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 is the first Office action on the merits of the claims.
All citations to the Manual of Patent Examining Procedure (MPEP) refer to Revision 01.2024, which was released in November 2024.
Status of the Claims
In the Preliminary Amendment filed 21 January 2025, Applicant amended claims 9, 13, 17, 20, 23, 28, 32, 34, 38, 43-44, 53, 57, 60-61, 64, and 76-78. Additionally, Applicant cancelled claims 2-8, 11-12, 14-16, 18-19, 21-22, 24-27, 29-31, 36-37, 40-42, 45-52, 54-56, 58-59, 62-63, 65-75, and 79. Claims 1, 9-10, 13, 17, 20, 23, 28, 32-35, 38-39, 43-44, 53, 57, 60-61, 64, and 76-78 are pending and under consideration.
Claim Objections
Claim 77 is objected to because of the following informality: the phrase “in said mammal” needs to be replaced with: “to said mammal.” Appropriate correction is required.
Claim 78 is objected to because of the following informality: the phrase “in said bird” needs to be replaced with: “to said bird.” Appropriate correction is required.
Claim Rejections - 35 U.S.C. 112(b)
The following is a quotation of 35 U.S.C. 112(b):
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.
Claim 32 is rejected under 35 U.S.C. 112(b) as being indefinite for failing to particularly point out and distinctly claim the subject matter that the inventor regards as the invention.
Regarding claim 32, the following functional limitation is unclear: “an excipient that reduces exposure of the RNA to water.” Persons having ordinary skill in the art can reasonably disagree at to which excipients serve the recited function (reducing RNA exposure to water) and, conversely, which do not. MPEP § 2173.05(g) (“the use of functional language in a claim may fail ‘to provide a clear-cut indication of the scope of the subject matter embraced by the claim’ and thus be indefinite”). Therefore, claim 32 is indefinite. See also MPEP § 2173.04 (“a genus claim that could be interpreted in such a way that it is not clear which species are covered would be indefinite (e.g., because there is more than one reasonable interpretation of what species are included in the claim)”).
Claim Rejections - 35 U.S.C. 102(a)
The following is a quotation of the appropriate paragraphs of 35 U.S.C. 102(a) that form the basis for the rejections under this section made in this Office action:
A person shall be entitled to a patent unless
(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; or
(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 1, 23, 32-35, 38-39, 53, 60, 64, and 76-77 are rejected under 35 U.S.C. 102(a)(1) and/or 35 U.S.C. 102(a)(2) as being anticipated by Brader (US 2019/0336452 A1).
Brader is directed to “[s]tabilized formulations of lipid nanoparticles.” Title.
Brader discloses: “In one aspect, the present disclosure provides a stabilized lipid nanoparticle (LNP) formulation comprising a plurality of LNPs and a stabilizing agent that mitigates the degradation of the LNPs or a subpopulation of the LNPs, wherein the LNPs comprise an ionizable lipid and a structural lipid, and the stabilizing agent comprises a cryoprotectant, a chelator, an antioxidant, or any combination thereof. In some embodiments, the stabilizing agent further comprises a surfactant.” Para. [0004]; see also page 62 at claim 1.
Table 4 of Brader (page 60), which is relevant to claim 1 of the present application, is reproduced below:
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Table 5 of Brader (pages 60-61) is similarly relevant, excerpts of which are reproduced on the next page:
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A person having ordinary skill in the art, following a review of Example 1 (Production of Lipid Nanoparticles) at paragraphs [0569]-[0577], would have readily recognized that the mRNA is encapsulated in the LNPs of Tables 4 and 5. See also Table 7 at pages 61-62 (showing data concerning “EE,” which refers to mRNA encapsulation efficiency) and Figure 2A.
Formulations 4-F1, 4-F2, 4-F3, and 4-F4 of Table 4 each comprise the following four excipients: polysorbate 20, ethanol, glycerol, and Tris buffer.
Formulations 6-F1 and 6-F2 of Table 5 each comprise the following three excipients: polysorbate 20, sucrose, and Tris buffer.
Formulations 9-F1 and 9-F2 of Table 5 each comprise the following three excipients: polysorbate 20, sorbitol, and Tris buffer.
Formulations 11-F1 and 11-F2 of Table 5 each comprise the following three excipients: polysorbate 20, sorbitol, and Tris buffer.
Those combinations of excipients stabilize the mRNA-LNPs, as disclosed in paragraphs [0585] and [0586]. See also Figures 20A-20D and 21-25.
Brader discloses that (i) “the formulation is stabilized for at least 2 months at 2 to 8° C” (para. [0162]) and (ii) “the formulation is stabilized for at least two weeks (e.g., at least one month, at least two months, or at least four months) at about 2° C. to about 8° C” (para. [0076]). Additionally (or alternatively), the stability limitation recited in claim 1 (i.e., “a combination of excipients providing stability for at least three months with refrigeration in the range of 2°C – 8°C”) of the present application is inherent. MPEP § 2112.01(I) (“when the structure recited in the reference is substantially identical to that of the claims, claimed properties or functions are presumed to be inherent”).
On the basis of the foregoing disclosure, claims 1, 32-35, and 64 are anticipated by Brader.
Regarding claims 23, 38-39, 53 and 60, Applicant is referred to Example 8 of Brader, which is set forth at paragraphs [0589]-[0595] and Table 7 (pages 61-62), the latter of which shows a corresponding pH of essentially 7.4. MPEP § 2131.03(I) (a specific example in the prior art that is within a claimed range anticipates the range). Paragraph [0592] discloses an mRNA-LNP formulation that comprises: 20 mM Tris Buffer, 5% w/v sucrose, 140 mM NaCl, and 0.4% w/v P188 (poloxamer 188, which is a non-ionic surfactant). The examiner notes that any limitation identified as optional is not required to satisfy the claim. MPEP § 2111 (“During patent examination, the pending claims must be ‘given their broadest reasonable interpretation consistent with the specification.’”).
Regarding claims 76 and 77, Applicant is referred to paragraphs [0091]-[0093], [0509], [0544], [0554] of Brader.
Claim Rejections - 35 U.S.C. 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(a) 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.
Claims 9-10, 13, 17, 28, 43-44, 57, 61, and 78 are rejected under 35 U.S.C. 103 as being unpatentable over Brader (US 2019/0336452 A1) alone or in view of Mousavi (US 2018/0273977 A1).
Brader is discussed above, in the rejection under 35 U.S.C. 102(a)(1) and/or 35 U.S.C. 102(a)(2). That discussion is incorporated by reference into this §103 rejection.
Regarding claims 9-10, 13, 17 and 57, none of the exemplary mRNA-LNP formulations disclosed in Tables 4-5 or Example 8 of Brader comprises an antioxidant. Consequently, Brader does not anticipate claims 9-10, 13, 17, or 57. However, Brader does disclose that “the stabilizing agent comprises a cryoprotectant, a chelator, an antioxidant, or any combination thereof.” (Emphasis added) Para. [0004]. Brader further discloses: “For example, the antioxidant comprises ascorbic acid, citric acid, malic acid, methionine, monothioglycerol, phosphoric acid, potassium metabisulfite, alpha-tocopherol, or any combination thereof.” (Emphasis added) Para. [0041]; see also para. [0180] and claim 71. Before the effective filing date of the claimed invention, the foregoing teachings of Brader would have motivated a person having ordinary skill in the art to attempt to further stabilize any of the exemplary mRNA-LNP formulations set forth in Tables 4-5 or Example 8 by adding thereto ascorbic acid, methionine, or any of the other identified species of antioxidant. MPEP § 2144.07 (the selection of a known material based on its suitability for its intended use can support a prima facie obviousness determination). Therefore, claims 9-10, 13, 17, and 57 are prima facie obvious.
Regarding claim 28, none of the exemplary mRNA-LNP formulations disclosed in Tables 4-5 or Example 8 of Brader comprises a chelator. Consequently, Brader does not anticipate claim 28. However, Brader does disclose that “the stabilizing agent comprises a cryoprotectant, a chelator, an antioxidant, or any combination thereof.” (Emphasis added) Para. [0004]. Brader further discloses: “For example, the chelator comprises diethylenetriamine pentaacetic acid (DTPA), ethylenediaminetetraacetic acid (EDTA), iminodisuccinic acid, polyaspartic acid, ethylenediamine-N,N′-disuccinic acid (EDDS), methylglycinediacetic acid (MGDA), L-glutamic acid N,N-diacetic acid (GLDA), or a salt thereof.” (Emphasis added) Para. [0040]; see also para. [0179] and claim 70. Before the effective filing date of the claimed invention, the foregoing teachings of Brader would have motivated a person having ordinary skill in the art to attempt to further stabilize any of the exemplary mRNA-LNP formulations set forth in Tables 4-5 or Example 8 by adding a chelator thereto. MPEP § 2144.07 (the selection of a known material based on its suitability for its intended use can support a prima facie obviousness determination). Therefore, claim 28 is prima facie obvious.
Regarding claims 43-44, although the exemplary mRNA-LNP formulations disclosed in Example 8 of Brader comprise sodium chloride (paras. [0592]-[0593]), they do not further comprise potassium sulfate, potassium chloride, and/or sodium sulfate. Consequently, Brader does not anticipate claims 43-44. However, Brader (i) identifies both sodium chloride and sodium sulfate as cryoprotectants and (ii) teaches that both those salts can be included in the same mRNA-LNP formulation. Paras. [0168]-[0169]. Therefore, claim 44 is prima facie obvious. MPEP § 2144.06(I) (combining equivalents known for the same purpose). In further regard to claim 43, potassium sulfate is a close analog of sodium sulfate, as both are alkali metal salts having the same counterion. MPEP § 2144.09(I) (rejection based on close structural similarity is founded on the expectation that compounds similar in structure will have similar properties).
Regarding claim 61, Brader (i) identifies both sodium chloride and sorbitol as cryoprotectants and (ii) teaches that both can be included in the same mRNA-LNP formulation. Para. [0168]. Before the effective filing date of the claimed invention, the foregoing teachings of Brader would have motivated a person having ordinary skill in the art to attempt to further stabilize either of the exemplary mRNA-LNP formulations set forth in Example 8 at paragraphs [0592]-[0593] by adding sorbitol thereto. Therefore, claim 61 is prima facie obvious. MPEP § 2144.06(I) (combining equivalents known for the same purpose).
Regarding claim 78, Brader discloses: “Subjects to which administration of the compositions is contemplated include, but are not limited to, humans, other primates, and other mammals, including commercially relevant mammals such as cattle, pigs, hoses, sheep, cats, dogs, mice, and/or rats.” Para. [0509]. A person having ordinary skill in the art, following a review of paragraph [0509], would have readily inferred that the mRNA LNP formulations disclosed in Brader could be administered with a reasonable expectation of success to chickens (or other commercially relevant livestock) raised for agricultural purposes, especially considering chickens — like all birds and other animals — use mRNA to carry genetic instructions from their DNA to their cellular machinery (ribosomes) responsible for building proteins. MPEP § 2144.01 (“[I]n considering the disclosure of a reference, it is proper to take into account not only specific teachings of the reference but also the inferences which one skilled in the art would reasonably be expected to draw therefrom.”). In the alternative, paragraph [0205] of the optional reference (Mousavi) compensates for any deficiency in Brader.
Claim 20 is rejected under 35 U.S.C. 103 as being unpatentable over Brader (US 2019/0336452 A1), as applied above in the §103 rejection of claims 9-10, 13, 17, 28, 43-44, 57, 61 and 78, in view of Rayaprolu (“Excipients in parenteral formulations: selection considerations and effective utilization with small molecules and biologics.” Drug development and industrial pharmacy 44.10 (2018): 1565-1571) and Pramanick (“Excipient selection in parenteral formulation development.” Pharma Times 45.3 (2013): 65-77).
Formulations 9-F1 and 9-F2 of Table 5 of Brader each comprise the following three excipients: polysorbate 20, sorbitol, and Tris buffer as shown below:
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The previous §103 rejection of claims 9-10, 13, 17, and 57 establishes that paragraph [0041], paragraph [0180], and claim 71 of Brader provide sufficient motivation to add the antioxidant methionine to either Formulation 9-F1 or 9-F2 (above). However, Brader is silent regarding glycine and, consequently, does not satisfy claim 20 of the present application. As explained below, the following two references compensate for this deficiency: Rayaprolu and Pramanick.
Rayaprolu teaches: “Sucrose, Trehalose (Sugars), Glycine, Arginine (Amino acids) and Sorbitol, Mannitol (Polyols) serve as both cryo and lyo protectants.” Page 1568, right column.
Pramanick teaches that both sorbitol and glycine are classified as bulking agents that offer lyoprotection. Page 66 at Table 1.
It is worth noting that Brader identifies sorbitol as a cryoprotectant in paragraphs [0015] and [0168].
Before the effective filing date of the claimed invention, the foregoing teachings of Rayaprolu and Pramanick would have motivated a person having ordinary skill in the art to attempt to further stabilize either Formulation 9-F1 or 9-F2 of Brader by substituting glycine for sorbitol in the course of routine experimentation. MPEP § 2144.06(II) (substituting equivalents known for the same purpose). Regarding the respective methionine and glycine concentration ranges recited in claim 20, Applicant is alerted that “[w]here 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.” MPEP § 2144.05(II)(A). In sum, claim 20 is prima facie obvious.
Conclusion
Claims 1, 9-10, 13, 17, 20, 23, 28, 32-35, 38-39, 43-44, 53, 57, 60-61, 64, and 76-78 are rejected.
Claims 77-78 are also objected to.
No claim is allowed.
Any inquiry concerning this communication or earlier communications from the examiner should be directed to PETER ANTHOPOLOS whose telephone number is 571-270-5989. The examiner can normally be reached on Monday – Friday (9:00 am – 5:00 pm). If attempts to reach the examiner by telephone are unsuccessful, the examiner’s supervisor, Bethany P. Barham, can be reached on Monday – Friday (9:00 am – 5:00 pm) at 571-272-6175. The fax number for the organization where this application or proceeding is assigned is 571-273-8300.
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/P.A./
29 May 2026
/BETHANY P BARHAM/Supervisory Patent Examiner, Art Unit 1611
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