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 .
Status of the Claims
A request for continued examination under 37 CFR 1.114, including the fee set forth in 37 CFR 1.17(e), was filed in this application after final rejection. Since this application is eligible for continued examination under 37 CFR 1.114, and the fee set forth in 37 CFR 1.17(e) has been timely paid, the finality of the previous Office action has been withdrawn pursuant to 37 CFR 1.114. Applicant's submission filed on 02/05/2026 has been entered.
Claims 3-7, 9, 12-13, 15-16, 18-19, 21, 23-24, 26-30, 33, 37-39, 42-43, 45-47, 49, and 51 are cancelled.
Claims 40-41, 44, 48, and 50 are withdrawn.
Claims 1-2, 8, 10-11, 14, 17, 20, 22, 25, 31-32, and 34-36 are under current examination. The claims were read in view of the species elections of (i) the mRNA encodes firefly luciferase, (ii) the lipids are ML-2, DOPE, cholesterol, and DMG-PEG, (iii) the permeability enhancer is sodium caprate, (iv) the mode of rectal delivery is by suppository, and (v) the mode of mucosal delivery is rectal in the reply filed on 05/13/2025.
Rejections and/or objections not reiterated from previous office actions are hereby withdrawn. The following rejections and/or objections are either reiterated or newly applied. They constitute the complete set presently being applied to the instant application.
Information Disclosure Statement
The information disclosure statement (IDS) submitted on 12/12/2025 has been considered by the Examiner.
Claim Interpretation
Applicants have elected the species of a combination of lipids of ML-2, DOPE, cholesterol, and DMG-PEG. As evidenced by Askew et al. (US 2019/0192688 A1; of record), it is interpreted that the lipid ML-2 is known in the art as being synonymous with the lipid cKK-E12, and also known as (3S,6R)-3,6-bis(4-(bis((R)-2-hydroxydodecyl)amino)butyl)piperazine-2,5-dione) (see Askew, paragraphs [0019] and [0293]).
The specification defines “the term "approximately" or "about," as applied to one or more values of interest, refers to a value that is similar to a stated reference value. In certain embodiments, the term "approximately" or "about" refers to a range of values that fall within 25%, 20%, 19%, 18%, 17%, 16%, 15%, 14%, 13%, 12%, 11 %, 10%, 9%, 8%, 7%, 6%, 5%, 4%, 3%, 2%, 1 %, or less in either direction (greater than or less than) of the stated reference value” (paragraph [0065]). The Examiner therefore interprets that values modified by the term “about” are inclusive of values “similar” to that value, as understood by one of ordinary skill in the art.
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 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 1-2, 8, 10-11, 17, 20, 25, 32, and 34-35 are rejected under 35 U.S.C. 103 as being unpatentable over Heartlein et al. (WO 2015/061467 A1, published April 30, 2015; included on IDS submitted 10/14/2022), hereafter “Heartlein” in view of Teng et al. (US 8,377,897 B2, patented February 19, 2013), hereafter “Teng” and Parab et al. (CN 1190001 A, published August 12, 1998; of record), hereafter “Parab”.
Regarding instant claim 1, Heartlein teaches methods of delivering mRNA in vivo including administering to a subject in need of delivery a composition comprising mRNA encoding a protein, encapsulated within a liposome such that the administering of the composition results in the expression of the protein encoded by the mRNA in vivo (see entire document, particularly abstract and claim 1). Suitable routes for delivery include rectal administration (paragraph [0418]). Heartlein further teaches that in some embodiments, the expression of the protein encoded by the mRNA is detectable 1 day, 2 days, 3 days, 4 days, 5 days, 6 days, and/or 7 days in serum or target tissues after a single administration (paragraph [0423]; claims 22-23). Heartlein teaches that delivery encompasses both local and systemic delivery, including situations in which an mRNA is delivered to a target tissue and the encoded protein is expressed and secreted into patient's circulation system (e.g., serum) and systematically distributed and taken up by other tissues (paragraph [0043]), and that liposome size can be selected to facilitate systemic distribution (paragraph [0412]). Heartlein further teaches that in some embodiments, a suitable liposome comprises cKK-E12, DOPE, cholesterol, and DMG-PEG2K (paragraph [0012]), consistent with the elected lipid combination. Condon-optimized firefly luciferase (FFL) is provided as an example of mRNA material that can be delivered (see paragraph [0429] and Examples 1-3 and 6).
Regarding instant claims 2 and 8, as noted above, Heartlein teaches that in some embodiments, a suitable liposome comprises cKK-E12, DOPE, cholesterol, and DMG-PEG2K (paragraph [0012]), consistent with the elected lipid combination; cKK-E12 is a cationic lipid (claim 2), DOPE is a non-cationic lipid, DMG-PEG2K is a PEG-modified lipid, and the liposome of Heartlein comprises cholesterol.
Regarding instant claims 10 and 11, Heartlein teaches that compositions can be supplied in suppository form for rectal application (paragraph [0419]).
Regarding instant claim 25, Heartlein exemplifies a concentration of encapsulated FFL mRNA of approximately 1.31 mg/mL (paragraph [0430]), or greater than 0.25 mg/mL.
Regarding instant claim 34, as noted above, Heartlein teaches that compositions can be supplied in suppository form for rectal application (paragraph [0419])
Regarding instant claim 35, as noted above, Heartlein teaches that the expression of the protein encoded by the mRNA is detectable 1 day, 2 days, 3 days, 4 days, 5 days, 6 days, and/or 7 days in serum or target tissues after a single administration (paragraph [0423]; claim 22). Heartlein further teaches that delivery encompasses both local and systemic delivery, including situations in which an mRNA is delivered to a target tissue and the encoded protein is expressed and secreted into patient's circulation system (e.g., serum) and systematically distributed and taken up by other tissues (paragraph [0043]).
Heartlein does not teach administration by rectal delivery of a permeability enhancer of sodium caprate, the elected species (instant claims 1, 17, and 34) or that the suppository comprises glycerin, gelatin, polyethylene glycol, or a combination thereof (instant claim 20). Heartlein further does not teach that the composition is administered to the subject after 30 minutes from when the permeability enhancer is administered (instant claim 1) or that the permeability enhancer is administered to the subject from about 45 minutes to about 12 hours prior to the administration of the composition (instant claim 32).
Teng teaches compositions and methods which enhance the local and systemic uptake and delivery of oligonucleotides and nucleic acids via non-parental routes of administration such as rectal delivery by suppositories, and teaches the inclusion one or more penetration enhancers for transport of nucleic acids across mucosal membranes (see entire document, particularly abstract and column 27, lines 49-58). Administration via non-parenteral means circumvents complications and expense which may be associated with intravenous and other parenteral modes of administration (column 2, lines 13-16), and absorption of drugs through mucous membranes such as the colon can be an effective route for systemic therapy (column 7, lines 10-16). Compositions can include liposome-containing formulations (column 4, line 65-column 5, line 2). Penetration enhancers facilitate the transport of drug molecules, such as nucleic acids, across mucosal membranes, and are selected such that they do not produce unacceptable side-effects such as toxicity, irritation, or allergic response (column 3, line 63-column 4, line 13 and column 4, lines 46-58). Penetration enhancers include fatty acid salts such as caprate (column 7, line 66-column 8, line 13), and Teng exemplifies the use of sodium caprate as a penetration enhancer (see Example 10 beginning at column 43, particularly Table 16 at column 45). Teng further teaches the inclusion of carriers which do not deleteriously react with nucleic acid including gelatin and water (column 22, lines 47-61), and excipients including gelatin which are selected with the planned manner of administration in mind to provide the desired bulk, consistency, etc. (column 9, lines 50-62).
Parab teaches a method for enhancing the skin penetration of a topically applied pharmacologically active compound comprising sequentially applying a composition comprising an active compound and a composition comprising a penetration enhancer for the active compound so that the active compound is released in a therapeutically effective amount to achieve the desired pharmacological effect (claim 1). One composition is applied within about one to thirty minutes of applying the other composition (claim 9, paragraph [0047]), and either composition may be administered first (paragraph [0048]). The compositions are suitable for use in treatment of the rectal mucosa (paragraph [0072]).
It would have been prima facie obvious to one of ordinary skill in the art before the effective filing date of the instant invention to modify the method of Heartlein to administer a permeability enhancer of sodium caprate, as suggested by Teng. One of ordinary skill in the art would have been motivated to do so with a reasonable expectation of success in order to administer a component that facilitates the transport of nucleic acids across mucous membranes via rectal delivery while avoiding unwanted side effects such as toxicity and irritation, as suggested by Teng. There is a reasonable expectation of success as Heartlein teaches methods of administering a composition comprising liposomal mRNA via rectal delivery, and Teng similarly teaches the administration of nucleic acids, such as by liposomal formulations, by rectal delivery; modification of the method of Heartlein with the administration of sodium caprate suggested by Teng would predictably result in a method that facilitates transport of the mRNA particles across mucous membranes of the rectum.
It would further have been prima facie obvious to one of ordinary skill in the art before the effective filing date of the instant invention to modify the method of Heartlein to incorporate gelatin into the administered suppository, as suggested by Teng. One of ordinary skill in the art would have been motivated to do so with a reasonable expectation of success in order to incorporate a carrier that is known to be compatible with nucleic acid and can provide the desired bulk and consistency in formulations for rectal administration via suppository, as suggested by Teng. There is a reasonable expectation of success as Heartlein teaches methods of administering a composition mRNA via rectal delivery.
It would further have been prima facie obvious to one of ordinary skill in the art before the effective filing date of the instant invention to administer the permeability enhancer about 30 minutes prior to administering the composition comprising mRNA, as suggested by Parab. One of ordinary skill in the art would have been motivated to do so with a reasonable expectation of success in order to administer the components in a manner that achieves the desired pharmacological effect while avoiding potential drug instability and degradation upon storage with the penetration enhancer, as suggested by Parab (claim 1, paragraph [0047]). There is a reasonable expectation of success as the combination of Heartlein and Teng teaches administration of liposomes comprising mRNA and a permeation enhancer of sodium caprate via rectal delivery; modification of the method of Heartlein in view of Teng to administer the permeation enhancer about 30 minutes prior to administration of the mRNA composition, as suggested by Parab, would predictably result in enhanced permeation of the mRNA particles while avoiding potential degradation of the mRNA.
The “about 1 to 30” suggested by Parab is interpreted as overlapping or close to the “after 30 minutes” recited in instant claim 1 and the “about 45” minutes recited in instant claim 32. Per MPEP 2144.05 I. “In the case where the claimed ranges "overlap or lie inside ranges disclosed by the prior art" a prima facie case of obviousness exists. In re Wertheim, 541 F.2d 257, 191 USPQ 90 (CCPA 1976); In re Woodruff, 919 F.2d 1575, 16 USPQ2d 1934 (Fed. Cir. 1990)” and “Similarly, a prima facie case of obviousness exists where the claimed ranges or amounts do not overlap with the prior art but are merely close. Titanium Metals Corp. of America v. Banner, 778 F.2d 775, 783, 227 USPQ 773, 779 (Fed. Cir. 1985)”.
Further, as noted above, Parab suggests separate administration of the compositions to avoid degradation of an active ingredient, and Heartlein teaches that mRNA is prone to degradation (paragraphs [0374] and [0410]). One of ordinary skill in the art would thus be motivated to routinely optimize the administration timing conditions, as suggested by Parab, to avoid such degradation. Per MPEP 2144.05 II. A. “"[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." In re Aller, 220 F.2d 454, 456, 105 USPQ 233, 235 (CCPA 1955)”.
Claim 14 is rejected under 35 U.S.C. 103 as being unpatentable over Heartlein in view of Teng and Parab as applied to claims 1-2, 8, 10-11, 17, 20, 25, 32, and 34-35 above, and further in view of Harwood et al. (US 4,439,194, patented March 27, 1984).
The teachings of the modified Heartlein are described above. As noted above, Teng teaches the inclusion of carriers including water and gelatin; Teng further teaches that formulations can be an aqueous suspension (column 22, lines 62-67). Teng further teaches that cocoa butter is known to be used as a base in suppositories (column 27, lines 49-58); cocoa butter is also called theobroma oil.
The combination of Heartlein, Teng, and Parab does not teach the limitation of instant claim 14 that the suppository melts at between 36 °C and 37 °C within 30 minutes of being administered to the subject.
Harwood teaches a rectal suppository comprising an aqueous core in a waxy housing of theobroma oil which melts at body temperature, specifically 35-37 °C (see entire document, particularly claims 1-2). As the waxy housing is taught to melt at body temperature, it is interpreted that it will begin melting upon administration (within 30 minutes) to a subject. The suppository can include a matrix of drug (column 2, lines 50-54) and water soluble/dispersible ingredients such as gelatin (column 4, lines 28-34).
It would have been prima facie obvious to one of ordinary skill in the art before the effective filing date of the instant invention to modify the administered suppository in the method of Heartlein in view of Teng and Parab to melt at a temperature 35-37 °C upon administration, as suggested by Harwood. One of ordinary skill in the art would have been motivated to do so with a reasonable expectation of success in order to formulate a drug delivery system that melts at body temperature, thus can effectively deliver active ingredients and aqueous components to environments low in body fluid volume (see column 1, lines 6-10). There is a reasonable expectation of success as Teng suggests the inclusion of cocoa butter (theobroma oil) in suppository formulations, and Harwood similarly teaches that theobroma oil is used in rectal suppositories and melts at body temperature.
Claims 22, 31, and 36 are rejected under 35 U.S.C. 103 as being unpatentable over Heartlein in view of Teng and Parab as applied to claims 1-2, 8, 10-11, 17, 20, 25, 32, and 34-35 above, and further in view of Coulter et al. (WO 2011/018504 A2, published February 17, 2011; of record), hereafter “Coulter”.
The teachings of the modified Heartlein are described above. Teng further teaches that the therapeutically active compound is present at a concentration of about 0.5 to about 95% by weight and compositions are formulated in a conventional manner using carriers or excipients as appropriate (column 28, line 64-column 29, line 3), suggesting that carriers such as gelatin may make up the remainder of the formulation, up to 99.5%.
However, the combination of Heartlein, Teng, and Parab does not explicitly provide motivation to adjust the amount of gelatin (instant claims 22 and 31) and does not teach the incorporation of glycerin and/or PEG in suppository formulations (instant claim 36).
Coulter teaches a pharmaceutical composition comprising a water-soluble polymer matrix in which are dispersed droplets of oil, the composition comprising at least one immunomodulator selected from an adjuvant, an antigen or a combination thereof (abstract, claim 1). The composition is brought into contact with a mucosal surface, such as a rectal surface (paragraph [00408]) and may be in the form of a suppository (paragraph [0068], claim 29). Examples of adjuvants and antigens include nucleic acids such as RNA (paragraph [00109]) and emulsion particles can have a lipid composition (paragraphs [0022], [00126]). The water soluble polymer is in particular selected from gelatin or agar (claim 14, paragraph [00210]), and the water soluble polymer matrix, e.g. gelatin, may assist in maintaining particles within the desired size range and preventing their aggregation or coalescence (paragraph [00242]). While Coulter teaches that a typical gelatin solution comprises 15-25% gelatin and water (paragraph [00252]), they further teach that the amount of gelatin affects the bloom strength, a measure of the strength of a gel (paragraphs [00214]-[00215]), and suggest that the content of gelatin affects the solidification and processing temperatures (paragraphs [00218] and [00253]). Coulter further teaches the addition of a plasticizer such as glycerin to achieve enhanced softness and flexibility of gelatin materials and to optimize dissolution (paragraph [00219]).
It would have been prima facie obvious to one of ordinary skill in the art before the effective filing date of the instant invention to routinely optimize the amount of gelatin in the administered suppository in the method of Heartlein in view of Teng and Parab within the general conditions taught by Teng and arrive at a concentration consistent with that of instant claims 22 and 31. One of ordinary skill in the art would have been motivated to do so to achieve a desired gel strength, solidification temperature, and processing temperature and achieve a matrix capable of maintaining lipid particles within a desired size range without aggregation, as suggested by Coulter. Per MPEP 2144.05 II. A., “Generally, differences in concentration or temperature will not support the patentability of subject matter encompassed by the prior art unless there is evidence indicating such concentration or temperature is critical. "[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." In re Aller, 220 F.2d 454, 456, 105 USPQ 233, 235 (CCPA 1955)”.
It would further have been prima facie obvious to one of ordinary skill in the art before the effective filing date of the instant invention to include glycerin as a plasticizer in the administered gelatin-based suppository, as suggested by Coulter. One of ordinary skill in the art would have been motivated to do so in order to achieve enhanced softness and flexibility of gelatin materials and to optimize dissolution, as suggested by Coulter. There is a reasonable expectation of success as the combined teachings of Heartlein, Teng, and Parab arrive at the administration of a gelatin-containing suppository, and, as noted above, Teng suggests the inclusion of excipients to achieve a desired consistency.
Response to Arguments
Applicant's arguments filed 02/05/2026 have been fully considered.
Regarding the claim rejections under 35 USC § 103, Applicant argues that the previously applied references of Heartlein and Teng fail to render obvious a method for providing systemic distribution of mRNA that involves administering to a subject, by rectal delivery, a permeability enhancer and a composition comprising a liposome encapsulating the mRNA. Applicant argues that Heartlein expressly states that local administration of a suppository by rectal delivery precludes the protein encoded by the mRNA from being present (and thus detectable) in the subject's circulation, citing to paragraphs [0419] and [0051]. Applicant argues that Teng fails to cure these deficiencies, and the applied references also fail to render obvious the amended claim limitation of prior administration of the permeability enhancer.
In response, the Examiner first notes that, as detailed above, the previous rejections under 35 USC § 103 have been withdrawn and new rejections which address the amended claim limitations are set forth above. The Examiner further draws attention to the fact that the newly applied reference of Teng (US 8,377,897 B2) is distinct from the previously applied Teng reference (WO 03/018134 A2).
Regarding Heartlein, the Examiner respectfully maintains that Heartlein reasonably suggest to one of ordinary skill in the art that the liposomal mRNA can be administered by rectal delivery (paragraph [0418]), and that delivery encompasses systemic delivery including “situations in which an mRNA is delivered to a target tissue and the encoded protein is expressed and secreted into patient's circulation system (e.g., serum) and systematically distributed and taken up by other tissues” (paragraph [0043]), indicating that even if delivery occurs to a target tissue, the encoded protein can be secreted to the circulation system. Heartlein further suggests that parameters other than the delivery method, such as liposome size, can be utilized to facilitate systemic distribution (paragraph [0412]). Paragraph [0419] provides a general teaching of ways that local delivery can be achieved, but state that this is “alternately or additionally” to other means of delivery. The Examiner further notes that this same language appears in the instant specification at paragraph [0288].
Further, the test for obviousness is not the claimed invention must be expressly suggested in any one or all of the references. Rather, the test is what the combined teachings of the references would have suggested to those of ordinary skill in the art. See In re Keller, 642 F.2d 413, 208 USPQ 871 (CCPA 1981). The newly cited prior art of Teng similarly teaches the local and systemic uptake of nucleic acids via non-parenteral routes such as rectal administration (abstract) of rectal suppositories (column 27, lines 49-58) and that absorption of drugs through mucous membranes such as the colon can be an effective route for systemic therapy (column 7, lines 10-16). When viewing the prior art as a whole, the teachings of the prior art suggest to an ordinary skilled artisan that systemic distribution can be achieved by rectal delivery of suppositories.
Regarding the cited prior art of Parab, Applicant argues that Parab does not permit its drug to be administered after 30 minutes from when its penetration enhancer is administered as it instead requires a shorter period of time (which cannot exceed 30 minutes), citing to paragraphs [0007] and [0049], and thus fails to cure the deficiencies of Heartlein and Teng regarding the timing of the administration of the permeability enhancer.
These arguments are unpersuasive. The Examiner respectfully maintains that Parab teaches administration of the compositions within “about 1 to 30 minutes” of each other (claim 9), and that about 30 minutes is consistent with the “after 30 minutes” of independent claim 1 and the “about 45 minutes” of claim 32. Further, as set forth above, Parab suggests separate administration of the compositions to avoid degradation of an active ingredient, and Heartlein teaches that mRNA is prone to degradation (paragraphs [0374] and [0410]). One of ordinary skill in the art would thus be motivated to routinely optimize the administration timing conditions, as suggested by Parab, to avoid such degradation. Per MPEP 2144.05 II. A. “"[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." In re Aller, 220 F.2d 454, 456, 105 USPQ 233, 235 (CCPA 1955)”. The Examiner notes that a prima facie case of obviousness can be rebutted by showing the criticality of a claimed range (see MPEP 2144.05 III. A.), but no evidence is currently of record demonstrating the criticality of the claimed “after 30 minutes”.
Conclusion
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/J.M.K./Examiner, Art Unit 1611
/TREVOR LOVE/Primary Examiner, Art Unit 1611
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