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 . 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.
Claim Rejections - 35 USC § 112 –
Scope of Enablement and Prevention
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.
Claim 83 is 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 “treating disorders associated with airway epithelial cell dysfunction or other disorders that would benefit from delivery of nucleic acid molecules or other payload molecules to airway epithelial cells”, does not reasonably provide enablement for “preventing a disease”, generally. 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 the invention commensurate in scope with these claims.
To be enabling, the specification of the patent must teach those skilled in the art how to make and use the full scope of the claimed invention without undue experimentation. In re Wright, 999 F.2d 1557, 1561 (Fed. Cir. 1993). Explaining what is meant by “undue experimentation,” the Federal Circuit has stated:
The test is not merely quantitative, since a considerable amount of experimentation is permissible, if it is merely routine, or if the specification in question provides a reasonable amount of guidance with respect to the direction in which the experimentation should proceed to enable the determination of how to practice a desired embodiment of the claimed invention. PPG v. Guardian, 75 F.3d 1558, 1564 (Fed. Cir. 1996).[1]
The factors that may be considered in determining whether a disclosure would require undue experimentation are set forth by In re Wands, 8 USPQ2d 1400 (CAFC 1988) at 1404 where the court set forth the eight factors to consider when assessing if a disclosure would have required undue experimentation. Citing Ex parte Forman, 230 USPQ 546 (BdApls 1986) at 547 the court recited eight factors:
1) the quantity of experimentation necessary,
2) the amount of direction or guidance provided,
3) the presence or absence of working examples,
4) the nature of the invention,
5) the state of the prior art,
6) the relative skill of those in the art,
7) the predictability of the art, and
8) the breadth of the claims.
These factors are always applied against the background understanding that scope of enablement varies inversely with the degree of unpredictability involved. In re Fisher, 57 CCPA 1099, 1108, 427 F.2d 833, 839, 166 USPQ 18, 24 (1970). Keeping that in mind, the Wands factors are relevant to the instant fact situation for the following reasons:
1. The nature of the invention, state and predictability of the art, and relative
skill level
The invention relates to “treating disorders associated with airway epithelial cell dysfunction or other disorders that would benefit from delivery of nucleic acid molecules or other payload molecules to airway epithelial cells” (Specification, ¶ [0003]). The relative skill of those in the art is high, that of an MD or PHD. That factor is outweighed, however, by the unpredictable nature of the art. As illustrative of the state of the art, the Examiner cites Dean et al, (Trends in Molecular Medicine, October 2017, 23(1), 871-873).
Dean taught that the lungs are capable of repair, but the extent to which this occurs varies widely. Recent data indicate that, following injury, different progenitor cell populations can arise, depending on the molecular environment. In turn, these result in either normal or aberrant alveolar repair [abstract]. At one end of the spectrum, excessive repair can potentially lead to fibrotic lung disease. For instance, idiopathic pulmonary fibrosis (IPF) can result from an aberrant wound healing response; and lung cancer can result from hyperproliferation. At the other end of the spectrum, morbidities in COPD and influenza infection have been linked to a lack of lung tissue repair [page 871, 1st paragraph].
The breadth of the claims
Since the instant specification provides no limiting definition of the term “prevention”, the term will be interpreted expansively. The term “prevention” may vary widely in meaning, from “preventing” a disease from occurring to “preventing” it from progressing. Nor is the term limited by any time frame.
The claims are thus very broad insofar as they suggest that one will not experience the disease when taking the claimed agent; that should one get the disease, it will not worsen; or that following its treatment, it will not recur. While such “prevention” might theoretically be possible under strictly controlled laboratory conditions, as a practical matter it is nearly impossible to achieve in the “real world” in which patients live.
3. The amount of direction or guidance provided and the presence or absence of working examples
The specification provides no direction or guidance for practicing the claimed invention in its “full scope”. No reasonably specific guidance is provided concerning useful protocols for carrying out the invention as claimed, other than “treating disorders associated with airway epithelial cell dysfunction or other disorders that would benefit from delivery of nucleic acid molecules or other payload molecules to airway epithelial cells”, The latter is corroborated by the working examples.
4. The quantity of experimentation necessary
Because of the known unpredictability of the art, and in the absence of experimental evidence, no one skilled in the art would accept the assertion that the instantly claimed agents could be predictably used as inferred by the claim and contemplated by the specification. Accordingly, the instant claims do not comply with the enablement requirement of §112, since to practice the claimed invention in its “full scope” a person of ordinary skill in the art would have to engage in undue experimentation, with no reasonable expectation of success.
Claim Rejections - 35 USC § 112 – Indefiniteness
And Broad Limitation followed by Narrow Limitation
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.
Claims 19-21, 62 are 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.
A broad range or limitation together with a narrow range or limitation that falls within the broad range or limitation (in the same claim) may be considered indefinite if the resulting claim does not clearly set forth the metes and bounds of the patent protection desired. See MPEP § 2173.05(c).
In the present instance, claims 19-21 recite the broad recitation of the alkyl, followed by, in parenthesis, what the alkyl group is bound to, which is the narrower statement of the range/limitation. In some instances, the broad recitation is NH or O, followed by, in parenthesis, the alkyl, heterocycloalkyl or heteroaryl group bound to NH or O.
Regarding claim 62, the Examiner recommends that the claim either recite the name of the lipid, or preferably, the abbreviation, without the parentheses. The Examiner also recommends removing the term “sodium salt” from parentheses, at each instance of occurrence.
The claim(s) are considered indefinite because there is a question or doubt as to whether the feature introduced by such narrower language is (a) merely exemplary of the remainder of the claim, and therefore not required, or (b) a required feature of the claims.
The Examiner notes that parentheses are generally not permitted in the claims. The Examiner recommends removing the parentheses from the claims, at each instance of occurrence.
Claim Rejections - 35 USC § 103 - Obviousness
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.
Claim(s) 1, 3-4, 9, 12, 26, 31, 35, 41, 55, 60-65, 71 and 80-83 are rejected under 35 U.S.C. 103 as being unpatentable over Smith et al (WO 2020/160397 A1).
Smith taught a method of producing a lipid nanoparticle (LNP) formulation, the method comprising: mixing a lipid solution comprising an ionizable lipid with an aqueous buffer solution comprising a first buffering agent, thereby forming a lipid nanoparticle solution comprising a lipid nanoparticle; and, adding a nucleic acid solution comprising a nucleic acid (e.g., reads on payload) to the lipid nanoparticle solution thereby forming a lipid nanoparticle (LNP) formulation comprising the lipid nanoparticle associated with the nucleic acid [claim 1]. At claim 42, the nucleic acid was taught as mRNA. The lipid solution further comprised a phospholipid, a PEG lipid and a structural lipid [claim 90]. The aqueous buffer solution had a pH of about 4.5 [claim 17]. Smith was drawn to targeted delivery [0681] to epithelial cells [0685].
At ¶ [0075], Smith disclosed that aqueous solutions are poor solvents of cationic lipids used in traditional processes of forming nucleic acid-loaded LNPs. In some embodiments, Smith’s LNP comprised a cationic lipid [0565].
Although Smith disclosed the LNPs as comprising cationic lipids, Smith was silent as to whether or not the cationic lipid was added to the composition after the filled nanoparticle was formed, as is instantly recited in claim 1(c). However, it would be prima facie obvious to one of ordinary skill in the art to add the cationic lipid as claimed. The ordinarily skilled artisan would be motivated by Smith’s disclosure that aqueous solutions are poor solvents of cationic lipids.
As previously discussed, it appears that Smith is silent as to when the cationic lipid is added to the LNP. In the interest of completeness of prosecution, purely arguendo, and for the purposes of this ground of rejection only, if Smith is found to add the cationic lipid at any step other than after the prefilled lipid nanoparticle is formed, as claimed, the Examiner notes that it would be prima facie obvious to perform the addition steps in the alternate order as claimed. The selection of any order of mixing ingredients is prima facie obvious. The selection of any order of performing process steps is prima facie obvious in the absence of new or unexpected results. See MPEP 2144.04IVC.
Claim 1 is rendered prima facie obvious over the teachings of Smith, because it is prima facie obvious to combine prior art elements according to known methods, in order to yield predictable results. In the instant case, all the claimed elements (e.g., lipid solution, aqueous buffer, cationic lipid) were known in the prior art (e.g., Smith et al.) and one skilled in the art could have combined the elements as claimed by known methods with no change in their respective functions, and the combination would yield nothing more than predictable results (e.g., a lipid nanoparticle composition) to one of ordinary skill in the art. MPEP 2143.A.
The instant claim 1 recites an aqueous buffer with a pH of about 4.5 or less.
The instant claim 41 recites an aqueous buffer with a pH of about 3.5 to about 4.5.
Smith taught an aqueous buffer with a pH of about 4.5. In the case where the claimed ranges "overlap or lie inside ranges disclosed by the prior art", a prima facie case of obviousness exists. MPEP 2144.05 A.
Smith reads on claims 1, 3, 41 and 71.
Claims 4 and 26 are rendered prima facie obvious because Smith taught that the nucleic acid solution comprises a nucleic acid in a buffer, where an exemplary suitable buffer was ammonium sulfate (e.g., reads on a buffer capable of maintaining acidic pH) [0100].
Claim 9 is rendered prima facie obvious because Smith taught providing an active agent solution having a pH in a range of about 4.5 to about 8.0 comprising a therapeutic and/or prophylactic agent and a lipid nanoparticle solution having a pH of about 4.5 [0007].
The instant claim 9 recites a pH of about 5 to about 6.
Smith taught a pH in a range of about 4.5 to about 8.0. A prima facie case of obviousness exists because of overlap, as discussed above.
Claim 31 is rendered prima facie obvious because Smith taught that the LNPs include surface active agents [0643, 0645, 0670]. Smith was silent as to when in the process of manufacturing the surface-acting agent was added, as recited in claim 31. However, it is prima facie obvious to perform the addition steps in any order, as previously discussed. The selection of any order of mixing ingredients is prima facie obvious. The selection of any order of performing process steps is prima facie obvious, in the absence of new or unexpected results.
Claims 35 and 55 are rendered prima facie obvious because Smith taught filtering [0114, iia], concentrating and adjusting the pH of the LNP solution [claims 75 and 78].
Claims 60-61 are rendered prima facie obvious because Smith taught, at claim 116,
PNG
media_image1.png
210
560
media_image1.png
Greyscale
, wherein R4 is hydrogen, unsubstituted C1-3 alkyl, or -(CH2)nQ, in which Q is -OH [see claim 114] and n is 1, 2, 3, 4 or 5 [see claim 112].
Claim 62 is rendered prima facie obvious because Smith taught DSPC [claim 110].
Claim 63 is rendered prima facie obvious because Smith taught the structural lipid as cholesterol [claim 108].
Claim 64 is rendered prima facie obvious because Smith taught PEG-modified phosphatidylethanolamine [claim 96].
Claim 65 is rendered prima facie obvious because Smith taught wherein the lipid nanoparticle and/or lipid nanoparticle formulation comprised about 30-60 mol % ionizable lipid; about 0-30 mol% phospholipid; about 15-50 mol% structural lipid; and about 0.01-10 mol% PEG lipid [claim 94].
The instant claim 65 recites about 30 mol % to about 60 mol % of ionizable lipid; about 5 mol % to about 15 mol % phospholipid; about 30 mol % to about 50 mol % structural lipid; and about 0.1 mol % to about 2 mol % of PEG-lipid.
Smith taught about 30-60 mol % ionizable lipid; about 0-30 mol% phospholipid; about 15-50 mol% structural lipid; and about 0.01-10 mol% PEG lipid A prima facie case of obviousness exists because of overlap, as discussed above.
Claim 80 is rendered prima facie obvious because Smith taught excipients [0119, 0254, 0643, 0650-0651].
Claims 81-82 are rendered prima facie obvious because Smith taught a lung (e.g., reads on an airway epithelium cell) as a target tissue or cell [0267, 0681, 0685]. Smith’s teachings of epithelial cells as target cells, was previously discussed.
Claim 83 is rendered prima facie obvious because Smith taught administering to a subject, in methods of treating a disease [007, 0009-0010].
Claim(s) 12, 19-20, 22, 24 and 70 are rejected under 35 U.S.C. 103 as being unpatentable over Smith et al (WO 2020/160397 A1), in view of Zhang et al (WO 2019/226925 A1).
The 35 U.S.C. 103 rejection over Smith was previously described.
Additionally, Smith taught a weight ratio of the lipid in the LNP to the therapeutic and/or prophylactic, such as a nucleic acid, at about 5:1 to about 60:1 [0204], wherein the amount of the lipid may vary within ± 10 % of the stated reference, or fall within 1-25 % in either direction of the stated reference [0230]. Although Smith generally taught cationic lipids, Smith did not teach the lipids of claims 19-20, 22 and 24, as instantly recited. Although Smith taught the lipid to therapeutic agent ratio, Smith was not specific the amount of the cationic agent (e.g., cationic lipid, as recited in claim 70.
Zhang taught compositions comprising cationic lipids useful for delivery and expression of mRNA, e.g., as a component of liposomal delivery vehicle (e.g., lipid nanoparticles taught at [0089]), useful for treating various diseases, disorders and conditions [abstract]. Suitable cationic lipids for use in the compositions included cholesterol-based cationic lipids of the following formula:
PNG
media_image2.png
100
313
media_image2.png
Greyscale
, where R1 is an imidazole and R2 is
PNG
media_image3.png
191
365
media_image3.png
Greyscale
(reads on instant claim 19) [0321]. In other embodiments, the cationic lipid was
PNG
media_image4.png
269
612
media_image4.png
Greyscale
(reads on instant claim 20) [0320]; or,
PNG
media_image5.png
266
646
media_image5.png
Greyscale
(reads on instant claim 24, compound SA5) [0322].
Cationic lipids were present in amounts of about 0.5 wt. % to about 30 wt. % [0235].
Since Smith generally taught cationic lipids, in the manufacture of lipid nanoparticles, and for the delivery of mRNA, it would have been prima facie obvious to one of ordinary skill in the art to include, within the teachings of Smith, the cationic lipids of Zhang. The ordinarily skilled artisan would have been motivated to include, within lipid nanoparticles, cationic lipids useful for delivery and expression of mRNA, as taught by Zhang at the abstract. Generally, it is prima facie obvious to select a known material for incorporation into a composition, based on its recognized suitability for its intended use. See MPEP 2144.07. In the instant case, it is prima facie obvious to select Zhang’s lipids for incorporation into lipid nanoparticles, based on their recognized suitability for the intended use as cationic lipids, as taught by Zhang.
It would have been prima facie obvious to one of ordinary skill in the art to include, within Smith, Zhang’s cationic lipids in amounts of about 0.5 wt. % to about 30 wt. %. The ordinarily skilled artisan would have been motivated to include, within Smith, amounts of the cationic lipid that were useful for delivery and expression of mRNA, as taught by Zhang at the abstract (see also Zhang’s teachings at [0214] of the cationic lipid facilitating the delivery of the encapsulated material (e.g., mRNA)).
As to claim 70, the claim requires a weight ratio of the cationic agent to payload at about 1:1 to about 4:1. Smith taught a weight ratio of the lipid in the LNP to the therapeutic and/or prophylactic, such as a nucleic acid, at about 5:1, where the amount of the lipid may vary within ± 10 % of the stated reference, or within 1-25 % in either direction of the stated reference. Zhang taught cationic lipids in amounts of about 0.5 wt. % to about 30 wt. %.
It is noted that no surprising effect has been provided in the present application coming from the claimed specific regimen, if compared with the amounts of the cationic lipid and therapeutic agent of the combined teachings of Smith, in view of Zhang. It is considered that in the absence of any effect linked to such a feature over those known from the prior art, the single structural modification such as variation of dosage regimen belongs to common experimental design that a skilled person, who is aware that for the manufacture of lipid nanoparticles for delivery of mRNA, where the cationic lipid facilitates delivery, the cationic lipids are required, would optimize in routine experiments. In the absence of evidence (experimental comparative data) in the present application showing that the specific amount of cationic lipids possesses an unexpected, surprising effect compared to the regimen known in the prior art, no inventive step can be acknowledged. Where the general conditions of a claim are disclosed in the prior art, it is not inventive to discover the optimum or workable ranges by routine experimentation. See MPEP 2144.05(II)(A). In this case, the general condition of delivery of mRNA by lipid nanoparticles comprising cationic lipids to treat various diseases and conditions, have been taught by the prior art (e.g., Smith and Zhang); as such, it would not have been inventive for the skilled artisan to have discovered the optimum amount of cationic lipids, in ratio with payload, via routine experimentation.
Smith, in view of Zhang, reads on the instant claims 12, 19-20, 22 and 24.
Claim(s) 25 is rejected under 35 U.S.C. 103 as being unpatentable over Smith et al (WO 2020/160397 A1), in view of Dohmen et al (WO 2019/207060 A1).
The 35 U.S.C. 103 rejection over Smith was previously described.
Although Smith generally taught cationic lipids, Smith did not teach the lipid of claim 25, as instantly recited.
Dohmen taught compositions, preferably in the form of lipid nanoparticles [page 33, line 24], suitable for the delivery of RNA, and comprising cholesterol-derivative lipids [abstract], including
PNG
media_image6.png
306
822
media_image6.png
Greyscale
, wherein n is preferably 0, R1 is –(CH2)r-NH-(CH2)s-NH2 and R2 is –(CH2)t-NH2, wherein r, s and t are integers of 2 to 6 [page 45, lines 1-9].
Since Smith taught lipid nanoparticle delivery of mRNA, it would have been prima facie obvious to one of ordinary skill in the art to include, within the teachings of Smith, the lipid of Dohmen. The ordinarily skilled artisan would have been motivated to form a lipid nanoparticle suitable for delivery of RNA, as taught by Dohmen [abstract and page 45 at lines 1-9].
Nonstatutory Double Patenting
A nonstatutory double patenting rejection is appropriate where the conflicting claims are not identical, but at least one examined application claim is not patentably distinct from the reference claim(s) because the examined application claim is either anticipated by, or would have been obvious over, the reference claim(s). See, e.g., In re Berg, 140 F.3d 1428, 46 USPQ2d 1226 (Fed. Cir. 1998); In re Goodman, 11 F.3d 1046, 29 USPQ2d 2010 (Fed. Cir. 1993); In re Longi, 759 F.2d 887, 225 USPQ 645 (Fed. Cir. 1985); In re Van Ornum, 686 F.2d 937, 214 USPQ 761 (CCPA 1982); In re Vogel, 422 F.2d 438, 164 USPQ 619 (CCPA 1970); In re Thorington, 418 F.2d 528, 163 USPQ 644 (CCPA 1969).
A timely filed terminal disclaimer in compliance with 37 CFR 1.321(c) or 1.321(d) may be used to overcome an actual or provisional rejection based on nonstatutory double patenting provided the reference application or patent either is shown to be commonly owned with the examined application, or claims an invention made as a result of activities undertaken within the scope of a joint research agreement. See MPEP § 717.02 for applications subject to examination under the first inventor to file provisions of the AIA as explained in MPEP § 2159. See MPEP § 2146 et seq. for applications not subject to examination under the first inventor to file provisions of the AIA . A terminal disclaimer must be signed in compliance with 37 CFR 1.321(b).
The filing of a terminal disclaimer by itself is not a complete reply to a nonstatutory double patenting (NSDP) rejection. A complete reply requires that the terminal disclaimer be accompanied by a reply requesting reconsideration of the prior Office action. Even where the NSDP rejection is provisional the reply must be complete. See MPEP § 804, subsection I.B.1. For a reply to a non-final Office action, see 37 CFR 1.111(a). For a reply to final Office action, see 37 CFR 1.113(c). A request for reconsideration while not provided for in 37 CFR 1.113(c) may be filed after final for consideration. See MPEP §§ 706.07(e) and 714.13.
The USPTO Internet website contains terminal disclaimer forms which may be used. Please visit www.uspto.gov/patent/patents-forms. The actual filing date of the application in which the form is filed determines what form (e.g., PTO/SB/25, PTO/SB/26, PTO/AIA /25, or PTO/AIA /26) should be used. A web-based eTerminal Disclaimer may be filled out completely online using web-screens. An eTerminal Disclaimer that meets all requirements is auto-processed and approved immediately upon submission. For more information about eTerminal Disclaimers, refer to www.uspto.gov/patents/apply/applying-online/eterminal-disclaimer.
Claims 1, 3-4, 9, 12, 19-26, 31, 35, 41, 55, 60-65, 70-71 and 80-83 are provisionally rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1, 4, 6, 8, 10, 13, 15, 20-22, 30, 40-42, 55, 57, 62-65, 70-71 and 73 of copending Application No. 18/291,707, in view of Smith et al (WO 2020/160397 A1), and further in view of Zhang et al (WO 2019/226925 A1) and Dohmen et al (WO 2019/207060 A1).
Claims 1, 3-4, 9, 12, 19-26, 31, 35, 41, 55, 60-65, 70-71 and 80-83 are provisionally rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1-8, 10-14, 16-17, 19, 22-24 and 41 of copending Application No. 18/682,685, in view of Smith et al (WO 2020/160397 A1), and further in view of Zhang et al (WO 2019/226925 A1) and Dohmen et al (WO 2019/207060 A1).
Claims 1, 3-4, 9, 12, 19-26, 31, 35, 41, 55, 60-65, 70-71 and 80-83 are provisionally rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1-18, 20 and 23 of copending Application No. 18/720,092, in view of Smith et al (WO 2020/160397 A1), and further in view of Zhang et al (WO 2019/226925 A1) and Dohmen et al (WO 2019/207060 A1).
Although the claims at issue are not identical, they are not patentably distinct from each other. The copending claims recite all of the features instantly recited for the lipid nanoparticle except for cationic lipid added after the lipid nanoparticle is formed, mRNA and targeting to epithelial cells [0685].
The instant claims require targeting to epithelial cells, further limited to airway epithelia, cationic lipids and mRNA, and instant claims 12 and 25 further limit the cationic lipids to sterol amines; such ingredients are not recited by the copending claims.
Smith taught a method of producing a lipid nanoparticle (LNP) formulation, the method comprising cationic lipids and mRNA, and was targeted to epithelia, including lung cells. Smith disclosed that aqueous solutions are poor solvents of cationic lipids used in traditional processes of forming nucleic acid-loaded LNPs.
Although Smith disclosed the LNPs as comprising cationic lipids, Smith was silent as to whether or not the cationic lipid was added to the composition after the filled nanoparticle was formed, as is instantly recited in claim 1(c). However, it would be prima facie obvious to one of ordinary skill in the art to add the cationic lipid as claimed. The ordinarily skilled artisan would be motivated by Smith’s disclosure that aqueous solutions are poor solvents of cationic lipids.
As discussed, it appears that Smith is silent as to when the cationic lipid is added to the LNP. In the interest of completeness of prosecution, purely arguendo, and for the purposes of this ground of rejection only, if Smith is found to add the cationic lipid at any step other than after the prefilled lipid nanoparticle is formed, as claimed, the Examiner notes that it would be prima facie obvious to perform the addition steps in the alternate order as claimed. The selection of any order of mixing ingredients is prima facie obvious. The selection of any order of performing process steps is prima facie obvious in the absence of new or unexpected results. See MPEP 2144.04IVC.
Although Smith generally taught cationic lipids, Smith did not teach sterol amines.
Zhang taught compositions comprising cationic lipids, including
PNG
media_image2.png
100
313
media_image2.png
Greyscale
, where R1 is an imidazole and R2 is
PNG
media_image3.png
191
365
media_image3.png
Greyscale
;
PNG
media_image4.png
269
612
media_image4.png
Greyscale
; and/or,
PNG
media_image5.png
266
646
media_image5.png
Greyscale
.
Dohmen taught compositions, preferably in the form of lipid nanoparticles, suitable for the delivery of RNA, comprising
PNG
media_image6.png
306
822
media_image6.png
Greyscale
, wherein n is preferably 0, R1 is –(CH2)r-NH-(CH2)s-NH2 and R2 is –(CH2)t-NH2, wherein r, s and t are integers of 2 to 6.
It would have been prima facie obvious to one of ordinary skill in the art to include, within the copending claims, cationic lipids as taught by Smith, Zhang and Dohmen. The ordinarily skilled artisan would have been motivated to form lipid nanoparticles that facilitated delivery of nucleic acids, as taught by the combined teachings of Smith, Zhang and Dohmen.
Claims 1, 3-4, 9, 12, 19-26, 31, 35, 41, 55, 60-65, 70-71 and 80-83 are provisionally rejected on the ground of nonstatutory double patenting as being unpatentable over claims 45-64 of copending Application No. 18/851,121, in view of Smith et al (WO 2020/160397 A1), and further in view of Zhang et al (WO 2019/226925 A1) and Dohmen et al (WO 2019/207060 A1).
Although the claims at issue are not identical, they are not patentably distinct from each other. The copending claims recite all of the features instantly recited for the lipid nanoparticle except for an ionizable lipid, phospholipid, structural lipid, a PEG-lipid, a cationic lipid added after the lipid nanoparticle is formed, mRNA as the payload and targeting to epithelial cells.
The instant claims require cationic lipids and mRNA, and instant claims 12 and 25 further limit the cationic lipids to sterol amines; such ingredients are not recited by the copending claims.
Smith taught a method of producing a lipid nanoparticle (LNP) formulation, the method comprising: mixing a lipid solution comprising an ionizable lipid with an aqueous buffer solution comprising a first buffering agent thereby forming a lipid nanoparticle solution comprising a lipid nanoparticle; and adding a nucleic acid solution comprising a nucleic acid to the lipid nanoparticle solution thereby forming a lipid nanoparticle (LNP) formulation comprising the lipid nanoparticle associated with the nucleic acid. The nucleic acid was taught as mRNA. The lipid solution further comprised a phospholipid, a PEG lipid and a structural lipid. The aqueous buffer solution had a pH of about 4.5. Smith was drawn to targeted delivery to epithelial cells, including lung cells.
Although Smith disclosed the LNPs as comprising cationic lipids, Smith was silent as to whether or not the cationic lipid was added to the composition after the filled nanoparticle was formed, as is instantly recited in claim 1(c). However, it would be prima facie obvious to one of ordinary skill in the art to add the cationic lipid as claimed. The ordinarily skilled artisan would be motivated by Smith’s disclosure that aqueous solutions are poor solvents of cationic lipids.
As discussed, it appears that Smith is silent as to when the cationic lipid is added to the LNP. In the interest of completeness of prosecution, purely arguendo, and for the purposes of this ground of rejection only, if Smith is found to add the cationic lipid at any step other than after the prefilled lipid nanoparticle is formed, as claimed, the Examiner notes that it would be prima facie obvious to perform the addition steps in the alternate order as claimed. The selection of any order of mixing ingredients is prima facie obvious. The selection of any order of performing process steps is prima facie obvious in the absence of new or unexpected results. See MPEP 2144.04IVC.
Although Smith generally taught cationic lipids, Smith did not teach sterol amines.
Zhang taught compositions comprising cationic lipids, including
PNG
media_image2.png
100
313
media_image2.png
Greyscale
, where R1 is an imidazole and R2 is
PNG
media_image3.png
191
365
media_image3.png
Greyscale
;
PNG
media_image4.png
269
612
media_image4.png
Greyscale
; and/or,
PNG
media_image5.png
266
646
media_image5.png
Greyscale
.
Dohmen taught compositions, preferably in the form of lipid nanoparticles, suitable for the delivery of RNA, comprising
PNG
media_image6.png
306
822
media_image6.png
Greyscale
, wherein n is preferably 0, R1 is –(CH2)r-NH-(CH2)s-NH2 and R2 is –(CH2)t-NH2, wherein r, s and t are integers of 2 to 6.
It would have been prima facie obvious to one of ordinary skill in the art to include, within the copending claims, cationic lipids as taught by Smith, Zhang and Dohmen. The ordinarily skilled artisan would have been motivated to form lipid nanoparticles that facilitated delivery of nucleic acids, as taught by the combined teachings of Smith, Zhang and Dohmen.
These are provisional nonstatutory double patenting rejections, because the patentably indistinct claims have not in fact been patented.
Claim Objections
Claims 21 and 23 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.
Claims 21 and 23 appear to free of the prior art.
Conclusion
Any inquiry concerning this communication or earlier communications from the examiner should be directed to CELESTE A RONEY whose telephone number is (571)272-5192. The examiner can normally be reached Monday-Friday; 8 AM-6 PM.
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, Frederick Krass can be reached at 571-272-0580. 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.
/CELESTE A RONEY/Primary Examiner, Art Unit 1612
[1] As pointed out by the court in In re Angstadt, 537 F.2d 498 at 504 (CCPA 1976), the key word is “undue”, not “experimentation”.