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 .
Continued Examination Under 37 CFR 1.114
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and the fee set forth in 37 CFR 1.17(e) has been timely paid, the finality of the previous Office action has been withdrawn pursuant to 37 CFR 1.114.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 10/31/2025 has been entered.
Claim Status
Claims 1, 4, 16-18, 97-103 are pending and examined here.
Priority
The application’s claim to benefit of 63/230,449, filed on 08/06/2021, is acknowledged. All claims enjoy the benefit of ‘449’s filing date.
Claim Objections
Objection to claim 4 is withdrawn, cholesterol is a lipid moiety with proper antecedent basis.
Claim Rejections - 35 USC § 112
The rejection of cl. 100 and 101 is maintained.
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 100 and 101 are rejected under 35 U.S.C. 112(a) or 35 U.S.C. 112 (pre-AIA ), first paragraph, as failing to comply with the enablement requirement. The claim(s) contains subject matter which was not described in the specification in such a way as to enable one skilled in the art to which it pertains, or with which it is most nearly connected, to make and/or use the invention. Briefly, a viral vector is made with unmodified nucleotides and not modified nucleotides and is explained in detail below.
When considering the scope of enablement, the Wands factors need to be reviewed, which poses whether the experimentation needed to practice the invention is undue or unreasonable. Determining undue experimentation requires analysis of, but 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.
In the instant case:
The breadth of the claims: Claim 100 requires the pharmaceutically-acceptable carrier is a viral vector, and claim 101 further limits the viral vector. Claim 100 is understood in light of the specification, see par. 39 and 40, that the viral vector is used to deliver the nucleic acid of SEQ ID NO: 4.
The nature of the invention: Claim 1 requires a pharmaceutical composition comprising a therapeutically-effective amount of a miRNA-221-5p mimic comprising SEQ ID NO: 4 and a pharmaceutically acceptable carrier. Claim 1 also recites that the mimic is modified with phosphorothioate (PS) linkages and 2’-O-methyl (2OMe) ribose modification at each ribose unit and is conjugated to a lipid moiety.
The state of the prior art: The purpose of using a viral vector is to deliver a gene of interest in a host cell/organism (see generally Dasgupta, 2021, Methods Protoc., 4, pg. 1-18). It is known in the art that modified nucleotides within a viral vector would interfere with replication, transcription and/or translation of the viral vector. The host or viral machinery would have difficulty recognizing the viral vector. It would also be cost-prohibitive to modify a large vector of 4.7 kb, such as AAV vector, which is the smallest of the viral vectors. The art of record does not teach making or using viral vector with nucleotides with 2OMe ribose modification and PS linkages to successfully deliver a gene of interest for therapeutic purpose.
The level of predictability in the art: Although viral vectors with unmodified nucleotides are used for transducing hosts to deliver and express gene of interest, it is highly unpredictable, and most likely unsuccessful, whether viral vectors with modified nucleotide would be able to perform the essential function of a viral vector and would require undue experimentation.
The amount of direction provided by the inventor/working examples: The specification suggests that nucleic acid will be delivered using viral vector: see par. 39: “Nucleic acids can be delivered administered [sic] to a subject via a viral vector;” and a similar language in par. 40. Neither the art of record nor the specification teach making or using a viral vector comprising 2OMe ribose and phosphorothioate linkages. Similar issue also applies to instant cl. 101.
The quantity of experimentation: Due to the lack of evidence from art of record nor the specification, it would require undue experimentation to successfully make or use a viral vector carrying a SEQ ID NO: 4 comprising 2OMe ribose and phosphorothioate linkages.
Thus claims 100 and 101 are rejected under 112(a) enablement.
Response to Arguments
Applicant's arguments filed 10/31/2025 (“the Remarks”) have been fully considered but they are not persuasive.
The arguments note that a) the claim amendment overcomes the enablement issue, and b) thus it is “clear that viral vector is a carrier for the compound, not that the viral vector comprises the recited 2OMe and/or PS-linkage nucleotide of the compound as recited in claim 1” (pg. 4-5).
The arguments are not persuasive.
The amendment does not cure the enablement rejection since claim 1 still requires a compound, which is a miRNA-221-5p mimic, that increases activity of miRNA-221-5p and a carrier. A strand is also miRNA-221-5p mimic that is modified. Basically, the compound is the strand. Claims 100 and 101 are viral vectors, which are delivering the miRNA-221-5p mimic modified strand. Viral vectors are not known in the art to be made with modified nucleotides. Simply an unmodified sequence of interest is ligated into the viral vector.
Claim Rejections - 35 USC § 103
The rejection of claims 1, 4, 17, 18, 97-98 is maintained, and new claims 102-103 are rejected as noted below.
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.
Claims 1, 4, 17, 18, 97-98, 102-103 are rejected under 35 U.S.C. 103 as being unpatentable over Zheng (2018, Int. J. of Molecular Sciences, 19, pg. 1-19, of record) and Duygu et al. (2019, Biochemical Pharmacology, 159, 106-115, referred as Duygu).
Regarding instant cl. 1, 102, Fig. 1 discloses the sequence of miRNA-221-5p SEQ ID NO: 4 as ACCUGGCAUACAAUGUAGAUUUC.
It should be noted that claim 17 recites the “the pharmaceutical composition is formulated for injection” and claim 18 recites “the pharmaceutical composition is formulated for intratendinous injection.” Claim 103 recites “the compound increases activity of miRNA-221-5p in reducing NLRP3 expression.” Under MPEP 2112.02(II), the formulation for either injection or intratendinous injection or increasing activity and thus reducing expression of target gene is the intended use for or the result following administration of the pharmaceutical composition. The intended use is not considered a further limitation on the structural limitation of claim 1 in a way that distinguishes it over the cited art.
Zheng (2018, Int. J. of Molecular Sciences, 19, pg. 1-19) discloses a miRNA mimic of miRNA-221-5p and discloses a sequence of miRNA-221-5p to be 5’-ACCUGGCAUACAAUGUAGAUUUCUGU, which comprises instant SEQ ID NO: 4 (Fig. 4A, pg. 7, relevant to instant cl. 1), discloses the overexpression of miR-221-5p mimic inhibits viral replication (see abstract, Fig. 2).
Zheng does not disclose the phosphorothioate/ribose 2OMe modifications of miRNA mimic, or conjugation to lipid moeity, which is cholesterol at either at 5’-end or 3’-end (cl. 1, 4, 97, 98).
Duygu et al. disclose testing various modified forms of antagomirs, also called antimirs, i.e. oligonucleotides that are complementary to miRNAs and inhibit the activity of miRNAs, i.e. an activity that is opposite of instant claimed invention (abstract). However, Duygu discloses that “strategies described above aid in increasing cell- and organ-specific delivery of antimirs and/or miR mimics” (pg. 113) suggesting that the modifications disclosed can apply to either antimirs or miR-mimics. Duygu tested various modifications, including a fully modified 2OMe antagomir with 2 PS linkage at 5’ end and at least 4 PS linkages at the 3’ end along with cholesterol bound at either 3’ or 5’ end (see edited Fig. 4a below, pg. 112; relevant for instant cl. 1, 4, 97, 98).
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The results indicate that antagomir as a “potent oligonucleotide chemical modification,” and moving the cholesterol group from 3’ to 5’ end resulted in further increase in potency (pg. 111). Duygu disclose that conjugation of cholesterol to phosphorothioate oligonucleotide is known to increase their plasma life-time and 60 min. after injection note that 3’-cholesterol conjugate were shown to be 3.8 times higher than those of unconjugated nucleotides, while the levels of 5’ conjugates have been shown to be 7.8 times higher (pg. 111). The universality in incorporating the modified nt. in oligonucleotides is based on the purposes of the modified nt.: modification of 2’ ribose site increase thermal stability of complementary hybridization, induce higher binding affinity, and increase stability protecting the RNA molecule from nuclease cleavage, while the incorporation of phosphorothioate linkage increases oligonucleotide stability in circulation and slow down removal by the liver, increasing the time available for uptake into target tissues (pg. 107). Thus a “combined strategy is to use 2’OME-modified nucleic acids linked with PS bonds at both ends of the molecule in order to protect against exonuclease activity, together with a cholesterol group attached to the 3’ end of the molecule to facilitate in vivo delivery” (pg. 107). Duygu further discloses the use of nanoparticle to deliver miRNA mimics, which are “safe, biodegradable, and successfully in enhancing the delivery of therapeutic agents” (pg. 113, nanoparticle is considered a pharmaceutically acceptable carrier, relevant to instant cl. 1).
One of the KSR rationale that may be used to support a conclusion of obviousness is that there is some teaching, suggestion, or motivation in the prior art that would have led one of ordinary skill to modify the prior art reference or to combine prior art reference teachings to arrive at the claimed invention. Therefore, it would have been prima facie obvious for one of ordinary skill in the art before the filing date of the claimed invention to have modified the miR-221 mimic of Zheng in view of Duygu and arrive at the claimed invention with a reasonable expectation of success. Here, Duygu provides that an oligonucleotide with 2OMe, PS-INL and cholesterol modifications improve the potency, stability and targeting of the oligonucleotide and can be delivered using nanoparticle, while Zheng discloses that overexpressing miR-221-5p increases its anti-viral activity; thus a skilled artisan modifying miR-221-5p of Zheng with 2OMe, PS-INL and cholesterol and incorporated with a nanoparticle of Duygu would expect reasonable success in producing a miR-221-mimic that has increased potency, stability and improved tissue targeting. Thus, claims 1, 4, 97, 98 are obvious.
Regarding instant cl. 17 and 18, 103, since here the structural limitation is noted in the prior art and there is no further structural limitation provided in claims 17 and 18, 103, Zheng and Duygu meet the requirement for the intended use of claims 17, 18 and 103. Absent evidence to the contrary such a composition is suitable for intratendinous injection also or reduces NLRP3 expression (relevant to instant cl. 18, 103).
Regarding instant cl. 102, the miR-221-5p mimic of Zheng is three nt. longer than instant SEQ ID NO: 4. Zheng’s mimic is not patentably distinct from instant SEQ ID NO: 4 even if it is a few nt. longer.
Claims 16 and 99 are rejected under 35 U.S.C. 103 as being unpatentable over Zheng et al. (2018, Int. J. of Molecular Sciences, 19, pg. 1-19, referred as Zheng) and Duygu et al. (2019, Biochemical Pharmacology, 159, 106-115, referred as Duygu) as applied to claim 1, 4, 17, 18, 97-99 above, and further in view of Akao et al. (2011, Molecular Therapy, 19, 395-399).
Neither Zheng nor Duygu disclose compound encapsulated in a microvesicle.
Akao disclose both preparation of microvesicle (MV) fraction containing chemically modified or control microRNAs (pg. 398) that were administered to mice inoculated with tumors (pg. 398, 399, see also Fig. 5). These microvesicles if isolated/purified from cells of patients would result in decreased toxic reactions (abstract) and the results demonstrated increased levels of treated microRNAs in serum, tumor and kidney of host animals (abstract, relevant to instant cl. 16). Here, a skilled artisan would recognize that a microvesicle carrier would comprise a lipid, since it is made up of cellular membrane contents, including lipid (relevant to instant cl. 99).
One of the KSR rationale that may be used to support a conclusion of obviousness is that there is some teaching, suggestion, or motivation in the prior art that would have led one of ordinary skill to modify the prior art reference or to combine prior art reference teachings to arrive at the claimed invention. Therefore, it would have been prima facie obvious for one of ordinary skill in the art before the filing date of the claimed invention to have prepared the miR-221 mimic of Zheng in view of Akao and arrive at the claimed invention with a reasonable expectation of success. Here, Akao provides that a chemically modified microRNA packaged in patient-derived microvesicles are safer for patients, while Zheng discloses that overexpressing miR-221-5p increases its anti-viral activity; thus a skilled artisan packaging miR-221-5p of Zheng in microvesicle from cells of a subject would expect reasonable success in producing a microvesicle containing miR-221-mimics that are safer for in vivo treatment. Thus, claims 16, 99 are obvious.
Response to Arguments
Applicant's arguments filed 10/31/2025 (“the Remarks”) have been fully considered but they are not persuasive.
The Remarks insist that Duygu does not cure the deficiency of Zheng and that Duygu focuses on antagomirs, which have an activity that is opposite of instant claimed invention. Then the Remarks interpret Duygu’s language of “strategies” to not apply to chemical modification of the therapeutic agent but rather narrowly only to “ultra-sound sensitive microbubbles” and “the use of negatively charged calcium phosphate nanocarriers” and nowhere does Duygu suggests that the chemical modifications that increase cell- and organ-specific delivery applies to miR mimics (pg. 6).
Regarding rejection of cl. 16 and 99, the Remarks repeat the argument that since Zheng and Duygu fails to teach limitations of cl. 1, Akao does not overcome the deficiencies: it does not teach claimed limitations of cl. 1 (pg. 6).
The argument is not persuasive.
Even if, as Applicant suggests, that the specific language of “strategies” should be narrowly applied to just delivery methods noted in preceding paragraph is correct. Duygu, on pg. 106, begins discussion of “miRNA-based therapeutics” to include “to restore miRNA expression levels either by increasing the downregulated miRNAs,” i.e. a skilled artisan would understand that one way to increase downregulated miRNAs is to use miRNA-mimics. Regardless, a skilled artisan understands the inherent function of nucleotide modifications, including ligand-conjugation, is for stability and delivery as taught by Duygu. Yamada and Marshall (CN102803284B, pub. 11/25/2015. Both foreign language and Google machine translated relevant pg. 1-2 are provided) disclose “present invention relates to chemical motifs of microRNA (miRNA or miR) inhibitors and mimetics, and in particular to chemically modified miRNA sense and antisense polynucleotides that, when administered to a patient, exhibit a significant increase in potency. , stability and/or toxicity” and provides that a “miRNA inhibitor or miRNA mimetic having one or a combination of 2' modifications as described herein, such as selected from O-alkyl (e.g., O-methyl or " OMe")” and “composition may include conjugates with cholesterol and other molecules, such as targeting ligands, for delivery of the polynucleotide to target mammalian cells” (pg. 2, underlined added for emphasis). Thus, it is known in the art, that these nucleotide modifications can be applied to any nucleotide, and, it does not matter if it is an miR-mimic or antagomir (“microRNA inhibitor”).
Thus, Duygu reference does cure Zheng and all references noted make the claimed invention obvious.
Thus the rejection of the claims is maintained.
Allowable Subject Matter
No claim allowed.
Conclusion
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/KEYUR A VYAS/Examiner, Art Unit 1637 /Soren Harward/Primary Examiner, TC 1600