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 05/19/2026 has been considered. Rejections and/or objections not reiterated from the previous office action mailed 02/19/2026 are hereby withdrawn.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 05/19/2026, claims 1-5, 7-13, 15-17, 19, 20, 24, 28 and 34 are pending and are currently under examination.
New Rejections
Claim Rejections - 35 USC § 102
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 the appropriate paragraphs of 35 U.S.C. 102 that form the basis for the rejections under this section made in this Office action:
A person shall be entitled to a patent unless –
(a)(1) the claimed invention was patented, described in a printed publication, or in public use, on sale or otherwise available to the public before the effective filing date of the claimed invention.
Claim(s) 1, 3, 5, 12, 13, 17-20, 24, 28 and 34 is/are rejected under 35 U.S.C. 102(a)(1) as being anticipated by Seth et al. (US 20170355727).
Seth et al. et al. teach an ASO gapmer comprising at least 14 nucleotides in length comprising a 5-10-5 configuration of 5’ and 3’ wings of locked nucleotides and a central gap having 10 nucleotides and conjugated to GalNac (see Table 21). Seth et al. teach GalNAc formulas (pg 102-104, 109, 116, 127). Seth et al. teach the ASO can have a G-clamp modified nucleotide (0499) and phosphorothioate linkages (0535-0537). Seth et al. teach pharmaceutical compositions and methods of targeting HBV and decreasing expression (0792).
Thus Seth et al. anticipates the instant claims.
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 7-11, is/are rejected under 35 U.S.C. 103 as being unpatentable over Seth et al. (US 20170355727) and Miroshnichenko et al. (PNAS | January 22, 2019 | vol. 116 | no. 4 | 1229–1234 cited on 892 mailed 09/18/2025).
Seth et al. is relied on as above.
Seth et al. do not teach using mesyl phosphoramidate linkages.
Miroshnichenko et al. teach the use of mesyl phosphoramidate linkages in antisense oligonucleotides as an alternative to phosphorothioate linkages (see page 1230 first col.). Miroshnichenko et al. teach an ASO fully modified with a mesyl phosphoramidate linkages. Miroshnichenko et al. concludes that μ-ODNs can be an attractive alternative to PS-ODNs as a potent tool in antisense applications and in other cases to prevent the synthesis, expression of RNAs and stability (see page 1233 last para col. 1 and abstract).
It would have been obvious to one of ordinary skill in the art to incorporate mesyl phosphoramidate linkages throughout the ASO taught by Seth et al. to improve effects often seen with phosphorothioate linkages. One would have wanted to use said linkages because they are known to have advantages such as RNA affinity and nuclease stability as taught by Miroshnichenko et al.
Miroshnichenko et al. teach ASOs with mesyl linkages have lower toxicity compared to phosphorothioate and more efficient activation of RNase H, one of skill in the art would have wanted to try incorporating the mesyl linkages into the gapmers in different locations on the nucleotide strand to improve the toxicity and functionality. Moreover, given there was a need to improve ASOs and Miroshnichenko et al. teach a finite number of options, incorporation of mesyl linkages, one of skill in the art would have used this option.
Therefore given Miroshnichenko et al.. teach mesyl linkages have lower toxicity compared to phosphorothioate and more efficient activation of RNase H, there is an expectation of an advantage for their use and thus a motivation to combine the prior art references for use with any type of oligonucleotide (see MPEP 2144).
MPEP 2144:
THE EXPECTATION OF SOME ADVANTAGE IS THE STRONGEST RATIONALE FOR COMBINING REFERENCES
The strongest rationale for combining references is a recognition, expressly or impliedly in the prior art or drawn from a convincing line of reasoning based on established scientific principles or legal precedent, that some advantage or expected beneficial result would have been produced by their combination. In re Sernaker, 702 F.2d 989, 994-95, 217 USPQ 1, 5-6 (Fed. Cir. 1983). See also Dystar Textilfarben GmbH & Co. Deutschland KG v. C.H. Patrick, 464 F.3d 1356, 1368, 80 USPQ2d 1641, 1651 (Fed. Cir. 2006) ("Indeed, we have repeatedly held that an implicit motivation to combine exists not only when a suggestion may be gleaned from the prior art as a whole, but when the ‘improvement’ is technology-independent and the combination of references results in a product or process that is more desirable, for example because it is stronger, cheaper, cleaner, faster, lighter, smaller, more durable, or more efficient. Because the desire to enhance commercial opportunities by improving a product or process is universal—and even common-sensical—we have held that there exists in these situations a motivation to combine prior art references even absent any hint of suggestion in the references themselves.").(emphasis added).
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.
Maintained Rejections
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 rejection of claims 7-11 under 35 U.S.C. 103 as being unpatentable over Miraglia et al. (US 20030203862) and Miroshnichenko et al. (PNAS | January 22, 2019 | vol. 116 | no. 4 | 1229–1234 cited on 892 mailed 09/18/2025) is maintained for the reasons of record. Claim 8 was inadvertently omitted should have been included in the rejection as the subject matter of the rejection encompassed claim 8.
Response to Arguments
Applicant disagrees that the combination is simple because both references involve RNase H. Applicant argues Miraglia et al. relates to gapmer ASO’s with phosphorothioate backbones and LNA wings and Miroshnichenko, by contrast, targets microRNAs using fully mesyl phosphoramidate-modified oligonucleotides. Applicant argues the Examiner cannot pick and choose discrete elements from objectively different compounds to make the combination obvious. Miroshnichenko et al. Applicant argues even if Miroshnichenko reports RNase H activity for fully mesyl-phosphoramidate ODNs in its particular anti-miR system, this does not provide a reasonable expectation that introducing mesyl phosphoramidate linkages into Miraglia's distinct gapmer architecture would successfully preserve RNase H-mediated activity and overall performance.
This argument is not persuasive. While it is true that Miroshnichenko et al. state most chemically modified ONs developed so far, such as RNA duplexes fully modified with 2’-OMe or 2’-MOE or LNAs, do not have RNase-H activity ability, this does not dissuade one of skill in the art for having the motivation to try introducing mesyl phosphoramidate linkages given the benefits taught by Miroshnichenko et al. Miroshnichenko et al. teach one of the incentives for chemical modification of AONs is the enhancement of their resistance to nuclease digestion. μ-ODNs have outstanding stability and such modifications provide higher binding affinity, nuclease resistance, and RNase H recruitment (conclusion). So even if some of the modifications argued by Applicant were true, Miroshnichenko et al. clearly provides the motivation to try adding mesyl phosphoramidate linkages to the gapmer taught by Miraglia et al. Miroshnichenko et al. concludes that μ-ODNs can be an at tractive alternative to PS-ODNs as a potent tool in antisense applications and in other cases to prevent the synthesis and expression of RNAs and that the μ-modification in the context of 2′-OMe or 2′-MOE RNA, LNA, or another non RNase H-supporting backbone may be suitable for steric block antisense approaches, such as splice modulation.
Applicant argues the Office Actions “finite number of options” rational amounts to selecting Applicant’s claimed modification pattern based on impermissible hindsight. In response, the claimed ASO does not have a modification pattern to incorporate a certain number of mesyl phosphoramidate. It would have been obvious to incorporate mesyl phosphoramidate linkages into the antisense oligonucleotide of Miraglia et al. to take advantage of the benefits taught by Miroshnichenko et al. MPEP 2144 states the expectation of some advantages is the strongest rational for combining references.
In response to applicant's argument that the examiner's conclusion of obviousness is based upon improper hindsight reasoning, it must be recognized that any judgment on obviousness is in a sense necessarily a reconstruction based upon hindsight reasoning. But so long as it takes into account only knowledge which was within the level of ordinary skill at the time the claimed invention was made, and does not include knowledge gleaned only from the applicant's disclosure, such a reconstruction is proper. See In re McLaughlin, 443 F.2d 1392, 170 USPQ 209 (CCPA 1971).
Claim Rejections - 35 USC § 112
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.
Claim 34 is 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 inhibiting expression of HBV using the claimed ASO gapmer comprising the claimed modifications, does not reasonably provide enablement for methods of decreasing expression of any target gene in a subject using the claimed ASO. 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/or 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 nature of the invention:
The breadth of claim 34 encompasses using any ASO comprising 14-22 nucleotides having a central, 5’ and 3’ region and comprising at least one modified nucleotides as in claim 1 to target any gene in any cell type and reduce expression of the gene.
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 state of the art teach that [w[]ile in vitro mRNA knockdown assays are typically reasonable predictors of in vivo results, G-Clamp modified antisense oligonucleotides have poor in vivo mRNA knockdown as compared to transfected cell based assays. For LNA gapmers, knockdown is seen to be highly sensitive to the length of the antisense and number of LNA insertion (see Stanton et al. "Chemical modification study of antisense gapmers." Nucleic acid therapeutics 22.5 (2012): 344-359) of record cited on 892 mailed 02/19/2026). Stanton et al. concludes that [t]he work presented has clearly shown the significant impact that subtle changes in chemical design and modification patterns can have on the activity, physical properties, and toxicity of short antisense gapmers. Stanton et al. teach the need to evaluate sequence modification combinations on a case by case basis and therefore teach the unpredictability of antisense gapmers on reducing target gene expression.
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 using any of the broadly claimed antisense gapmers can reduce expression of any target gene in any cell, 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 using sequences of the claimed antisense gapmer targeted to HBV in vivo and in vitro that showed improved potency (Ex. 5). The working embodiments do not describe inhibiting expression of any target gene using any antisense oligonucleotide 14-22 nucleotides in length comprising any of the claimed modified nucleotides.
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 the claimed antisense oligonucleotides having in reducing expression of any target gene in any cell or subject 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.
Reasons for Allowable Subject Matter
Claims 2 and 4 are free of the prior art searched. The prior art does not teach or make obvious an antisense oligonucleotide having a gapmer motif comprising a combination of G-clamp, Gutb, Nmln or 5prnl modified nucleotides.
The prior art of Flanagan et al. (of record cited on 892 mailed 02/19/2026) teach the G-clamp heterocycle modification, a cytosine analog that clamps on to guanine by forming an additional hydrogen bond, was rationally designed to enhance oligonucleotide-RNA hybrid affinity. Flanagan et al. teach incorporation of a single G-clamp modification into a previously optimized 20-mer phosphorothioate antisense S-ON targeting c-raf increased the potency of the S-ON 25-fold. The G-clamp heterocycle is a potent, mismatch-sensitive, automated synthesizer- compatible antisense S-ON modification that will have important applications in the elucidation of gene function, the validation of gene targets, and the development of more potent antisense-based pharmaceuticals (see abstract).
The prior art of Shrestha et al. (of record cited on 892 mailed 02/19/2026) teach guanidine bridged nucleic acids (GuNA) modification of an antisense oligonucleotide, placed at the terminal ends, increased the binding affinity for the target and had increased stability (see Fig. 1 and page 576).
Neither of these reference teach or make obvious the combination as claimed.
Conclusion
Any inquiry concerning this communication or earlier communications from the examiner should be directed to Kimberly Chong at (571)272-3111. The examiner can normally be reached Monday thru Friday between M-F 8:00am-4:30pm.
If attempts to reach the examiner by telephone are unsuccessful please contact the SPE for 1636 Neil Hammell at 571-272-5919. The fax phone number for the organization where this application or proceeding is assigned is 571-273-8300.
Patent applicants with problems or questions regarding electronic images that can be viewed in the Patent Application Information Retrieval system (PAIR) can now contact the USPTO’s Patent Electronic Business Center (Patent EBC) for assistance. Representatives are available to answer your questions daily from 6 am to midnight (EST). The toll free number is (866) 217-9197. When calling please have your application serial or patent number, the type of document you are having an image problem with, the number of pages and the specific nature of the problem. The Patent Electronic Business Center will notify applicants of the resolution of the problem within 5-7 business days. Applicants can also check PAIR to confirm that the problem has been corrected. The USPTO’s Patent Electronic Business Center is a complete service center supporting all patent business on the Internet. The USPTO’s PAIR system provides Internet-based access to patent application status and history information. It also enables applicants to view the scanned images of their own application file folder(s) as well as general patent information available to the public. For more information about the PAIR system, see http://pair-direct.uspto.gov.
For all other customer support, please call the USPTO Call Center (UCC) at 800-786-9199.
/KIMBERLY CHONG/
Primary Examiner Art Unit 1636
Prosecution Insights