Notice of Pre-AIA or AIA Status
The present application is being examined under the pre-AIA first to invent provisions.
DETAILED ACTION
Applicant’s amendments and remarks filed on February 11, 2026 are acknowledged. Claims 2, 25, 28, and 30-54 have been canceled. Claims 1 and 26 were amended. Claims 1, 3-24, 26, 27, 29, and 55-57 are pending and are examined on the merits herein.
Priority
This application claims priority to PCT/US2020/033156 filed on May 15, 2020 which claims priority to U.S. provisional application 62/911,512, filed on October 7, 2019 and U.S. provisional application 62/849,605 filed on May 17, 2019.
Withdrawn Objections
In view of Applicant’s amendments and response, the objection to the specification is withdrawn.
Claim Rejections - 35 USC § 112
The following is a quotation of the first paragraph of 35 U.S.C. 112(a):
(a) IN GENERAL.—The specification shall contain a written description of the invention, and of the manner and process of making and using it, in such full, clear, concise, and exact terms as to enable any person skilled in the art to which it pertains, or with which it is most nearly connected, to make and use the same, and shall set forth the best mode contemplated by the inventor or joint inventor of carrying out the invention.
The following is a quotation of the first paragraph of pre-AIA 35 U.S.C. 112:
The specification shall contain a written description of the invention, and of the manner and process of making and using it, in such full, clear, concise, and exact terms as to enable any person skilled in the art to which it pertains, or with which it is most nearly connected, to make and use the same, and shall set forth the best mode contemplated by the inventor of carrying out his invention.
Claims 1, 3-24, 26, 27, 29, and 55-57 are rejected under 35 U.S.C. 112(a) or 35 U.S.C. 112 (pre-AIA ), first paragraph, because the specification, while being enabling for a method for reducing or inhibiting the expression of a target gene in a subject comprising orally administering to the subject in need thereof a formulation comprising a double-stranded iRNA agent and a penetration enhancer wherein the penetration enhancer is capric acid, lauric acid, or oleic acid, a pharmaceutically acceptable salt thereof, or a mixture thereof, does not reasonably provide enablement for a method for reducing or inhibiting the expression of a target gene in a subject comprising orally administering to the subject in need thereof a formulation comprising a double-stranded iRNA agent and a penetration enhancer wherein the penetration enhancer is any other C8-C18 saturated or unsaturated fatty acid. The specification does not enable any person skilled in the art to which it pertains, or with which it is most nearly connected, to use the invention commensurate in scope with these claims.
There are many factors to be considered when determining whether there is sufficient evidence to support a determination that a disclosure does not satisfy the enablement requirement and whether any necessary experimentation is "undue". These factors include, but are not limited to: (A) The breadth of the claims; (B) The nature of the invention; (C) The state of the prior art; (D) The level of one of ordinary skill; (E) The level of predictability in the art; (F) The amount of direction provided by the inventor; (G) The existence of working examples; and (H) The quantity of experimentation needed to make or use the invention based on the content of the disclosure. All of the Wands factors have been considered with regard to the instant claims, with the most relevant factors discussed below.
Breadth of claims and nature of the invention:
Claims 1, 3-24, 26, 27, 29, and 55-57 are drawn to a method for reducing or inhibiting the expression of a target gene in a subject comprising orally administering to the subject in need thereof a formulation comprising a double-stranded iRNA agent and a penetration enhancer wherein the penetration enhancer is a C8-C18 saturated or unsaturated fatty acid, a pharmaceutically acceptable salt thereof, or a mixture thereof. The broadest reasonable interpretation of claim 1 is that the method encompasses reducing or inhibiting the expression of a target gene in a subject comprising orally administering to the subject in need thereof a formulation comprising a double-stranded iRNA agent and a penetration enhancer wherein the penetration enhancer is any C8-C18 saturated or unsaturated fatty acid, a pharmaceutically acceptable salt thereof, or a mixture thereof.
State of the prior art, level of predictability in the art, and level of one of ordinary skill:
A review of the prior art shows that oral delivery of antisense oligonucleotides is underdeveloped.
O’Driscoll et al. (European Journal of Pharmaceutical Sciences 2019; reference previously cited by the Examiner) discloses that the delivery of nucleic acids, in particular by the oral route, remains a major hurdle [abstract]. Specifically, nucleic acids administered by the oral route must overcome physicochemical and physiological barriers [page 201, third paragraph]. Further, O’Driscoll et al. discloses that it is difficult at this stage to provide a clear timeline for clinical translation of oral nucleic acid therapeutics as many formulation and regulatory barriers remain outstanding, however existing pre-clinical data look convincing and particularly promising for local delivery [page 201, fifth paragraph].
Maher et al. (Pharmaceutics 2019; reference previously cited by the Examiner) discloses that the use of chemical permeation enhancers is one of the simplest and widely tested approaches to improve transmucosal permeability via oral, nasal, buccal, ocular and pulmonary routes. To date, only a small number of permeation enhancers have progressed to clinical trials, and only one product that includes a permeation enhancer has reached the pharmaceutical market [abstract]. Further, even in oral formulations that have advanced in clinical trials, the persistence of generally low and variable drug absorption hampers progress [page 2, first full paragraph].
Although post-filing, Crooke et al. (J. Biol. Chem. 2021; reference previously cited by the Examiner) discloses that a key final step remains and that is the development of commercially attractive oral formulations, but current clinical trials of new oral formulations suggest that this route of administration may be feasible [page 32, left column, second full paragraph].
Amount of direction provided by the inventor and existence of working examples:
Working example 2A evaluated in vivo oral delivery of the formulation containing GalNAc-siRNA conjugates in mice wherein a siRNA targeting F12 ELF with GalNAc conjugate and a 5’-vinyl phosphonate modification was used. Working example 2A demonstrated that the formulation containing the penetration enhancer C10 had a significantly better activity than the formulation without C10. In addition, the formulation containing the GalNAc-conjugated siRNA had a significantly better activity than the formulation containing the unconjugated siRNA.
Working example 2B evaluated in vivo oral delivery of the formulation containing GalNAc-siRNA conjugates in mice wherein a siRNA targeting F12 with GalNAc conjugate and a 5’-vinyl phosphonate modification was used. Working example 2B demonstrated that GalNAc conjugation significantly improved activity after oral gavage. In addition, VP modification at the 5’-end of the antisense strand of the GalNAc-siRNA has a minimal effect on the activity of the liver-targeting GalNAc-siRNA in oral delivery.
Working example 3A evaluated in vivo oral delivery of the formulation containing GalNAc-siRNA conjugates in non-human primates wherein non-human primates were orally administered a formulation containing a GalNAc-siRNA with 150 mM C10. The relative F12 levels following oral delivery is shown in Figure 10 (reproduced below).
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Working example 3B evaluated in vivo oral delivery of the formulation containing GalNAc-siRNA conjugates in non-human primates wherein siRNAs targeting F12 or TTR with GalNAc conjugate and a 5’-VP modification were used. Robust and durable reduction in circulating F12 and TTR following oral gavage was observed.
Working example 4A evaluated various intestinal penetration enhancers including sodium salt of caprylic acid, capric acid, lauric acid, and oleic acid and the results are shown in Figure 18 (reproduced below).
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Working example 4B also evaluated various intestinal penetration enhancers including SNAC, EDTA, C8, C10, C12, and C18:1 and demonstrated that maximum KD was achieved through oral administration of a formulation containing GalNAc-siRNA with 75 mM of C10, C12, or C18:1 wherein the level of KD was greater and more durable than that obtained from a subcutaneous administration of the same GalNAc-siRNA when the formulation contained any of these three penetration enhancers.
As evidenced by the instant specification, not all fatty acids are capable of providing sufficient penetration enhancing function effective to deliver the double-stranded iRNA agent. Specifically, as shown in Figure 23 (reproduced below), the C8 penetration enhancer does not provide the function of reducing or inhibiting expression of a target gene.
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Quantity of experimentation:
The quantity of experimentation necessary to make and use the full scope of the claimed invention is high. One of skill would be required to determine the functionality of each penetration enhancer compound because one would not know beforehand whether or not the particular compound would provide the claimed function. Furthermore, success with one penetration enhancer compound does not translate to success with another penetration enhancer compound.
In view of the breadth of the claims which embrace reducing or inhibiting the expression of a target gene in a subject comprising orally administering to the subject in need thereof a formulation comprising a double-stranded iRNA agent and a penetration enhancer wherein the penetration enhancer is any C8-C18 saturated or unsaturated fatty acid, a pharmaceutically acceptable salt thereof, or a mixture thereof, the state and level of predictability in the art, and the failure to provide adequate guidance to overcome the state and level of predictability of the art, the experimentation required to make and use the full scope of the invention would be undue.
Response to Arguments
Applicant's arguments filed February 11, 2026 have been fully considered but they are not persuasive.
Applicant asserts that the specification enables fatty acids or salts thereof having a chain length of C8 because the specification provides working examples of oral formulations comprising four chain-length species for the fatty acids (C8, C10, C12, and C18:1) to demonstrate effective silencing activities. Applicant further asserts that Example 4B and Figure 23 were provided to report a PD study in mice directed to identifying which penetration enhancer containing oral formulation produced the maximum KD at a specific dosing regimen. Thus, the data in Example 4B compared the relative performance of different penetration enhancers to determine which produced the greatest and most durable KD. Applicant further asserts that the fact that certain penetration enhancers did not provide the maximum and most desirable KD does not establish that those penetration enhancers are ineffective or incapable of providing any level of KD. Applicant points to Example 4A and Figures 18-22 demonstrating that C8, C10, C12, and C18:1 produced at least some level of KD and effective silencing activities. Further, Applicant asserts that the claims are directed to a narrowly defined subset of penetration enhancers with a limited breadth. Specifically, Applicant is only claiming fatty acids or salts thereof having a specific chain length range of C8-C18. Given the narrow, specific nature of the claimed penetration enhancers, Applicant asserts that the specification provides more than sufficient guidance to enable one skilled in the art to practice the claimed invention without undue experimentation because the working examples include C8, C10, C12, C18:1, and one mixture of C10+C8 which is representative of and span the full scope of the claimed genus.
These arguments are not found persuasive. Although the working examples tested C8, C10, C12, and C18:1 as Applicant asserts, the specification discloses that Figure 23 shows that maximum KD was achieved through oral administration of a formulation containing GalNAc-siRNA with 75 mM of C10, C12, or C18:1. Specifically, the level of KD was greater and more durable in formulations containing any of these three penetration enhancers than that obtained from a subcutaneous administration of the same GalNAc-siRNA. Furthermore, the specification discloses that oral administration of a formulation containing GalNAc-siRNA with 75 mM of SNAC or C8 did not appear to have a significant impact on the plasma F12 level at this dosing regimen [0787]. Although varying levels of KD was achieved using C10, C12, or C18:1; however, it is evident from Figure 23 that C8 did not reduce or inhibit expression of a target gene. In working example 4A, various intestinal penetration enhancers were used including the sodium salt of C8, C10, C12, and C18:1 [0779]. The Examiner agrees with Applicant’s assertions that the results in Figures 18-22 show that the penetration enhancers tested did produce some level of KD; however, success with one penetration enhancer compound does not translate to success with another penetration enhancer compound as evident by the results obtained with C8 in Figure 23 and the sodium salt of C8 in Figure 18.
Claim Rejections - 35 USC § 103
In the event the determination of the status of the application as subject to AIA 35 U.S.C. 102 and 103 (or as subject to pre-AIA 35 U.S.C. 102 and 103) is incorrect, any correction of the statutory basis (i.e., changing from AIA to pre-AIA ) for the rejection will not be considered a new ground of rejection if the prior art relied upon, and the rationale supporting the rejection, would be the same under either status.
The following is a quotation of 35 U.S.C. 103 which forms the basis for all obviousness rejections set forth in this Office action:
A patent for a claimed invention may not be obtained, notwithstanding that the claimed invention is not identically disclosed as set forth in section 102, if the differences between the claimed invention and the prior art are such that the claimed invention as a whole would have been obvious before the effective filing date of the claimed invention to a person having ordinary skill in the art to which the claimed invention pertains. Patentability shall not be negated by the manner in which the invention was made.
The factual inquiries for establishing a background for determining obviousness under 35 U.S.C. 103 are summarized as follows:
1. Determining the scope and contents of the prior art.
2. Ascertaining the differences between the prior art and the claims at issue.
3. Resolving the level of ordinary skill in the pertinent art.
4. Considering objective evidence present in the application indicating obviousness or nonobviousness.
This application currently names joint inventors. In considering patentability of the claims the examiner presumes that the subject matter of the various claims was commonly owned as of the effective filing date of the claimed invention(s) absent any evidence to the contrary. Applicant is advised of the obligation under 37 CFR 1.56 to point out the inventor and effective filing dates of each claim that was not commonly owned as of the effective filing date of the later invention in order for the examiner to consider the applicability of 35 U.S.C. 102(b)(2)(C) for any potential 35 U.S.C. 102(a)(2) prior art against the later invention.
Claims 1, 3-4, 7-12, 16-24, 26, 27, 29, and 55-57 are rejected under 35 U.S.C. 103 as being unpatentable over Sehgal et al. (US 9,574,192; reference previously cited by the Examiner) in view of Tillman et al. (Journal of Pharmaceutical Sciences 2008; reference previously cited by the Examiner).
Regarding claims 1, 3-4, 22-24, 26, 27, and 55-57, Sehgal et al. teaches RNAi agents, e.g., double-stranded RNAi agents, targeting the Serpina1 gene, and methods of using such RNAi agents to inhibit expression of Serpina1 and methods of treating subjects having a Serpina1 associated disease, such as a liver disorder [abstract]. Sehgal et al. teaches that the double stranded RNAi agents comprise a sense strand and an antisense strand forming a double stranded region wherein substantially all of the nucleotides of the sense strand comprise a modification selected from the group consisting of a 2′-O-methyl modification and a 2′-fluoro modification and wherein substantially all of the nucleotides of the antisense strand comprise a modification selected from the group consisting of a 2′-O-methyl modification and a 2′-fluoro modification [column 7, tenth paragraph]. See e.g. claim 24 which discloses a dsRNA agent with twenty one 2’-OMe nucleotides. Sehgal et al. also teaches that the pharmaceutical compositions can be administered in a number of ways depending upon whether local or systemic treatment is desired and upon the area to be treated (e.g., oral administration) [column 66, last paragraph bridging to column 67]. Further, Sehgal et al. teaches that oral formulations are those in which dsRNAs are administered in conjunction with one or more penetration enhancer surfactants and chelators. Suitable surfactants include fatty acids and/or esters or salts thereof, bile acids and/or salts thereof [column 84, first paragraph]. Sehgal et al. also teaches that the ligand is one or more GalNAc derivatives attached through a bivalent or trivalent branched linker. The ligand is shown below and attached to the 3’ end of the sense strand
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[column 4, last paragraph and column 5, first paragraph]. Sehgal et al. teaches that the pharmaceutical compositions may be administered in dosages sufficient to inhibit expression of a Serpina1 gene. In general, a suitable dose of an iRNA will be in the range of about 0.001 to about 200.0 milligrams per kilogram body weight of the recipient per day, generally in the range of about 1 to 50 mg per kilogram body weight per day [column 62, fourth full paragraph]. Sehgal et al. also teaches that oral formulations are those in which dsRNAs are administered in conjunction with one or more penetration enhancer surfactants and chelators. Suitable surfactants include fatty acids and/or esters or salts thereof, bile acids and/or salts thereof. Suitable fatty acids include arachidonic acid, undecanoic acid, oleic acid, lauric acid, capric acid, myristic acid, palmitic acid, stearic acid, linoleic acid, linolenic acid, dicaprate, tricaprate, monoolein, dilaurin, glyceryl 1-monocaprate, 1-dodecylazacycloheptan-2-one, an acylcarnitine, an acylcholine, or a monoglyceride, a diglyceride or a pharmaceutically acceptable salt thereof (e.g., sodium) [column 84, first paragraph].
Regarding claims 7-8, Sehgal et al. teaches that the pharmaceutical composition can be administered once daily or as two, three, or more sub-doses [column 66, second paragraph].
Regarding claims 9-12, Sehgal et al. teaches that the sense strand has a total of 21 nucleotides and the antisense strand has a total of 23 nucleotides [column 7, lines 10-12]. Sehgal et al. also teaches that at least one strand comprises a 3′ overhang of at least 1 nucleotide or at least 2 nucleotides [column 3, lines 5-8]. Further, the overhangs can be the result of one strand being longer than the other, or the result of two strands of the same length being staggered [column 25, sixth full paragraph].
Regarding claims 16-17, Sehgal et al. teaches that the RNAi agent may further comprise at least one phosphorothioate or methylphosphonate internucleotide linkage. The phosphorothioate or methylphosphonate internucleotide linkage modification may occur on any nucleotide of the sense strand or antisense strand or both strands in any position of the strand. Further, Sehgal et al. teaches that the internucleotide linkage modification may occur on every nucleotide on the sense strand and/or antisense strand; each internucleotide linkage modification may occur in an alternating pattern on the sense strand and/or antisense strand; or the sense strand or antisense strand may contain both internucleotide linkage modifications in an alternating pattern [column 34, fourth full paragraph].
Regarding claims 18-20, Sehgal et al. teaches that exemplary combinations of the sense strand and antisense strand forming a RNAi duplex include the formulas below:
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[column 39, second through sixth full paragraph]. Sehgal et al. also teaches that all of the nucleotides of the sense strand and all of the nucleotides of the antisense strand are modified nucleotides [column 2, fifth full paragraph]. Further, the modifications on the nucleotides are 2′-O-methyl or 2′-fluoro modifications [column 4, lines 63-64].
Regarding claim 21, Sehgal et al. teaches that the RNAi agents may be conjugated to a ligand via a carrier, wherein the carrier can be cyclic group or acyclic group; preferably, the cyclic group is selected from pyrrolidinyl, pyrazolinyl, pyrazolidinyl, imidazolinyl, imidazolidinyl, piperidinyl, piperazinyl, [1,3]dioxolane, oxazolidinyl, isoxazolidinyl, morpholinyl, thiazolidinyl, isothiazolidinyl, quinoxalinyl, pyridazinonyl, tetrahydrofuryl and decalin; preferably, the acyclic group is selected from serinol backbone or diethanolamine backbone [column 42, first full paragraph]. This carrier can be arbitrarily considered to “replace” one or more nucleotides at the 3’ terminus of the dsRNA sense strand.
Regarding claim 29, Sehgal et al. teaches that compositions and formulations for oral administration include powders or granules, microparticulates, nanoparticulates, suspensions or solutions in water or non-aqueous media, capsules, gel capsules, sachets, tablets or minitablets [column 83, lines 64-67].
However, Sehgal et al. does not explicitly teach oral administration of the double stranded RNAi agent.
Tillman et al. teaches that treatment of systemic disease with phosphorothioate antisense oligonucleotides has been accomplished using local or parenteral routes of administration. Tillman et al. describes effective oral delivery of second generation oligonucleotides where significant milligram amounts of intact drug is absorbed in human subjects. Tillman et al. evaluated a variety of oral solid dosage formulations and determined that pulsing the delivery of sodium caprate (C10), a well-known permeation enhancer, may provide optimal ASO plasma bioavailability [abstract].
It would have been obvious for one of ordinary skill in the art before the effective filing date of the claimed invention to orally administer the double-stranded iRNA agent of Sehgal et al. with a reasonable expectation of success because Sehgal et al. and Tillman et al. both teach compositions comprising penetration enhancers so it would have amounted to applying a known technique to yield predictable results. One would have been motivated to do so because Tillman et al. teaches that oral delivery of formulations comprising C10 may provide optimal ASO plasma bioavailability and a significant amount of drug is absorbed via oral delivery.
Claims 5-6 are rejected under 35 U.S.C. 103 as being unpatentable over Sehgal et al. (US 9,574,192; reference previously cited by the Examiner) and Tillman et al. (Journal of Pharmaceutical Sciences 2008; reference previously cited by the Examiner) as applied to claims 1, 3-4, 7-12, 16-24, 26, 27, 29, and 55-57 above, and further in view of Sohi et al. (Drug Development and Industrial Pharmacy 2010; reference previously cited by the Examiner).
Regarding claims 5-6, the teachings of Sehgal et al. and Tillman et al. are discussed above.
However, Sehgal et al. and Tillman et al. do not explicitly teach the concentration of the penetration enhancer.
Sohi et al. teaches that one of the major limitations associated with buccal delivery is low permeation of therapeutic agents across the mucosa. Various substances have been explored as permeation enhancers to increase the flux/absorption of drugs through the mucosa, but irritation, membrane damage, and toxicity are always associated with them and limit their use. A clinically accepted permeation enhancer must increase membrane permeability without causing toxicity and permanent membrane damage. Sohi et al. also teaches that although optimizing the concentration of enhancer to limit its toxicity will be a challenge, advances in permeability modulation and formulation with appropriate enhancers can be effective and feasible buccal drug delivery for many drugs [abstract].
It would have been obvious for one of ordinary skill in the art before the effective filing date of the claimed invention to determine the optimal concentration of the penetration enhancer in the formulation of Sehgal et al. and Tillman et al. because Sohi et al. taught that penetration enhancers can affect the effectiveness of buccal drug delivery. One would have been motivated to optimize the penetration enhancer concentration and would have arrived at the instantly claimed range to improve buccal drug delivery.
Claims 13-15 are rejected under 35 U.S.C. 103 as being unpatentable over Sehgal et al. (US 9,574,192; reference previously cited by the Examiner) and Tillman et al. (Journal of Pharmaceutical Sciences 2008; reference previously cited by the Examiner) as applied to claims 1, 3-4, 7-12, 16-24, 26, 27, 29, and 55-57 above, and further in view of Parmar et al. (Chembiochem 2016; reference previously cited by the Examiner).
Regarding claims 13-15, the teachings of Sehgal et al. and Tillman et al. are discussed above.
However, Sehgal et al. and Tillman et al. do not teach that the double-stranded iRNA agent comprises a phosphate mimic.
Parmar et al. teaches that the presence of 5’-phosphate (5’-P) is reported to be critical for efficient RISC loading of the antisense strand (AS) by anchoring it to the mid-domain of the Argonaute2 (Ago2) protein. Further, Parmar et al. teaches that incorporating 5’-(E)-vinylphosphonate (5’-VP), a metabolically stable phosphate mimic, to siRNA-GalNAc conjugates results in up to 20-fold improved in vitro potency and up to a threefold benefit in in vivo activity by promoting Ago2 loading and enhancing metabolic stability [abstract].
It would have been obvious for one of ordinary skill in the art before the effective filing date of the claimed invention to have modified the double-stranded iRNA agent of Sehgal et al. and Tillman et al. with the chemical modification taught by Parmar et al. One would have been motivated to incorporate 5’-(E)-vinylphosphonate (5’-VP) in order to increase stability and activity of the double-stranded iRNA as taught by Parmar et al.
Response to Arguments
Applicant's arguments filed February 11, 2026 have been fully considered but they are not persuasive.
Applicant asserts the following:
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These arguments are not found persuasive. Sehgal et al. teaches that oral formulations are those in which dsRNAs are administered in conjunction with one or more penetration enhancer surfactants and chelators. Suitable surfactants include fatty acids and/or esters or salts thereof, bile acids and/or salts thereof. Suitable fatty acids include oleic acid, lauric acid, capric acid, or a pharmaceutically acceptable salt thereof (e.g., sodium) [column 84, first paragraph]. Thus, Sehgal et al. provides a suggestion for oral administration of pharmaceutical compositions and does not teach away nor disparage oral administration. Furthermore, Sehgal et al. discloses that suitable fatty acids administered in conjunction with the dsRNAs include those recited in the amended claims (oleic acid (C18:1), lauric acid (C12), and capric acid (C10)). Nonetheless, Tillman et al. was used in combination with Sehgal et al. to render obvious the claim limitation of oral administration of a double stranded RNAi agent because Sehgal et al. does not explicitly teach oral administration of the double stranded RNAi agent.
Applicant asserts the following:
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These arguments are not found persuasive. Tillman et al. discloses that in vitro and in vivo preclinical studies have examined the potential of using medium chain fatty acids with chain length of about 6–12 carbon atoms, as well as bile salts, to facilitate the absorption of poorly permeable compounds across the intestinal mucosa. Tillman et al. also discloses that sodium caprate (C10) has been used as a permeation enhancer in both preclinical and clinical studies of Class III compounds which include oligonucleotides because oligonucleotides are highly water soluble therapeutics that have low membrane permeability [page 226, left column, first and second full paragraphs]. Further, Tillman et al. evaluated a variety of oral solid dosage formulations and it was determined that pulsing the delivery of sodium caprate (C10), a well-known permeation enhancer, in a novel manner may provide optimal ASO plasma bioavailability [abstract]. Thus, based on the teachings of Tillman et al., there would have been a reasonable expectation of success in oral delivery of the double-stranded iRNA agent of Sehgal et al.
Applicant asserts that neither Sohi et al. nor Parmar et al. teaches or suggests the claimed oral administration of a dsRNA formulation containing the claimed penetration enhancers.
The Examiner agrees with Applicant’s assertions. The 35 U.S.C. 103 rejection is based on the combination of Sehgal et al., Tillman et al., and Sohi et al. (claims 5-6) because Sehgal et al. and Tillman et al. do not explicitly teach the concentration of the penetration enhancer. The 35 U.S.C. 103 rejection is also based on the combination of Sehgal et al., Tillman et al., and Parmar et al. (claims 13-15) because Sehgal et al. and Tillman et al. do not teach a phosphate mimic. Thus, Sohi et al. and Parmar et al. were used to meet the limitations of penetration enhancer concentration and phosphate mimic.
Applicant asserts that the Examiner dismissed the technical results previously submitted by the Applicant as allegedly failing to provide evidence of unexpected results. Applicant’s arguments previously presented on September 30, 2025 indicate that the claimed method provides surprisingly good and robust results for in vivo oral delivery of a double-stranded iRNA agent and can achieve effective and efficient oral delivery of the double-stranded iRNA agent at a clinically relevant dose regimen. Applicant indicates that Example 2A demonstrates that oral administration of a claimed oral formulation containing an anti-F12 double-stranded iRNA and a penetration enhancer (a sodium salt of a C10 fatty acid, a claimed penetration enhancer), at a dosage level of 25 mg/kg (within the claimed oral dosage range), to a mouse resulted in a significantly better activity than oral administration of a formulation with the same siRNA without the penetration enhancer, and resulted in an activity comparable to the subcutaneous administration of a formulation with the same siRNA. Applicant also indicates that Example 3B demonstrates that oral administration of a claimed oral formulation containing an anti-TTR double-stranded iRNA and a penetration enhancer (a sodium salt of a C10 fatty acid, a claimed penetration enhancer), at a dosage level of 3 and 10 mg/kg (within the claimed oral dosage range) to a non-human primate resulted in robust and durable inhibition of TTR and resulted in an activity even better than the subcutaneous formulation with the same siRNA.
These arguments are not found persuasive. In an assertion of unexpected results, one must compare the claimed subject matter with the closest prior art to be effective to rebut a prima facie case of obviousness. In re Burckel, 592 F.2d 1175, 201 USPQ 67 (CCPA 1979). See MPEP 716.02(e). Contrary to Applicant’s assertions that a comparison against the claimed invention and the closest subject matter has been provided, the comparative studies of the instant specification are not a comparison to the closest prior art. The specification provides a comparison of the same siRNA formulated with and without a penetration enhancer. However, Sehgal et al. (the closest prior art) teaches that oral formulations are those in which dsRNAs are administered in conjunction with one or more penetration enhancer surfactants and chelators. Furthermore, Sehgal et al. taught employing various penetration enhancers to affect the efficient delivery of nucleic acids, particularly iRNAs [column 89, third full paragraph]. In addition, Sohi et al. taught that penetration enhancers can affect the effectiveness of buccal drug delivery. Therefore, the provided comparison does not provide evidence of unexpected results because Sehgal et al. taught that penetration enhancers can affect the efficient delivery of nucleic acids and Sohi et al. taught that penetration enhancers can affect the effectiveness of buccal drug delivery. In addition, the specification does not provide a comparison of varying dosages of siRNAs with and without a phosphate mimic similar to the comparison provided of siRNAs formulated with and without a penetration enhancer.
Double Patenting
The nonstatutory double patenting rejection is based on a judicially created doctrine grounded in public policy (a policy reflected in the statute) so as to prevent the unjustified or improper timewise extension of the “right to exclude” granted by a patent and to prevent possible harassment by multiple assignees. 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.
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Claims 1, 3-24, 26, 27, 29, and 55-57 are provisionally rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1-7, 9-16, 18-29, 39, 40, and 42-44 of copending Application No. 17/941,436 in view of Sehgal et al. (US 9,574,192; reference previously cited by the Examiner), Tillman et al. (Journal of Pharmaceutical Sciences 2008; reference previously cited by the Examiner), Sohi et al. (Drug Development and Industrial Pharmacy 2010; reference previously cited by the Examiner), and Parmar et al. (Chembiochem 2016; reference previously cited by the Examiner).
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However, copending application ‘436 does not teach a penetration enhancer or the dosage of double-stranded iRNA agent to be administered. Copending application ‘436 also does not teach oral administration of the dsRNA agent.
Sehgal et al. teaches that penetration enhancers can improve the properties of the formulation and enhance the absorption of the iRNAs and nucleic acids [column 89, first full paragraph]. Sehgal et al. teaches that oral formulations are those in which dsRNAs are administered in conjunction with one or more penetration enhancer surfactants and chelators. Suitable surfactants include fatty acids and/or esters or salts thereof, bile acids and/or salts thereof. Suitable fatty acids include arachidonic acid, undecanoic acid, oleic acid, lauric acid, caprylic acid, capric acid, myristic acid, palmitic acid, stearic acid, linoleic acid, linolenic acid, dicaprate, tricaprate, monoolein, dilaurin, glyceryl 1-monocaprate, 1-dodecylazacycloheptan-2-one, an acylcarnitine, an acylcholine, or a monoglyceride, a diglyceride or a pharmaceutically acceptable salt thereof (e.g., sodium). Sehgal et al. also teaches that suitable complexing agents include chitosan or N-trimethylchitosan [column 84, first paragraph]. Sehgal et al. teaches that the pharmaceutical compositions may be administered in dosages sufficient to inhibit expression of a Serpina1 gene. In general, a suitable dose of an iRNA will be in the range of about 0.001 to about 200.0 milligrams per kilogram body weight of the recipient per day, generally in the range of about 1 to 50 mg per kilogram body weight per day [column 62, fourth full paragraph].
Tillman et al. teaches that treatment of systemic disease with phosphorothioate antisense oligonucleotides has been accomplished using local or parenteral routes of administration. Tillman et al. describes effective oral delivery of second generation oligonucleotides where significant milligram amounts of intact drug is absorbed in human subjects. Tillman et al. evaluated a variety of oral solid dosage formulations and determined that pulsing the delivery of sodium caprate (C10), a well-known permeation enhancer, may provide optimal ASO plasma bioavailability [abstract].
Sohi et al. teaches that one of the major limitations associated with buccal delivery is low permeation of therapeutic agents across the mucosa. Various substances have been explored as permeation enhancers to increase the flux/absorption of drugs through the mucosa, but irritation, membrane damage, and toxicity are always associated with them and limit their use. A clinically accepted permeation enhancer must increase membrane permeability without causing toxicity and permanent membrane damage. Sohi et al. also teaches that although optimizing the concentration of enhancer to limit its toxicity will be a challenge, advances in permeability modulation and formulation with appropriate enhancers can be effective and feasible buccal drug delivery for many drugs [abstract].
Parmar et al. teaches that the presence of 5’-phosphate (5’-P) is reported to be critical for efficient RISC loading of the antisense strand (AS) by anchoring it to the mid-domain of the Argonaute2 (Ago2) protein. Further, Parmar et al. teaches that incorporating 5’-(E)-vinylphosphonate (5’-VP), a metabolically stable phosphate mimic, to siRNA-GalNAc conjugates results in up to 20-fold improved in vitro potency and up to a threefold benefit in in vivo activity by promoting Ago2 loading and enhancing metabolic stability [abstract].
It would have been obvious for one of ordinary skill in the art before the effective filing date of the claimed invention to orally administer the dsRNA agent of copending application ‘436 as taught by Tillman et al. and incorporate a penetration enhancer as taught by Sehgal et al. to improve the properties of the formulation and enhance the absorption of the dsRNA agent. Further, it would have been obvious to determine the optimal concentration of the penetration enhancer because Sohi et al. taught that penetration enhancers can affect the effectiveness of buccal drug delivery. One would have been motivated to optimize the penetration enhancer concentration and would have arrived at the instantly claimed range to improve buccal drug delivery.
It would have been obvious for one of ordinary skill in the art before the effective filing date of the claimed invention to administer the dsRNA agent of copending application ‘436 in a dosage as taught by Sehgal et al. with a reasonable expectation of success in order to achieve the result of inhibiting expression of a Serpina1 gene.
It would have been obvious for one of ordinary skill in the art before the effective filing date of the claimed invention to have modified the double-stranded iRNA agent of copending application ‘436 with the chemical modification taught by Parmar et al. One would have been motivated to incorporate 5’-(E)-vinylphosphonate (5’-VP) in order to increase stability and activity of the double-stranded iRNA as taught by Parmar et al.
This is a provisional nonstatutory double patenting rejection.
Response to Arguments
Applicant's arguments filed February 11, 2026 have been fully considered but they are not persuasive.
Applicant asserts that Sehgal et al., Tillman et al., Sohi et al., and Parmar et al. do not teach or suggest the claimed invention as recited in independent claim 1 and its dependent claims. Thus, the Applicant asserts that the claimed invention is patentably distinct from the claims of the ‘436 application.
Applicant’s remarks are addressed in the 35 U.S.C. 103 rejection above and applies here.
Conclusion
No claims are allowed.
Applicant's amendment necessitated the new ground(s) of rejection presented in this Office action. Accordingly, THIS ACTION IS MADE FINAL. See MPEP § 706.07(a). Applicant is reminded of the extension of time policy as set forth in 37 CFR 1.136(a).
A shortened statutory period for reply to this final action is set to expire THREE MONTHS from the mailing date of this action. In the event a first reply is filed within TWO MONTHS of the mailing date of this final action and the advisory action is not mailed until after the end of the THREE-MONTH shortened statutory period, then the shortened statutory period will expire on the date the advisory action is mailed, and any nonprovisional extension fee (37 CFR 1.17(a)) pursuant to 37 CFR 1.136(a) will be calculated from the mailing date of the advisory action. In no event, however, will the statutory period for reply expire later than SIX MONTHS from the mailing date of this final action.
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/C.T./
Examiner, Art Unit 1637
/Jennifer Dunston/Supervisory Patent Examiner, Art Unit 1637
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