids in any species of the instant delivery complexes in vivo via aerosol delivery would result in successful treatment or prevention of any possible disease. To practice the claimed invention, one of skill in the art would have to de novo determine; the effect of the nucleic acid on any given disease state; the stability of the molecule in vivo, delivery of the molecule to the whole organism, specificity to the target tissue in vivo, dosage and toxicity in vivo, and entry of the molecule into the cell in vivo and the effective action therein. Without further guidance, one of skill in the art would have to practice a substantial amount of trial and error experimentation, an amount considered undue and not routine, to practice the instantly claimed invention.
A conclusion of lack of enablement means that, based on the evidence regarding each of the above factors, the specification, at the time the application was filed, would not have taught one skilled in the art how to make and/or use the full scope of the claimed invention without undue experimentation (see MPEP 2164.01(a)).
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.
(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) 1-3, 7-15, 17, and 20 is/are rejected under 35 U.S.C. 102(a)(1) and (a)(2) as being anticipated by Yan et al. (Biomaterials 118 (2017) 84-93).
Yan et al. teach aerosol delivery of stabilized polyester-siRNA nanoparticles to silence gene expression in orthotopic lung tumors (title). Yan et al. teach an aqueous suspension formulation comprising lipid nanoparticles comprising ionizable lipid suspended in the solution (PE4K of Yan et al.) wherein the nanoparticle comprises a siRNA (instant nucleic acid) and a triblock copolymer which contains one poly(propylene oxide) and two poly(ethylene oxide) blocks (see PEO101-PPO56-PEO101 Pluronic F-127 of Yan et al.) (instant claims 1, 7, and 14).
Yan et al. teach that the concentration of the siRNA is 50 ng/uL, which is .05 mg/mL (instant claim 2). The nanoparticles have diameters in the instantly recited range of claims 3, 12, and 20 (see Figure 5a). Instant claims 3, 12, and 20 are composition claims and the method of determining the diameter does not alter the recited diameters.
Yan et al. teach that lipid nanoparticles have a typical diameter of 80-100 nm (page 84) and that nanoparticles larger than 200 nm are usually less effective (page 87) (instant claim 3, 12, and 20).
Yan et al. teach a method of treating orthotopic lung tumors in mice via delivery of the F-127 nanoparticle composition comprising a siRNA targeted to Cy5.5 via aerosol mist using a micropump nebulizer (instant claims 9, 10, 13, 15, and 17).
Yan et al. teach siRNA silencing in orthotopic lung tumors. Yan et al. teach: The same NP solution was diluted 2-fold with PBS delivered to mice bearing orthotopic A549-Luc lung tumors (1 mg/kg, total NP volume of 400 mL) as an aerosol mist using a micropump nebulizer (Aeroneb Lab, Kent Scientific). The Aeronab Lab nebulizer (Kent Scientific) produces aerosol droplets ranging from 2.5 µm – 4.0 µm (small size) or 4.0 µm – 6.0 µm (standard size), which meets the instant limitation of diameter from 2 to 10 µm (instant claim 11). The biodistribution of NPs through aerosol inhalation was investigated by replacing the siLuc with Cy5.5-siRNA following the same procedure above (instant claim 8).
Therefore, the claims are anticipated by Yan et al.
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.
Claim(s) 4-6, 16, and 18 is/are rejected under 35 U.S.C. 103 as being unpatentable over Yan et al. (Biomaterials 118 (2017) 84-93), as applied to claims 1-3, 7-15, 17, and 20 above, and further in view of Kabanov et al. (WO 98/56334), Semple et al. (nature biotechnology, 28, 2010, 172-178), and Akinc et al. (NATURE BIOTECHNOLOGY, 26, 5, MAY 2008, 561-569).
The Yan et al. reference is of record and cited on the IDS filed on 8/18/23).
Yan et al. teach aerosol delivery of stabilized polyester-siRNA nanoparticles to silence gene expression in orthotopic lung tumors (title). Yan et al. teach an aqueous suspension formulation comprising lipid nanoparticles comprising ionizable lipid suspended in the solution (PE4K of Yan et al.) wherein the nanoparticle comprises a siRNA (instant nucleic acid) and a triblock copolymer which contains one poly(propylene oxide) and two poly(ethylene oxide) blocks (see PEO101-PPO56-PEO101 Pluronic F-127 of Yan et al.) (instant claims 1, 7, and 14).
Yan et al. teach that the concentration of the siRNA is 50 ng/uL, which is .05 mg/mL (instant claim 2). The nanoparticles have diameters in the instantly recited range of claims 3, 12, and 20 (see Figure 5a). Instant claims 3, 12, and 20 are composition claims and the method of determining the diameter does not alter the recited diameters.
Yan et al. teach that lipid nanoparticles have a typical diameter of 80-100 nm (page 84) and that nanoparticles larger than 200 nm are usually less effective (page 87).
Yan et al. teach a method of treating orthotopic lung tumors in mice via delivery of the F-127 nanoparticle composition comprising a siRNA targeted to Cy5.5 via aerosol mist using a nebulizer (instant claims 9, 10, 13, 15, and 17).
Yan et al. teach siRNA silencing in orthotopic lung tumors. Yan et al. teach: The same NP solution was diluted 2-fold with PBS delivered to mice bearing orthotopic A549-Luc lung tumors (1 mg/kg, total NP volume of 400 mL) as an aerosol mist using a micropump nebulizer (Aeroneb Lab, Kent Scientific). The luciferase signal in the lungs of living mice was measured at 24 and 48 h after aerosol inhalation as described above. The biodistribution of NPs through aerosol inhalation was investigated by replacing the siLuc with Cy5.5-siRNA following the same procedure above (instant claim 8).
It is noted that it would have been obvious to utilize the nanoparticle composition of Yan et al. to treat a pulmonary disease as a matter of design choice if the disease desired to be treated is a pulmonary disease. It would have been obvious to select a siRNA known to treat a pulmonary disease and to incorporate it into the nanoparticle composition of Yan et al. with the expectation of the delivery benefits taught by Yan et al. (instant claim 16).
It would have been obvious as a matter of design choice to select the number of PEO blocks to be between 50-100 or 60-90 as recited in instant claims 18 and 19 because Yan et al. teaches that F-127 comprising PEO subunits (PEO101-PPO56-PEO101; Pluronic F-127, Mw=12,600,PDI=1.05) reduced the surface charge of the NPs resulting in an increase in serum stability (abstract) (instant claims 18 and 19). F-127 has PEO repeats of approximately 101 and PPO repeats of approximately 56. Selection of the quantity of each type of the blocks is considered to be a matter of design choice given that the combination was known and the benefits of the combination were known.
Yan et al. do not teach the addition of one of the components of instant claim 4, although it was known to incorporate a PEG-conjugate lipid into aqueous suspension formulations for the delivery of nucleic acids, as evidenced by Kabanov et al.
Kabanov et al. teach lipid formulations for facilitated delivery of nucleic acids (abstract and page 1). Kabanov et al. teach that the ionizable lipid comprises poly(ethylene oxide) blocks (page 1). Kabonov et al. teach block copolymers with at least two different polymer segments including a triblock schematic (page 6) and teach that the copolymers can include multiple segments of each (page 8). Kabonov et al. teach that the copolymers can include poly(ethylene oxide) or poly(propylene oxide) (page 9).
Kabanov et al. teach incorporation of a cationic polymer (pages 1, 3, and 16) or PEG (page 10) (instant claim 4). Kabonov et al. teach that the compositions have the advantage of facilitating administration by increasing their aqueous solubility, increasing stability, and decreasing side effects (page 4).
Kabanov et al. teach that the composition is aqueous (page 33) and can be used in oral and pulmonary delivery (page 32). Kabanov et al. teach that for pulmonary administration, diluents and/or carriers are selected for formation of an aerosol (page 33).
Kabanov et al. teaches incorporation of .1 ng/mL active agent (page 35) (instant claim 2); and taches that teach of the blocks can be a plurality, more specifically 20-500 (page 8).
Therefore, it was known that a PEG or cationic polymer could be incorporated into a nucleic acid delivery composition with include poly(ethylene oxide) or poly(propylene oxide) copolymers with the advantages of facilitating administration by increasing their aqueous solubility, increasing stability, and decreasing side effects (instant claim 4).
Regarding instant claim 5, Semple et al. teach rational design of cationic lipids for siRNA delivery (title) and teach preformed vesicles composed of ionizable cationic lipid/DSPC/cholesterol/PEG-lipid (40:10:40:10 mol%) (page 177). Therefore, it was known to incorporate the ionizable lipid in the instantly recited 30-65 mol% and the cholesterol in the range of 10-50 mole % as instantly claimed. It would have been obvious to incorporate these design parameters into the composition of Yan et al. with expectation of delivery as taught by Semple et al. (instant claim 5).
Regarding instant claim 6, Yan et al. teach that lipids and lipidoid nanoparticles are the most efficacious for gene silencing in the liver (page 84) and Akinc et al. teach lipidoid structures for siRNA delivery (Figure 1) meeting the limitations of instant claim 6. It would have been obvious to incorporate the lipidoids of Akinc et al. into the delivery system of Yan et al. with a reasonable expectation of successful delivery because Akinc et al. teach that the lipidoids facilitate high levels of specific silencing of endogenous gene transcripts when formulated with either double-stranded small interfering RNA (siRNA) (abstract).
Conclusion
Any inquiry concerning this communication or earlier communications from the examiner should be directed to Amy R Hudson whose telephone number is (571)272-0755. The examiner can normally be reached M-F 8:00am-6:00pm.
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, Neil Hammell can be reached at 571-270-5919. 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.
/AMY ROSE HUDSON/Primary Examiner, Art Unit 1636
Prosecution Insights