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 .
Application Status
Claims 9-22, 24-25, 27-29 and 36-37 are pending and under examination.
There is a typographical error in the claim set filed February 2, 2024. Claim 36 is indicated as both “cancelled” and “currently amended”. In the claim set as originally filed, claim 36 is directed to a “kit” which is also the claimed subject matter for claim 36 in the 2/2/2024 claim set. As such, the 2/2/2026 claim set should read “30-35 (Cancelled)”.
Drawings
The drawings are objected to because they were submitted in color, but there is no granted petition to accept color drawings. See 37 CFR 1.84(a)(2) (“The Office will accept color drawings in utility patent applications only after granting a petition filed under this paragraph explaining why the color drawings are necessary”). Applicants must either provide that explanation via a petition and comply with all requirements of 37 CFR 1.84(a)(2)(i)-(iii) OR submit replacement sheets in black and white and include a clear instruction to replace the color drawings with the replacement sheets. The examiner takes no position on whether color drawings are necessary as the only practical medium by which to disclose the subject matter sought to be patented in this utility patent application.
Corrected drawing sheets in compliance with 37 CFR 1.121(d) are required in reply to the Office action to avoid abandonment of the application. Any amended replacement drawing sheet should include all of the figures appearing on the immediate prior version of the sheet, even if only one figure is being amended. The figure or figure number of an amended drawing should not be labeled as “amended.” If a drawing figure is to be canceled, the appropriate figure must be removed from the replacement sheet, and where necessary, the remaining figures must be renumbered and appropriate changes made to the brief description of the several views of the drawings for consistency. Additional replacement sheets may be necessary to show the renumbering of the remaining figures. Each drawing sheet submitted after the filing date of an application must be labeled in the top margin as either “Replacement Sheet” or “New Sheet” pursuant to 37 CFR 1.121(d). If the changes are not accepted by the examiner, the applicant will be notified and informed of any required corrective action in the next Office action. The objection to the drawings will not be held in abeyance.
Specification
The use of the term QuikChange®, Gibson Assembly®, gBlock®, Magnosphere®, GlycoBlueTM, Stratalinker®, HighPrepTM, SYBR®, QiaQuick®, TapeStation®, MiSeq®, NovaSEQTM, TRizolTM, TURBO DNaseTM, Magna MeRIPTM, Incucyte®, OptiMEM®, Freestyle®, and Lipofectamine®, which are trade names or marks used in commerce, has been noted in this application. The term should be accompanied by the generic terminology; furthermore the term should be capitalized wherever it appears or, where appropriate, include a proper symbol indicating use in commerce such as ™, SM , or ® following the term.
Although the use of trade names and marks used in commerce (i.e., trademarks, service marks, certification marks, and collective marks) are permissible in patent applications, the proprietary nature of the marks should be respected and every effort made to prevent their use in any manner which might adversely affect their validity as commercial marks.
Claim Objections
Claims 15, 18 and 36 are objected to because “anti-sense” should not be hyphenated. The term of the art is “antisense oligonucleotide”.
Appropriate correction is required.
Claim Interpretation
The claims recite “an antisense oligonucleotide (ASO)”. Although, the specification does not define an ASO, it provides examples of ASO sequences/structures ([0052]). Each of the exemplified ASOs are 20 nucleotides in length and are 100% complementary to the HOTAIR lncRNA ([0052]). Additionally, the specification discusses CRISPR genome editing and guide RNAs for genome editing ([0053]). Although CRISPR guide RNAs are known in the art to be complementary to (i.e., antisense of) their target sequence, they are not referred to antisense oligonucleotides or ASOs. Therefore “an antisense oligonucleotide (ASO)” is interpreted a 15-30 nucleotide single stranded polynucleotide comprised of DNA, RNA or a combination of DNA/RNA nucleotides that is capable of hybridizing to the HOTAIR lncRNA at the A783 residue and flanking sequences, but does not associate with CRISPR effectors.
The claims also recite that the ASOs are capable of binding to, interfering with, reducing or blocking methylation of position A783. As such, the ASOs are also interpreted as being capable of the function of binding to, interfering with, reducing, or blocking methylation of the A783 site. Although claim 24 recites a composition comprising the ASOs reduce one or more of HOTAIR activities or reduces HOTAIR expression, claim 24 ultimate depends from claim 1 and so the ASOs must also being capable of functions including interfering with, reducing, or blocking methylation of the A783 site.
Claim Rejections - 35 USC § 112(b)
The following is a quotation of 35 U.S.C. 112(b):
(b) CONCLUSION.—The specification shall conclude with one or more claims particularly pointing out and distinctly claiming the subject matter which the inventor or a joint inventor regards as the invention.
The following is a quotation of 35 U.S.C. 112 (pre-AIA ), second paragraph:
The specification shall conclude with one or more claims particularly pointing out and distinctly claiming the subject matter which the applicant regards as his invention.
Claim 27 is rejected under 35 U.S.C. 112(b) or 35 U.S.C. 112 (pre-AIA ), second paragraph, as being indefinite for failing to particularly point out and distinctly claim the subject matter which the inventor or a joint inventor (or for applications subject to pre-AIA 35 U.S.C. 112, the applicant), regards as the invention.
Claim 27 recites “The method according to any one of claims 19-26, wherein…” Claim 26 is cancelled. Claim 27 is rejected as being incomplete because it depends directly from a canceled base claim. See MPEP 608.01(n)(V). This claim has not been further treated because it is incomplete.
Claim Rejections - 35 USC § 112(a) – Written Description
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 9-22, 24-25, 28-29 and 36-37 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 written description requirement. The claim(s) contains subject matter which was not described in the specification in such a way as to reasonably convey to one skilled in the relevant art that the inventor or a joint inventor, or for applications subject to pre-AIA 35 U.S.C. 112, the inventor(s), at the time the application was filed, had possession of the claimed invention.
MPEP 2163.II.A3.(a).(i) states, “whether the specification shows that applicant was in possession of the claimed invention is not a single, simple determination, but rather is a factual determination reached by considering a number of factors. Factors to be considered in determining whether there is sufficient evidence of possession include the level of skill and knowledge in the art, partial structure, physical and/or chemical properties, functional characteristics alone or coupled with a known or disclosed correlation between structure and function, and the method of making the claimed invention.”
Claim 9 recites ASOs capable of binding to, interfering with, reducing or blocking methylation of position A783 of the HOTAIR lncRNA. ASOs are known in the art to be 15-30 nucleotides in length that can hybridize to their target through base pairing. ASOs are typically 100% complementary to their target sequence but can have a mismatch. Thus, the genus of claimed ASOs encompasses short polynucleotides with 90-100% complementary to a region comprising position A783 and flanking sequence of SEQ ID NO 1, the HOTAIR lncRNA sequence. For the reasons explained below, at the time of the effective filing date (EFD) of the claimed invention, Applicant has not sufficiently described the ASOs that have the claimed function of binding to, interfering with reducing or blocking methylation of position A783 of the HOTAIR lncRNA.
The Specification provides 20 ASO sequences that are described as being able to “associate” with wildtype HOTAIR, each of which is 100% complementary to SEQ ID NO 1 ([0052]). However, Applicant does not demonstrate that the ASOs have any effect on A783 methylation or are capable of binding to A783 that has an m6A modification. As such it was unpredictable whether the recited ASOs were actually capable of binding to, interfering with, reducing or blocking methylation of position A783 of HOTAIR.
ASOs directed to HOTAIR have been used previously to reduced HOTAIR levels in cells. See e.g., Liu et al., BMC Cancer (2013), 13:464. Liu teaches three siRNAs (i.e., antisense oligonucleotides) targeted to HOTAIR were able to reduce HOTAIR expression by about 60% (Fig 2). Liu teaches the sequence of the siRNAs (page 2, ¶1), which are complementary to positions 1134-1158, 1447-1471 and 1606-1630 of SEQ ID NO 1. There is no indication in Liu that the siRNAs are capable of binding methylated RNA residues or affect N6 methyltransferase activity. Lennox and Behlke used various ASOs and siRNAs to target HOTAIR (Nucleic Acids Research (2016), 44: 863–877). They found that both siRNAs and ASOs were capable of reducing expression of HOTAIR between 40-95% (Fig 3), but like Liu, did not disclose whether the RNAi compounds could affect methylation status of HOTAIR. In fact, before the effective filing date of the claimed invention, it was completely unknown whether ASOs in general could block RNA methyltransferases from methylating adenosines in RNA.
N6-adenosine methylation is catalyzed by methyltransferases also known as “writers”. For a thorough review of N6-methladenosine methyltransferases published around the effective filing date of the claimed invention see Huang et al., J. Hematol Oncol (2021), 14:117. Up until 2019, the only means to effect N6-adenosine methylation was through inhibition of expression or activity of the methyltransferases, which would affect global N6-adenosine methylation (pages 11-12). In 2019 and 2021, two reports used CRISPR effectors fused to methyltransferases or demethylases to target the enzymes to specific residues on target RNAs (Fig 4). However, as noted above in paragraphs 9-10, the claimed ASOs do not encompass CRISPR guide RNAs that would function to target CRISPR effector fusions to HOTAIR. Liu does not mention ASOs or siRNAs a single time in reference to the methylated RNA target. Thus, at the EFD of the claimed invention it was entirely unpredictable whether ASOs would have any effect on methylation at an m6A site in a target RNA.
The first demonstration of using ASOs to affect RNA methylation did not come until July 2026, over 5 years after the EFD of the claimed invention (Ma et al., Nature Biomedical Engineering (2026): 1-14). Ma demonstrates that an ASO targeted to a known m6A site could reduce methylation of that site (Fig 3). However, Ma had to develop an entirely new technology to determine the effectiveness of the ASO, since quantifying the m6A level at a specific site is challenging (page 4, ¶2). Because it was not demonstrated that ASOs in general could modulate m6A methylation of a specific RNA until five years after the EFD, the skilled artisan would have concluded that Applicant did not possess ASOs that were known to be capable of interfering with, reducing or blocking methylation of position A783 of the HOTAIR lncRNA at the EFD of the claimed invention.
Dependent Claims
Claims 10-15 and 37 recite additional characteristics of the HOTAIR ASOs, such as length, specific sequences, conjugates and chemical modifications. However, because in 2021 it was completely unknown whether ASOs in general could block or interfere with RNA N6-adenosine methylation, the skilled artisan would have concluded that Applicant did not possess ASOs with the claimed function.
Claims 16-18 and 16 recite compositions and a kit comprising the ASOs, but without altering the functional limitations. The claims are rejected for the reasons described above for claim 9.
Claims 19-22, 24 and 28 recite methods of treating cancer using the ASO of claim 17, which is a composition comprising the ASO of claim 9. Although ASOs in general are known to decrease expression of the targeted RNA, and HOTAIR siRNAs have been used to increase apoptosis rates of cancer cells (Liu, Fig 3), the methods still encompass the ASOs having the claimed function of blocking or interfering with RNA N6-adenosine methylation altering the functional limitations. Thus, the claims are rejected for the reasons described above for claim 9.
Conclusion
No claims are allowed.
Any inquiry concerning this communication or earlier communications from the examiner should be directed to CATHERINE KONOPKA whose telephone number is (571)272-0330. The examiner can normally be reached Mon - Fri 7- 4.
Examiner interviews are available via telephone, in-person, and video conferencing using a USPTO supplied web-based collaboration tool. To schedule an interview, applicant is encouraged to use the USPTO Automated Interview Request (AIR) at http://www.uspto.gov/interviewpractice.
If attempts to reach the examiner by telephone are unsuccessful, the examiner’s supervisor, Ram Shukla can be reached at (571)272-0735. The fax phone number for the organization where this application or proceeding is assigned is 571-273-8300.
Information regarding the status of published or unpublished applications may be obtained from Patent Center. Unpublished application information in Patent Center is available to registered users. To file and manage patent submissions in Patent Center, visit: https://patentcenter.uspto.gov. Visit https://www.uspto.gov/patents/apply/patent-center for more information about Patent Center and https://www.uspto.gov/patents/docx for information about filing in DOCX format. For additional questions, contact the Electronic Business Center (EBC) at 866-217-9197 (toll-free). If you would like assistance from a USPTO Customer Service Representative, call 800-786-9199 (IN USA OR CANADA) or 571-272-1000.
/CATHERINE KONOPKA/Primary Examiner, Art Unit 1635
Prosecution Insights