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 .
DETAILED ACTION
Status of Application/Amendment/Claims
Applicant's response filed 06/25/2026 has been considered. Rejections and/or objections not reiterated from the previous office action mailed 04/01/2026 are hereby withdrawn. The following rejections and/or objections are either newly applied or are reiterated and are the only rejections and/or objections presently applied to the instant application. The text of those sections of Title 35, U.S. Code not included in this action can be found in a prior Office action.
With entry of the amendment filed on 06/25/2026, claims 15-24 and 26-38 are pending in the application. Claims 15-24 remain rejected. In the interest of compact prosecution, claims 26-38 are rejoined and examined.
The previous 103 rejection is withdrawn in view of the new rejection herein.
The Terminal Disclaimer filed 06/25/2026 has been approved and therefore the Double Patenting rejection over claims 1-20 of U.S. Applicant No. 18/288,887 (App887) is withdrawn.
New Claim Objections and Rejections
Claim Objections
Claim 30 is objected to because of the following informalities: The claim recites “The method according to claim 27, wherein a reducing rate of miR-33b level of the substance reducing miR-33b level is higher than a reducing rate of miR- 33a level of the substance reducing miR-33b level” and should recite “ “The method according to claim 27, wherein a reducing rate of miR-33b level of the substance reducing miR-33b level is higher than a reducing rate of miR- 33a level of the substance reducing miR-33a level”
Appropriate correction is required.
Claim 32 is objected to because it appear the word ‘the” is missing from line 4 between “with” and “9th”. Appropriate correction is required.
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 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 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 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 15-17, 19, 20, 21, 24-31, 35 and 39 is/are rejected under 35 U.S.C. 103 as being unpatentable over Nakao et al. (Arterioscler Thromb Vasc Biol. 2017;37: 2161-2170 of record 11/30/2022), Dávalos et al. (miR-33a/b contribute to the regulation of fatty acid metabolism and insulin signaling. Proc Natl Acad Sci U S A. 2011 May 16;108(22):9232–9237 of record 11/30/2022), Koyama (Koyama et al. Identification of Differential Roles of MicroRNA-33a and -33b During Atherosclerosis Progression With Genetically Modified Mice. J Am Heart Assoc. 2019; 8:e012609 of record 11/30/2022), Lima (Lima et al. Anti-miRNA oligonucleotides: A comprehensive guide for design. RNA Biology, 2018. Vol. .15, No. 3, 338-352.) and Bennett et al. (Annu. Rev. Med. 2019. 70:307–21).
Regarding claims 26 and 39, Nakao et al. found elevated miR-33 expression in abdominal aortic aneurysm (AAA) which is the third most common cause of cardiovascular death (page 2161 first para). Nakao et al. teach humans have 2 homologues of miR-33 (a and b), rodents have only 1 miR-33 locus, which is equivalent to miR-33a and therefore developed a mouse model of AAA for in vivo deletion of miR-33 (page 2162 results). Nakao et al. teach miRNAs can be suppressed by antisense oligonucleotides, some of which, including anti–miR-33, are currently being investigated in clinical or preclinical trials and these results strongly suggest that inhibition of miR-33 may be a novel therapeutic strategy for AAA (conclusion). Nakao et al. do not specifically teach using an antisense targeted to miR-33b as claimed.
Regarding claims 24-29, 31, Dávalos teaches an miR-33b inhibitor (anti–miR-33b oligonucleotides) that is a miR-33b-level-reducing (threefold decrease in expression) substance (pp 9233-9234). Dávalos teachings that the inhibitor is a nucleic acid (pp 9233-9234). Dávalos teachings that the inhibitor is an antisense oligonucleotide against miR-33b (pp 9233-9234) in an acceptable pharmaceutical reagent (see S1 materials and methods).
Regarding claims 15, 27, 32, 33, Koyama teaches that the sequences of miR-33a and miR-33b are almost the same except at the 9th and 10th position immediately after the seed sequences (Figure 1B). While Koyama does not provide any particular guidance regarding how to design anti-miRs, Lima teaches that anti-miRs are typically designed to be a perfect match to the miRNA target, especially to the seed region (p. 342).
Regarding claim 32, Koyama teaches the has-miR-33b-5p target sequence is 5’-GUGCAUUGCUGUUGCAUUGC-3’ and differs from miR-33a at the 9th and 10th positions, while Lima teaches that anti-miRs should be a perfect match (i.e., not less than 90% complementary to the target). Lima also teach the seed region at positions 2-7 from the 5’ end of the miRNA sequence is fully paired and is essential for interaction (see page 339 firs para). Lima et al. teach that the designed antisense sequence can have the same length, be shorter, or be longer than the target (§ 4), although Lima notes that shorter sequence had shown lower toxicity and are more likely to improve mismatch discrimination (p. 344). The full mature sequence of miR-33b-5p is 20 nucleotides long, while the seed sequence is 6 nucleotides long.
Koyama teaches that miR-33b has a seed sequence of 5’-UGCAUU-3’ and differs from the miR-33a sequence at the 9th and 10th positions. The recited antisense oligonucleotide of SEQ ID No. 5 has the sequence of AACAGCAATGCA, which is a perfect reverse complement to all but the terminal nucleotide of the 5’ end of miR-33b (5’-UGCAUUGCUGUU-3’) starting at the seed region, as suggested by Lima.
Regarding claims 16, 17, 19, 21, 34, 35 Lima teaches that, “chemical modifications should be employed into the design of AMOs” such as sugar modifications and phosphorothioate backbones (para 3.1 page 342).
Regarding claims 20 and 33, it is well known in the art that further modifications, such as 5’-methycytosine, are used in modifications of antisense oligonucleotides along with sugar modifications and phosphorothioate backbones to increase the binding and stability of the oligonucleotide as taught by Bennett et al. (page 312-313) Bennett et al. further teach pharmaceutical compositions.
Regarding claim 30, it would have obvious that the oligonucleotide would reduce the level of miR-33b higher than miR-33a given it is specifically designed to target mir-33b.
It would have been prima facie obvious to a person having ordinary skill in the art before the effective filing date of the claimed invention to have designed an antisense oligonucleotide for inhibiting miR-33b, as taught by Dávalos, Koyama and Lima, to be specific to the miR-33b sequence and not to miR-33a. Based on the combination of Koyama’s teachings of the sequences of miR-33a and -33b and the differences between them, and Lima’s teachings that anti-miRs should be a perfect match to their target (including the seed sequence) and should be chemically modified, the ordinary artisan would have predicted, with a reasonable expectation of success, that a chemically modified anti-miR designed to be a perfect match to the seed sequence of the miR-33b sequence, but not the miR-33a sequence, would have effectively reduced miR-33b more than miR-33a. It was well known in the art to use sugar and backbone modifications as taught by Bennett et al. and it would have been obvious to modify the antisense oligonucleotide to increase stability and binding and formulate in a pharmaceutical composition as claimed.
It would further have been obvious to try optimizing the length of the anti-miR to reduce toxicity and improve specificity. Given the requirement for a perfect match to the seed region and the limited size of the target microRNA, there would have been a finite number of possible anti-miR sequences to try. Lima notes that shorter sequence has shown lower toxicity and are more likely to improve mismatch discrimination (p. 344) and it would have been obvious to one of skill to try oligonucleotides shorter than the target region to arrive at the claimed oligonucleotide.
Furthermore, KSR states an obvious to try rationale may be proper when the possible options for solving a problem are known, finite, and predictable, with a reasonable expectation of success. KSR, 550 U.S. at 418, 82 USPQ2d at 1396. Also, see MPEP § 2143.
Claims 15, 18, 22, 23, 36, 27 and 38 is/are rejected under 35 U.S.C. 103 as being unpatentable over Nakao et al. (Arterioscler Thromb Vasc Biol. 2017;37: 2161-2170 of record 11/30/2022), Dávalos (Dávalos et al. miR-33a/b contribute to the regulation of fatty acid metabolism and insulin signaling. Proc Natl Acad Sci U S A. 2011 May 16;108(22):9232–9237 of record 11/30/2022), Koyama (Koyama et al. Identification of Differential Roles of MicroRNA-33a and -33b During Atherosclerosis Progression With Genetically Modified Mice. J Am Heart Assoc. 2019; 8:e012609 of record IDS 11/30/2022), Lima (Lima et al. Anti-miRNA oligonucleotides: A comprehensive guide for design. RNA Biology, 2018. Vol. .15, No. 3, 338-352.), Yahara et al. (Amido-Bridged Nucleic Acids (AmNAs): Synthesis, Duplex Stability, Nuclease Resistance, and in Vitro Antisense Potency. ChemBioChem 2012, 13, 2513 – 2516 of record IDS 06/24/2024) and Touznik et al. (LNA/DNA mixmer-based antisense oligonucleotides correct alternative splicing of the SMN2 gene and restore SMN protein expression in type 1 SMA fibroblasts. Sci Rep 7, 3672 (2017).
Nakao et al., Davalos et al., Koyama et al. and Lima et al. are relied upon as above but do not teach wherein the modified sugar is an AmNA, as depicted in the claim, or the nucleobase sequence with the specific modification patterns.
Yahara teaches that amido-bridged nucleic acids (AmNAs) are LNA analogues with improved properties (compared to LNAs), including high nuclease resistance along with high RNA selectivity when incorporated into antisense oligonucleotides (p. 2513).
Touznik teaches LNA/DNA mixmer-based antisense oligonucleotides which showed significantly higher efficacy than all-LNA oligonucleotides with the equivalent sequence (Abstract).
It would have been prima facie obvious to a person having ordinary skill in the art before the effective filing date of the claimed invention to have modified the nucleobase sequence of the anti-miR as taught by Davalos et al., Koyama et al. and Lima et al. to incorporate amido-bridged nucleic acids, as taught by Yahara, because Yahara teaches that AmNAs had superior properties to LNAs. It would further have been obvious to incorporate the AmNAs in a LNA/DNA mixmer pattern, as taught by Touznik, while substituting the LNAs with AmNAs, to achieve the predictable outcome of an anti-miR with higher nuclease resistance, RNA selectivity and efficacy than an LNA/DNA mixmer or an all-LNA oligonucleotide.
Thus in the absence of evidence to the contrary, the invention as a whole would have been prima facie obvious to one of ordinary skill in the art at the time the invention was filed.
Claim Rejections - 35 USC § 112
Enablement
The following is a quotation 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 35 U.S.C. 112 (pre-AIA ), first paragraph:
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 26-39 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 methods of using miR-33b knock-out in mice in a calcium chloride-induced aortic aneurism model and methods of suppressing aneurysm formation using an antisense oligonucleotides 33b-2-AmNA (12) (SEQ ID No. 8 in Table 1) in a calcium chloride-induced aortic aneurism mouse model,
does not reasonably provide enablement for methods of preventing or treating any type of aneurysm comprising administering an effective amount of any mir-33b substance in a subject in need thereof.
The specification does not enable any person skilled in the art to which it pertains, or with which it is most nearly connected, to make and use the invention commensurate in scope with these claims.
The following factors have been considered in the analysis of enablement: (1) the breadth of the claims, (2) the nature of the invention, (3) the state of the prior art, (4) the level of one of ordinary skill, (5) the level of predictability in the art, (6) the amount of direction provided by the inventor, (7) the existence of working examples, (8) the quantity of experimentation needed to make or use the invention based on the content of the disclosure.
The breadth of the claims and the nature of the invention:
The broadest reasonable interpretation of the claims is using any mir-33b inhibiting substance to prevent and treat any type of aneurysm in a subject.
Whether the specification would have been enabling as of the filing date involves consideration of the nature of the invention, the state of the prior art, and the level of skill in the art. The state of the prior art is what one skilled in the art would have known, at the time the application was filed, about the subject matter to which the claimed invention pertains. The relative skill of those in the art refers to the skill of those in the art in relation to the subject matter to which the claimed invention pertains at the time the application was filed. See MPEP § 2164.05(b). The state of the prior art provides evidence for the degree of predictability in the art and is related to the amount of direction or guidance needed in the specification as filed to meet the enablement requirement. The state of the prior art is also related to the need for working examples in the specification.
The state of the prior art:
The prior art found elevated miR-33 expression in abdominal aortic aneurysm (AAA) which is the third most common cause of cardiovascular death (page 2161 first para) (Nakao et al. cited above) and further teach humans have 2 homologues of miR-33 (a and b), rodents have only 1 miR-33 locus, which is equivalent to miR-33a and therefore developed a mouse model of AAA for in vivo deletion of miR-33 (page 2162 results). Nakao et al. teach miRNAs can be suppressed by antisense oligonucleotides, some of which, including anti–miR-33, are currently being investigated in clinical or preclinical trials and these results strongly suggest that inhibition of miR-33 may be a novel therapeutic strategy for AAA.
A review of the prior art does not provide a correlation between administration of any mir-33b inhibiting substance to prevent and treat any type of aneurysm in a subject.
The level of one of ordinary skill:
While the level of one of ordinary skill practicing said invention would be high, the level of predictability is considered variable as evident in the prior art discussed above and is not considered to provide sufficient enablement to practice the claimed invention.
Because the state of the prior art does not provide evidence of the degree of predictability that methods for treating any mir-33b inhibiting substance to prevent and treat any type of aneurysm in a subject, one of ordinary skill in the art would look for guidance or direction in the instant specification.
The level of predictability in the art:
“The “predictability or lack thereof” in the art refers to the ability of one skilled in the art to extrapolate the disclosed or known results to the claimed invention. If one skilled in the art can readily anticipate the effect of a change within the subject matter to which the claimed invention pertains, then there is predictability in the art. On the other hand, if one skilled in the art cannot readily anticipate the effect of a change within the subject matter to which that claimed invention pertains, then there is lack of predictability in the art. Accordingly, what is known in the art provides evidence as to the question of predictability.” (MPEP 2164.03).
The amount of direction provided by the inventor:
The amount of guidance or direction needed to enable the invention is inversely related to the amount of knowledge in the state of the art as well as the predictability in the art. In re Fisher, 427 F.2d 833, 839, 166 USPQ 18, 24 (CCPA 1970). The “amount of guidance or direction” refers to that information in the application, as originally filed, that teaches exactly how to make or use the invention. The more that is known in the prior art about the nature of the invention, how to make, and how to use the invention, and the more predictable the art is, the less information needs to be explicitly stated in the specification. In contrast, if little is known in the prior art about the nature of the invention and the art is unpredictable, the specification would need more detail as to how to make and use the invention in order to be enabling. >See, e.g., Chiron Corp. v. Genentech Inc., 363 F.3d 1247, 1254, 70 USPQ2d 1321, 1326 (Fed. Cir. 2004).
The existence of working examples:
The working embodiment in the instant application describes methods of using miR-33b knock-out in mice in a calcium chloride-induced aortic aneurism model and methods of suppressing aneurysm formation using an antisense oligonucleotides 33b-2-AmNA (12) (SEQ ID No. 8 in Table 1) in a calcium chloride-induced aortic aneurism mouse model. The working embodiments do not describe methods of preventing and treating any type of aneurism in a subject.
The standard of an enabling disclosure is not the ability to make and test if the invention works but one of the ability to make and use with a reasonable expectation of success. A patent is granted for a completed invention, not the general suggestion of an idea (MPEP 2164.03 and Chiron Corp. v. Genentech Inc., 363 F.3d 1247, 1254, 70 USPQ2d 1321, 1325-26 (Fed. Cir. 2004).
While the MPEP 2164.02 states the specification need not contain an example if the invention is otherwise disclosed in such manner that one skilled in the art will be able to practice it without an undue amount of experimentation. In re Borkowski, 422 F.2d 904, 908, 164 USPQ 642, 645 (CCPA 1970), the lack of a working example, however, is a factor to be considered, especially in a case involving an unpredictable and undeveloped art.
The quantity of experimentation needed to make or use the invention based on the content of the disclosure:
The prior art is undeveloped for the role miR-33b plays in all types of aneurysms. The specification does not provide sufficient guidance on using any miR-33b inhibitor and without further guidance, one of skill in the art would have to practice a substantial amount of trial and error experimentation, an amount considered undue and not routine, to practice the instantly claimed invention.
Conclusion
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/KIMBERLY CHONG/
Primary Examiner Art Unit 1636
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