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 .
Response to Amendment
The amendment filed February 6th, 2026 is acknowledged. Regarding the Office Action mailed October 8th, 2025:
The objections to the claims are withdrawn in view of the amendments.
Maintained, modified, or new grounds of rejection are set forth below, as necessitated by the amendments. Responses to arguments, if necessary, follow their respective rejection sections.
Claim Summary
Claims 1, 8, and 9 have been amended. Claims 6-7 and 11-17 have been canceled. Claims 1-5, 8-9, and 18-20 are pending. Claims 18-20 are withdrawn from consideration as being drawn to a non-elected invention/species. Claims 1-5 and 8-9 are under examination and discussed in this Office action.
Nucleotide and/or Amino Acid Sequence Disclosures - New - Necessitated by Further Considerations
REQUIREMENTS FOR PATENT APPLICATIONS CONTAINING NUCLEOTIDE AND/OR AMINO ACID SEQUENCE DISCLOSURES
Items 1) and 2) provide general guidance related to requirements for sequence disclosures.
37 CFR 1.821(c) requires that patent applications which contain disclosures of nucleotide and/or amino acid sequences that fall within the definitions of 37 CFR 1.821(a) must contain a "Sequence Listing," as a separate part of the disclosure, which presents the nucleotide and/or amino acid sequences and associated information using the symbols and format in accordance with the requirements of 37 CFR 1.821 - 1.825. This "Sequence Listing" part of the disclosure may be submitted:
In accordance with 37 CFR 1.821(c)(1) via the USPTO patent electronic filing system (see Section I.1 of the Legal Framework for Patent Electronic System (https://www.uspto.gov/PatentLegalFramework), hereinafter "Legal Framework") as an ASCII text file, together with an incorporation-by-reference of the material in the ASCII text file in a separate paragraph of the specification as required by 37 CFR 1.823(b)(1) identifying:
the name of the ASCII text file;
ii) the date of creation; and
iii) the size of the ASCII text file in bytes;
In accordance with 37 CFR 1.821(c)(1) on read-only optical disc(s) as permitted by 37 CFR 1.52(e)(1)(ii), labeled according to 37 CFR 1.52(e)(5), with an incorporation-by-reference of the material in the ASCII text file according to 37 CFR 1.52(e)(8) and 37 CFR 1.823(b)(1) in a separate paragraph of the specification identifying:
the name of the ASCII text file;
the date of creation; and
the size of the ASCII text file in bytes;
In accordance with 37 CFR 1.821(c)(2) via the USPTO patent electronic filing system as a PDF file (not recommended); or
In accordance with 37 CFR 1.821(c)(3) on physical sheets of paper (not recommended).
When a “Sequence Listing” has been submitted as a PDF file as in 1(c) above (37 CFR 1.821(c)(2)) or on physical sheets of paper as in 1(d) above (37 CFR 1.821(c)(3)), 37 CFR 1.821(e)(1) requires a computer readable form (CRF) of the “Sequence Listing” in accordance with the requirements of 37 CFR 1.824.
If the "Sequence Listing" required by 37 CFR 1.821(c) is filed via the USPTO patent electronic filing system as a PDF, then 37 CFR 1.821(e)(1)(ii) or 1.821(e)(2)(ii) requires submission of a statement that the "Sequence Listing" content of the PDF copy and the CRF copy (the ASCII text file copy) are identical.
If the "Sequence Listing" required by 37 CFR 1.821(c) is filed on paper or read-only optical disc, then 37 CFR 1.821(e)(1)(ii) or 1.821(e)(2)(ii) requires submission of a statement that the "Sequence Listing" content of the paper or read-only optical disc copy and the CRF are identical.
Specific deficiencies and the required response to this Office Action are as follows:
Specific deficiency - This application contains sequence disclosures in accordance with the definitions for nucleotide and/or amino acid sequences set forth in 37 CFR 1.821(a)(1) and (a)(2). However, this application fails to comply with the requirements of 37 CFR 1.821 - 1.825.
A SEQ ID appearing in the specification but not the sequence listing is noted on page 22 of the specification. The oligo designated SEQ ID NO:12 does not appear in the sequence listing as filed.
Required response – Applicant must provide:
A "Sequence Listing" part of the disclosure, as described above in item 1); as well as
An amendment specifically directing entry of the "Sequence Listing" part of the disclosure into the application in accordance with 1.825(b)(2);
A statement that the "Sequence Listing" includes no new matter in accordance with 1.825(b)(5); and
A statement that indicates support for the amendment in the application, as filed, as required by 37 CFR 1.825(b)(4).
If the "Sequence Listing" part of the disclosure is submitted according to item 1) a) or b) above, Applicant must also provide:
A substitute specification in compliance with 37 CFR 1.52, 1.121(b)(3) and 1.125 inserting the required incorporation-by-reference paragraph, consisting of:
A copy of the previously-submitted specification, with deletions shown with strikethrough or brackets and insertions shown with underlining (marked-up version);
A copy of the amended specification without markings (clean version); and
A statement that the substitute specification contains no new matter;
If the "Sequence Listing" part of the disclosure is submitted according to item 1) b), c), or d) above, Applicant must also provide:
A replacement CRF in accordance with 1.825(b)(6); and
Statement according to item 2) a) or b) above.
The Examiner would also like to note for the Applicant that there are a number of sequence informalities identified in the specification, described below.
Specification
The disclosure is objected to because of the following informalities: on pages 22-23, there are several informalities regarding the disclosed oligos and primers. These are:
Because SEQ ID NO:12 is missing from the sequence listing as noted above, all disclosed sequences following SEQ ID NO:12 have the incorrect sequence identifier as compared to the currently filed sequence listing.
The sequence noted as SEQ ID NO:17 in the specification has one additional nucleotide on the end of the sequence as compared to the corresponding sequence, SEQ ID NO:16, in the sequence listing (SEQ ID NO:16 in the listing given the above discrepancy caused by the missing sequence).
The sequence noted as SEQ ID NO:21 in the specification has one additional nucleotide on the end of the sequence as compared to the corresponding sequence, SEQ ID NO:20, in the sequence listing (SEQ ID NO:20 in the listing given the above discrepancy caused by the missing sequence).
The sequence noted as SEQ ID NO:5 in the specification appears to indicate that there are 25 T’s near the end of the primer. This is also how the sequence is described earlier in the specification on page 17. However, SEQ ID NO:5 as it appears in the sequence listing has 1 T followed by 24 A’s near the end of the primer.
The Examiner advises the Applicant to closely review both the sequence listing and specification to clarify these noted informalities and bring both the sequence listing and specification into agreeance. Appropriate correction is required.
Claim Rejections - 35 USC § 112(b) - Modified - Necessitated by Amendment
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.
Claims 1-5 and 8-9 are 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 1 recites the limitation "wherein the enzymatically adenylating the phosphorylated 5' ends of the plurality of the RNA fragments is performed using a cyclase and a polymerase configured as a single fusion protein, wherein the cyclase comprises an RtcA enzyme; e) enzymatically polyadenylating 3' ends of the plurality of RNA fragments comprising the free 3' hydroxyls using the single fusion protein to provide a plurality of RNA fragments comprising polyadenylated 3' ends". It is unclear from this recitation which aspects of the adenylation are accomplished by which enzymatic function of the fusion protein. As currently written, there is a lack of clarity as to if 5’ ends are adenylated by both the cyclase and polymerase function, 5’ ends are adenylated by the cyclase function, 5’ ends are adenylated by the polymerase function, 3’ ends are polyadenylated by both the cyclase and polymerase function, 3’ ends are polyadenylated by the cyclase function, or 3’ ends are polyadenylated by the polymerase function. Claims 2-5 and 8-9 are also rejected here for their dependence on claim 1 and not fully rectifying the identified issues.
Response to Arguments
Applicant's arguments filed February 6th, 2026 have been fully considered but they are not persuasive.
The Applicant argues that given the amendment to specify that the cyclase and polymerase are present in a single fusion protein, it is therefore clear that the fusion protein performs both functions as claimed (Page 5 of the Remarks filed February 6th, 2026).
In response to this argument, it is noted that while the amendment has introduced a fusion protein, the claim language as written recites that the enzymatic activities are performed using a cyclase and a polymerase. It is well known in the art that cyclase can enzymatically adenylate phosphorylated 5’ ends of RNA (see Chakravarty, RNA 3′-Phosphate Cyclase (RtcA) Catalyzes Ligase-like Adenylylation of DNA and RNA 5′-Monophosphate Ends, Journal of Biological Chemistry, February 2011, 286, 4117-4122; cited in the IDS filed August 3rd, 2022), with no identified 3’ polyadenylation function. Similarly, it is well known in the art that a poly(A) polymerase can enzymatically polyadenylate 3’ ends of RNA (see Introduction of Hajnsdorf, RNA polyadenylation and its consequences in prokaryotes, Philosophical Transactions of the Royal Society B, November 2018, 373, 1-9), with no identified 5’ adenylation function. By maintaining the recitation that these enzymatic functions are performed using a cyclase and a polymerase, even with them being configured as a fusion protein, it is still unclear which part of the fusion protein is intended to perform which function. Thus, the argument is not persuasive and the rejection is maintained.
Claim Rejections - 35 USC § 112(a) - New - Necessitated by Amendment
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.
Scope of Enablement
Claims 1-5 and 8-9 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 polynucleotide kinase (PNK) enzymatically phosphorylating the 5’ ends of the plurality of RNA fragments comprising mono-phosphorylated 5’ ends and PNK enzymatically dephosphorylating 3’ ends of RNA fragments to provide fragments with free 3’ hydroxyls, it does not reasonably provide enablement for any kinase enzymatically phosphorylating the 5’ ends of the plurality of RNA fragments comprising mono-phosphorylated 5’ ends and any kinase enzymatically dephosphorylating 3’ ends of RNA fragments to provide fragments with free 3’ hydroxyls as embraced by the claims. 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.” See MPEP § 2164. These factors include, but are not limited to: the breadth of the claims, the nature of the invention, the state of the prior art, the level of one of ordinary skill, the level of predictability in the art, the amount of direction provided by the inventor, the existence of working examples, the quantity of experimentation needed to make or use the invention based on the content of the disclosure.
The office has analyzed the specification in direct accordance to the factors outlines in In re Wands. MPEP 2164.04 states: “[W]hile the analysis and conclusion of a lack of enablement are based on factors discussed in MPEP 2164.01(a) and the evidence as whole, it is not necessary to discuss each factor in written enablement rejection.” These factors will be analyzed, in turn, to demonstrate that one of ordinary skill in the art would have had to perform “undue experimentation” to make and/or use the invention and therefore, applicant’s claims are not enabled.
(A) With respect to the breadth of the claims: Claim 1 as currently drafted encompasses a method for determining nucleotide sequences of RNA polynucleotides, comprising steps of enzymatically phosphorylating 5’ ends of RNA fragments and enzymatically dephosphorylating 3’ ends of RNA fragments with a kinase. “A kinase” does not limit the kinase in question to the PNK as described in the specification. Consequently, the breadth of the claim is expansive. Claims 2-5 an 8-9 encompass the same breadth as claim 1 since they do not limit the kinase to PNK.
(B) The nature of the invention: The invention is in the field of improved compositions and methods for RNA sequence (Page 1 of the instant specification).
(C), (D), (E) With respect to the state of the prior art, the level of one of ordinary skill and predictability of the art: Dobson (The phosphatase activity of mammalian polynucleotide kinase takes precedence over its kinase activity in repair of single strand breaks, Nucleic Acids Research, April 2006, 34, 2230-2237) teaches on mammalian PNKs and their bifunctional activities of 5’ kinase and 3’ phosphatase (e.g. 5’ phosphorylation and 3’ dephosphorylation) (Page 2230, column 2, paragraph 2).
Zhu (Structure–function analysis of the 3′ phosphatase component of T4 polynucleotide kinase/phosphatase, Virology, September 2007, 366, 126-126; previously cited) teaches on T4 polynucleotide kinase, an enzyme capable of converting broken ends of RNA or DNA from 3′PO4/5′OH ends to 3′OH/5′PO4 ends (e.g. 5’ phosphorylation and 3’ dephosphorylation) (Page 127, Introduction). This is accomplished by the enzyme possessing both a kinase and a phosphatase domain (Page 127, Introduction).
Taken together, the art supports use of PNKs for both 5’ phosphorylation and 3’ dephosphorylation enzymatic activity on RNA ends. There is no art found by the Examiner that suggests there are other types of kinase with both of these enzymatic activities. Therefore, methods comprising any kinase remain highly unpredictable.
The invention is drawn to biological molecules, and is therefore in a class of invention which the CAFC has characterized as “the unpredictable arts such as chemistry and biology.” Mycogen Plant Sci., Inc. v. Monsanto Co., 243 F.3d 1316, 1330 (Fed. Cir. 2001). The level of skill in the art is therefore deemed to be high.
(F), (G) With respect to the amount of direction and working examples provided by the applicant: The Applicant has provided description and working examples directed to the use of a PNK for both 5’ phosphorylation and 3’ dephosphorylation of RNA fragments (Page 9, lines 9-12; Page 17, lines 16-20; Page 21, For adenylation; Page 24, 3’ & 5’ Adenylation). The Applicant clearly states on Page 17 that a PNK is suitable for use to phosphorylate 5’ ends and dephosphorylate 3’ ends of RNA.
The applicants have not provided description or working examples comprising any other kinases capable of performing these enzymatic activities.
(H) Undue experimentation would be required to practice the invention as claimed due to the amount of experimentation necessary because of the expansive breadth of the claims, the state of the prior art and its high predictability, and the limited amount of guidance in the form of varied working examples in the specification. A skilled artisan recognizes that PNKs are a distinct type of kinase with the enzymatic activities as claimed, and thus applicability of the claimed method to any kinase as embraced by the claim remains unpredictable, requiring undue experimentation.
For instance, to determine if any other kinase was capable of 5’ phosphorylation and 3’ dephosphorylation of RNA, all available kinases would need to be experimentally examined for this enzymatic behavior. This is a large amount of experimentation with unpredictable results as it applies to the usefulness of any kinase in the method as claimed.
MPEP §2164.01(a), 4th paragraph, provides that, “A conclusion of lack of enablement means that, based on the evidence regarding each of the above factors, the specification, at the time the application was filed, would not have taught one skilled in the art how to make and/or use the full scope of the claimed invention without undue experimentation. In re Wright, 999 F.2d 1157, 1562; 27 USPQ2d 1510, 1513 (Fed. Cir. 1993).
Genentech Inc. v. Novo Nordisk A/S, 42 USPQ2d 1001, 1005 (CA FC), states that, “[p]atent protection is granted in return for an enabling disclosure of an invention, not for vague intimations of general ideas that may or may not be workable,” citing Brenner v. Manson, 383 U.S. 519, 536 (1966) (stating, in the context of the utility requirement, that “a patent is not a hunting license. It is not a reward for search, but compensation for its successful conclusion”). The Genentech decision continued, “tossing out the mere germ of an idea does not constitute enabling disclosure. While every aspect of a generic claim certainly need not have been carried out by an inventor, or exemplified in the specification, reasonable detail must be provided in order to enable members of the public to understand and carry out the invention.” Id. at p. 1005.
After applying the Wands factors and analysis to claims 1-5 and 8-9, in view of the applicant’s entire disclosure, and considering the In re Wright, In re Fisher and Genentech decisions discussed above, it is concluded that the practice of the full scope of the invention as claimed would not be enabled by the written disclosure. Therefore, claims 1-5 and 8-9 are rejected under 35 U.S.C. §112(a) for failing to disclose sufficient information to enable a person of skill in the art to practice the claimed invention to it the full scope embraced by the claims.
Prior Art
It is noted that the prior art made of record and not relied upon in the previous Office Action remains the closest prior art to the method as claimed. However, it is particularly noted that there is no prior art that teaches or suggests a cyclase and a polymerase configured as a fusion protein. Therefore, there is no prior art rejection given the lack of prior teaching or suggestion of this fusion protein.
Conclusion
All claims stand rejected.
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.
Any inquiry concerning this communication or earlier communications from the examiner should be directed to Allison E Schloop whose telephone number is (703)756-4597. The examiner can normally be reached Monday-Friday 8:30-5 ET.
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/ALLISON E SCHLOOP/Examiner, Art Unit 1683
/ANNE M. GUSSOW/Supervisory Patent Examiner, Art Unit 1683
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