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 .
Claim Objections
Claim 20 is objected to because of the following informalities:
Claim 20 recites: “…comprise (i) one or more nucleic acid active agents, (ii) lipid excipients comprising a sterol or derivative thereof, a phospholipid, a stealth lipid, and an amino lipid, and (iii) a GalNAc-lipid receptor targeting conjugate…” in lines 2-4 and then in line 8 recites “…(i) the lipid excipient and (ii) at least a portion of the receptor targeting conjugate…”. For the sake of consistency, the Examiner suggest amending the second phrase to “…(ii) the lipid excipient-s and (iii) at least a portion of the receptor targeting conjugate…” so that the numbering system matches.
Appropriate correction is required.
Claim Rejections - 35 USC § 112(b)
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.
Claims 20, 22-34 and 38-39 are rejected under 35 U.S.C. 112(b) as being indefinite for failing to particularly point out and distinctly claim the subject matter which the inventor or a joint inventor regards as the invention.
Claim 20 recites the limitation "a mixture of the first and second solutions" in line 11. In view of the article “a” before “mixture, it is unclear if this mixture is the same as the mixture of first and second solutions described in step c or a different mixture. The Examiner suggests amending the article “a” to “the” to make such clear and obviate this 112b rejection.
Claims 20 and 25 recite “optionally carrying out one or more dilution, buffer exchange, concentration, filtration, and GalNAc-lipid nanoparticle evaluation processes” in the last 2 lines. It is unclear what is meant by “carrying out…concentration”. Does such mean modifying the concentration of an ingredient and if so, which ingredient(s)? Furthermore, it is unclear what is meant by “carrying out…GalNAc-lipid nanoparticle evaluation processes”. What is being evaluated?
Claims depending from rejected claims have also been rejected because they incorporate all of the limitations of the claims from which they depend, but fail to resolve the indefinite concerns outlined above.
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.
The factual inquiries set forth in Graham v. John Deere Co., 383 U.S. 1, 148 USPQ 459 (1966), that are applied 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 20, 22-33 and 38-39 are rejected under 35 U.S.C. 103 as being unpatentable over Heartlein (US 2016/0184458; published: 6/30/16), in view of Akinc et al. (US 2016/0017330; published: 1/21/16), Burke et al. (US 2013/0037977; published: 2/14/13).
Determination of the Scope and Content of the Prior Art
(MPEP §2141.01)
Heartlein is directed to compositions and methods for producing therapeutic fusion proteins in vivo (Abstract).
With regards to instant claims 20, 24-26, 30, Heartlein teaches the following method: aliquots of 50 mg/mL ethanolic solutions of DODAP (i.e., the claimed amino lipid), DOPE (i.e., the claimed phospholipid, cholesterol (i.e., the claimed sterol or derivative thereof) and DMG-PEG2K (i.e., the claimed stealth lipid) (18:56:20:6) are mixed and diluted with ethanol to 3 mL final volume (i.e., the claimed method step 20b and 25 b). Separately, an aqueous buffered solution (10 mM citrate/150 mM NaCl, pH 4.5) of mRNA (i.e., the claimed one or more nucleic acid active agent) is prepared from a 1 mg/mL stock (i.e., the claimed method step 20a and 25a). The lipid solution is injected rapidly into the aqueous mRNA solution and shaken to yield a final suspension in 20% ethanol (i.e., the claimed method steps 20c-d and 25d-e). The resulting nanoparticle suspension is filtered, diafiltrated with 1×PBS (pH 7.4) (i.e., the claimed buffer exchange process), concentrated and stored at 2-8° C (i.e., the claimed method step 20e and 25f). Final concentration=1.35 mg/mL EPO mRNA (encapsulated). Zave=75.9 nm (Dv(50)=57.3 nm; Dv(90)=92.1 nm) (Example 1, Formulation 2).
With regards to the claimed targeting conjugate, Heartlein teaches active targeting, which involves the use of targeting ligands that may be bound either covalently or non-covalently to the transfer vehicle to encourage localization of such transfer vehicle at certain target cells or target tissues [0121]. Targeting ligands may be linked to the outer bilayer of the lipid particle during formulation or post-formulation, wherein methods are well known in the art [0122]. Suitable ligands and are selected based upon their physical, chemical or biological properties (e.g., selective affinity and/or recognition of target cell surface markers or features) [0123].
With regards to the instant claims 32-33 and 38-39, Heartlein teach that non-cationic lipid (e.g., DOPE) may comprise a molar ratio of 55 to about 90%, or preferably about 10% to about 70% of the total lipid present in the transfer vehicle [0105]; PEG-modified phospholipid and derivatized lipids (e.g., DMG-PEG2k) of the present invention may comprise a molar ratio from about 0% to about 20%, about 0.5% to about 20%, about 1% to about 15%, about 4% to about 10%, or about 2% of the total lipid present in the liposomal transfer vehicle [0106]; and more specifically, MC3, DSPC, cholesterol, PEG-DSG/GalNAc-PEGDSG in a molar ratio of 50:10:35:4.5:0.5 [0108].
Ascertainment of the Difference Between the Scope of the Prior Art and Claims
(MPEP §2141.012)
Heartlein does not teach wherein the targeting ligand is specifically GlaNAc-lipid receptor targeting conjugate, as required by instant claims 20 and 25. However, this deficiency is cured by Akinc.
Akinc is directed to iRNA compositions targeting the Serpinc 1 gene (Abstract). Akinc teaches a dsRNA further comprising a ligand such as N-acetylgalactosamine, wherein the dsRNA is conjugate to said ligand [0014-0015], [0033]. Coupling of GalNAc3 directs the agent to a site of interest, e.g., the liver [0117]. In table 1, Akinc teach a lipid-dsRNA formulation, LNP15 (lipid nanoparticle) comprising (6Z,9Z,28Z,31Z)-heptatriaconta-6,9,28,31-tetraen-19-yl 4-(dimethylamino)butanoate (MC3) (i.e., a cationic lipid) and DSPC/Chol/PEG-DSG/GalNAc-PEG-DSG (Table 1), which is the same PEG-DSG/GalNAc-PEG-DSG taught by Heartlein [0108].
Heartlein and Akinc do not teach the method step of including at least a portion of the receptor targeting conjugate in the claimed second solution before mixing the first and second solution, as required by instant claims 20 and 25.
Furthermore, they do not teach wherein the mixing s performed by an inline mixing apparatus having a first mixing chamber that includes a first port that separately introduces the first solution to the first mixing chamber and a second port that separately and simultaneously introduces the second solution into the first mixing chamber and further comprising adding a second portion of the receptor targeting conjugate after the first solution and the second solution are mixed, wherein the addition of the second portion of the receptor targeting conjugate is pre- dissolved in a water miscible organic solvent and combined with an aqueous solution to form an aqueous dilution buffer that is mixed with the previously mixed first and second solutions in a second mixing chamber conjoined with and downstream from the first mixing chamber of the inline mixing apparatus prior to incubation, as required by instant claims 22-23 and 27-29.
However, such methods were known and routinely used in the prior art as described in Burke. Burke teaches a process for producing lipid nanoparticles encapsulating therapeutic products, said process comprising: a) providing one or more aqueous solutions in one or more reservoirs; b) providing one or more organic solutions in one or more reservoirs, wherein one or more of the organic solutions contains a lipid and wherein one or more of the aqueous solutions and/or one or more of the organic solutions includes therapeutic products; c) mixing said one or more aqueous solutions with said one or more organic solutions in a first mixing region, wherein said first mixing region is a Multi-Inlet Vortex Mixer (MIVM), wherein said one or more aqueous solutions and said one or more organic solutions are introduced tangentially into a mixing chamber within the MIVM so as to substantially instantaneously produce a lipid nanoparticle solution containing lipid nanoparticles encapsulating therapeutic products (See entire reference, e.g., Abstract).
Heartlein does not teach wherein the formulation comprises two or more GalNAc-lipid receptor targeting conjugates, as required by instant claim 31.
Finding of Prima Facie Obviousness Rationale and Motivation
(MPEP §2142-2143)
Since Heartlein teach the basic method of forming the lipid nanoparticle comprising claimed components (i) and (ii) and furthermore, indicate that active targeting can be achieved by binding a targeting ligand either covalently or non-covalently to the transfer vehicle [0121] and wherein the transfer vehicle combined with multiple lipids and/or polymer components can be, for example, MC3, DSPC, cholesterol, PEG-DSG/GalNAc-PEGDSG (an option in a list in [0108]). Akinc teaches that such lipid nanoparticle can targeting the Serpinc1 gene and be used to inhibit expression of Serpinc1, which can be used to treat subjects having a bleeding disorder, such as a hemophilia (See entire reference; e.g., Abstract and Figures). Based on these teachings, it would have been prima facie obvious to one of ordinary skill in the art, before the effective filing date of the claimed invention, to modify the method of Heartlein by further incorporating the GalNAc receptor targeting conjugate to achieve the predictable result of obtaining a biologically effective lipid nanoparticle formulation. One of ordinary skill in the art would have been motivated to do so because Akinc teach that it is advantageous for treating a bleeding disorder such as hemophilia.
It would have been obvious to one of ordinary skill in the art, before the effective filing date of the claimed invention, to modify the method of Heartlein by using an inline mixing apparatus, such as that taught by Burke, to achieve the predictable result of obtaining a lipid nanoparticle with improved process efficiency compared to manual injection and shaking as taught by Heartlein.
The idea for combining compounds each of which is known to be useful for the same purpose, in order to form a composition which is to be used for the same purpose, flows logically from their having been used individually in the prior art. See In re Kerkhoven 626 F.2d 846, 850, 205 USPQ 1069, 1072 (CCPA 1980). As shown by the recited teachings, the instant claims define nothing more than the concomitant use of conventional GalNAc receptor targeting conjugates used in targeted delivery of biologically active agents. It would follow that the recited claims define prima facie obvious subject matter. (See MPEP 2144.06).
From the teachings of the references, it is apparent that one of ordinary skill in the art would have had a reasonable expectation of success in producing the claimed invention. Therefore, the invention as a whole would have been prima facie obvious to one of ordinary skill in the art before the invention was effectively filed, as evidenced by the references, especially in the absence of evidence to the contrary.
Thus, the claimed invention was prima facie obvious before the effective filing date of the claimed invention.
Claim 34 is rejected under 35 U.S.C. 103 as being unpatentable over Heartlein (US 2016/0184458; published: 6/30/16), in view of Akinc et al. (US 2016/0017330; published: 1/21/16) and Burke et al. (US 2013/0037977; published: 2/14/13) as applied to claims 20, 22-33 and 38-39 above, and further in view of Tondera et al. (US 2019/0390195; published: 12/26/19).
Determination of the Scope and Content of the Prior Art
(MPEP §2141.01)
Heartlein, Akinc and Burke teach the limitation of instant claims 20, 22-33 and 38-39 (See above rejection for details
Ascertainment of the Difference Between the Scope of the Prior Art and Claims
(MPEP §2141.012)
Heartlein, Akinc and Burke do not teach wherein the the one or more nucleic acid active agents comprise an mRNA encoding a gene editor nuclease or a base editor and one or more guide RNAs, as required by instant claim 34. However, this deficiency is cured by Tondera.
Tondera is directed to modified guide RNAs (Title). Tondera teaches that lipid nanoparticles may be used to improve the efficacy of the modified guide RNAs for example by increasing cell transfection, increasing the translation of encoded protein or increasing the stability [0094].
Finding of Prima Facie Obviousness Rationale and Motivation
(MPEP §2142-2143)
Heartlein and Tondera et al. are both directed to GalNAc-containing lipid nanoparticle that can be used in biologically active delivery. Based on these teachings, it would have been prima facie obvious to one of ordinary skill in the art, before the effective filing date of the claimed invention, to modify the lipid nanoparticle of Heartlein by further incorporating a modified guide RNA to achieve the predictable result of obtaining a composition suitable for producing biological activity. One of ordinary skill in the art would have been motivated to do so because Tondera teach that it is advantageous for increasing cell transfection, increasing the translation of encoded protein or increasing the stability [0094].
From the teachings of the references, it is apparent that one of ordinary skill in the art would have had a reasonable expectation of success in producing the claimed invention. Therefore, the invention as a whole would have been prima facie obvious to one of ordinary skill in the art before the invention was effectively filed, as evidenced by the references, especially in the absence of evidence to the contrary.
Thus, the claimed invention was prima facie obvious before the effective filing date of the claimed invention.
Conclusion
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/GENEVIEVE S ALLEY/Primary Examiner, Art Unit 1617