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
This action is written in response to applicant’s correspondence received on 02/17/2026. Claims 19-38 are currently pending. Claims 26-29, 33-38 are withdrawn from prosecution as being drawn to nonelected subject matter. Accordingly, claims 19-25, 30-32 are examined herein. The restriction requirement mailed on 12/18/2025 is still deemed proper. Applicant elected Group I without traverse in the reply filed on 02/17/2026.
Election/Restrictions
Claims 26-29, 33-38 are withdrawn from further consideration pursuant to 37 CFR 1.142(b), as being drawn to a nonelected Group II, III, there being no allowable generic or linking claim. The newly added claims 37 and 38 are not elected in the response filed on 02/17/2026.
Information Disclosure Statement
The listing of references in the specification is not a proper information disclosure statement. 37 CFR 1.98(b) requires a list of all patents, publications, or other information submitted for consideration by the Office, and MPEP § 609.04(a) states, "the list may not be incorporated into the specification but must be submitted in a separate paper." Therefore, unless the references have been cited by the examiner on form PTO-892, they have not been considered.
Priority
Acknowledgment is made of applicant's claim for foreign priority based on an application filed in EP20306298 on 10/29/2020.
Receipt is acknowledged of certified copies of papers required by 37 CFR 1.55.
Drawings
The drawing is objected to because 37 CFR 1.84 (u)(1) states “View numbers must be preceded by the abbreviation "FIG.”.
In the current case, the view number for FIG 1 is preceded by the word "FIGURE" instead of
the abbreviation "FIG.".
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 disclosure is objected to because it contains an embedded hyperlink and/or other form of browser-executable code on page 30. Applicant is required to delete the embedded hyperlink and/or other form of browser-executable code; references to websites should be limited to the top-level domain name without any prefix such as http:// or other browser-executable code. See MPEP § 608.01.
The use of the term New England Biolabs, ThermoFisher, NzyTech, 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 Interpretation
Based on the specification (Pages 5-6, ¶[0014]-¶[0015]), the recitation “(alkyne/azide)” is interpreted as a nucleoside base modification which is independent from the 3’-O-blocking group, hence not impacted by the deblocking step in (b)(ii). The parentheses in the recited “(alkyne/azide)” are interpretated as that an nucleobase modification with either an alkyne group or an azide group is required for the nucleoside.
Claim Rejections - 35 USC § 112
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 19-25, 30-32 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.
Regarding claim 19, step (b) (ii) requires “deblocking the 3’-O-blocked elongated fragment…” in each cycle of the repeated elongation cycles set forth in step (b), such that after the final cycle, “deblocking is omitted”, indicating that at the end of step (b), the 3’-O-blocking group would have been removed in the ensuing deblocking step except for the 3’ terminal nucleoside.
1). Claim 19 recites “reacting a first label having an (alkyne/azide) group with the 3’-O-blocked-(alkyne/azide)-nucleoside triphosphate…” in step (c). This is considered indefinite because there is insufficient antecedent basis for this limitation in the claim, because the incorporated (alkyne/azide)-nucleoside triphosphate no longer carries a 3’-O-blocked group after deblocking in step (b).
2). The recitation “the 3’-blocked-(alkyne/azide)-nucleoside triphosphate” in step (c) is also considered indefinite because there is insufficient antecedent basis for this limitation in the claim, as step (A) only recites “3’-O-blocked-(alkyne/azide)-nucleoside triphosphate or a 3’-O-blocked …”.
3). Step (A) recites “a 3’-O-blocked-(protected alkyne/protected azide)-nucleoside triphosphate” as an alternative. Although the specification teaches that “deprotection must be carried out prior to performance of a "click" reaction” (¶[0014]; Page 6, line 2), the claim does not require “deprotection” of this specific group. Step (c) of the claim also does not recite this alternative of a 3’-O-blocked-(protected alkyne/protected azide)-nucleoside triphosphate. Therefore, it is not clear whether a 3’-O-blocked-(protected alkyne/protected azide)-nucleoside triphosphate is required for the claimed method.
Those claims identified in the statement of rejection but not explicitly referenced in the rejection are also rejected for depending from a rejected claim 19 but failing to remedy the indefiniteness therein.
Claim Rejections - 35 USC § 112 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 1-5, 9-23, 27 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 claims contain 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 pre-AIA the inventor(s), at the time the application was filed, had possession of the claimed invention.
MPEP 2163.II.A.3.(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”.
For claims drawn to a genus, MPEP § 2163 states the written description requirement for a claimed genus may be satisfied through sufficient description of a representative number of species by actual reduction to practice, reduction to drawings, or by disclosure of relevant, identifying characteristics, i.e., structure or other physical and/or chemical properties, by functional characteristics coupled with a known or disclosed correlation between function and structure, or by a combination of such identifying characteristics, sufficient to show the applicant was in possession of the claimed genus. See Eli Lilly, 119 F.3d at 1568, 43 USPQ2d at 1406.
The independent claim 19 directs to a method of synthesizing polynucleotide probe with a plurality of labels using an extremely broad genus of enzyme variants wherein the claimed product genus relies on a functional limitation “template-independent DNA polymerase”, whereas no common structure underlying the functional limitation is disclosed. In another word, it claims what the product does instead of what the product is.
The specification mentions terminal deoxynucleotidyl transferase (TdT) or variants thereof under conditions effective for the enzymatic incorporation of the 3'-O-protected-dNTP onto the 3' end of the initiator polynucleotides (Page 10, ¶[0024], lines 4-7). However, not a single example of template-independent DNA polymerase is described in the specification to demonstrate the capacity to incorporate nucleosides with dual modifications, i.e. 1) a 3’-O-blocking group ribose modification AND 2) a (alkyne/azide) click chemistry nucleobase modification, for one or more repeated cycles of polynucleotide elongation, as required by the claim. Although numerous mutant variants of TdT are recited in the specification on pages 20-22 in Table 1 and Table 2, there is no teaching regarding the capacity of any of these variants or the structural underpinnings that enable repeated cycles of polynucleotide elongation using nucleosides with dual modifications. Hence, the disclosure is silent on the structure enabling the completion of the claimed steps, thus does not sufficiently represent the genus as claimed.
Regarding the state of the art, Chen (WO2020161480A1, published on 08/13/2020) teaches that terminal deoxynucleotidyl transferase (TdT) enzymes, the homologous enzymes Polμ, Polβ, Polλ, and PolΘ of any species, or the homologous X family polymerases of any species, can be used in a method of template independent nucleic acid synthesis (Page 2, lines 4-10). Also, under the Broadest Reasonable Interpretation (BRI), the genus encompasses any mutated variants of wildtype template-independent DNA polymerases described above. Yamtich (Biochim Biophys Acta. 2010 May;1804(5):1136-50) teaches that, despite sequence homology among the members of the polymerase family X, Pols β, λ, and μ participate in different cellular functions due to subtle structural differences and tissue-specific expression. These structural differences result in enzymes that interact with DNA in different ways (Page 1146, Table 1; Right column, 2nd ¶, lines 1-5). No record of the art indicates that any of these species is capable of catalyzing repeated cycles of polynucleotide elongation using nucleosides with dual modifications.
These are clear evidence that there is a high degree of structural variance and unpredictability regarding the structure of template-independent DNA polymerases. However, there is insufficient description of what structure meets the functional limitations set forth by the claim.
The disclosure of zero working species of a broad genus, the high degree of variation in the art, and the failure to disclose correlation between structure in the specification and the claimed function led to the determination that claim 19 is overly broad with insufficient evidence of possession at the time of filing to one skilled in the art. Thus, claim 19 does not meet the written description requirement, and the specification demonstrates a clear lack of possession of the full genus as claimed.
Claims 20-25, 30-32 are also rejected for depending from the rejected claim 19 and failing to remedy the lack of written description therein.
Claim Rejections - 35 USC § 112 Enablement
Claims 19-25, 30-32 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 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.
The test of enablement is whether one skilled in the art could make and use the claimed invention from the disclosures in the specification coupled with information known in the art without undue experimentation (United States v. Telectronics., 8 USPQ2d 1217 (Fed. Cir. 1988)). Whether undue experimentation is needed is not based upon a single factor but rather is a conclusion reached by weighing many factors. These factors were outlined in Ex parte Forman, 230 USPQ 546 (Bd. Pat. App. & Inter. 1986) and again in In re Wands, 8 USPQ2d 1400 (Fed. Cir. 1988), and the most relevant factors are indicated below:
Nature of the Invention
The claimed invention directs to a method of template-independent enzymatic oligonucleotide synthesis (TiEOS) of a polynucleotide probe with predetermined sequences, the method incorporates nucleosides with dual modifications (3’-O-blockgroup on ribose and either an alkyne or an azide group on nucleobase) catalyzed by a template-independent DNA polymerase. Thus, the methods require a reliable implementation of: i) repeated cycles of incorporation of single nucleoside with dual modifications into the polynucleotide; ii) click chemistry reaction to attach a first label on an internal nucleotide; iii) orthogonal attachment of a second label on the terminal nucleotide; iv) cleavage of the polynucleotide with a plurality of labels from the initiator.
The Breadth of the Claims
The scope of the independent claim 19 limits the method to using any template-independent DNA polymerase, or variants thereof, to catalyze the repeated cycles of polynucleotide elongation. There is no structural limitation as to what specific requirements are for the polymerase to complete the steps of the claimed method. Despite the references to TdT and variants in the specification, no working example is offered to support the breadth of the claims.
Guidance of the Specification
The specification is silent as to what structural requirements are necessary for each species of the claimed genus of template-independent DNA polymerases to meet the functional limitations.
Furthermore, there is no example disclosed in the specification. The specification only describes the standard TiEOS protocol on pages 9-23 (¶[0023]-¶[0050]), Kits on pages 23-24 (¶[0051]-¶[0053]), a Real Time PCR assay on page 25 (¶[0055]), followed by Definitions from pages 25-31 (¶[0055]-¶[0064]). The independent claim 19 requires “in at least one elongation cycle…” to implement the incorporation of a nucleoside with dual modifications, which is not the terminal nucleoside. However, no guidance is provided in the specification, and there is a lack of prior teaching that supports repeated cycles of enzymatic incorporation of nucleosides with dual modifications.
To one skilled in the art, the “guidance” in the instant specification, e.g. FIG. 1, is a prophetic, demonstrative, hypothetical, but is not seen as working example.
The State of the Prior Art
Chen (2020) teaches specific mutations in the TdT variants that resulted in improvements in TdT modified-base incorporation relative to wild-type bovine and wild-type spotted gar TdTs (Page 38, lines 24-26; Figure 3). The inability of wildtype bovine or spotted gar TdTs to incorporate these dual-modified reversibly terminated nucleotides has been reported (Page 38, lines 22-24). However, Chen does not teach repeated cycles of incorporation of nucleosides with dual modifications, because the prior art only teaches a single terminal addition of these nucleosides.
Winz (Nucleic Acids Res. 2015 Sep 30;43(17):e110; Cited on IDS filed on 05/20/2024) teaches that only a terminal single nucleotide carrying a single click chemistry modification, i.e. either an alkyne or an azide nucleobase modification without 3’-O-blocking group, can be added to the terminal position of a polynucleotide (Page 2, Figure 1C), and it is not accomplished in the context of a TiEOS synthesis. Rather, it is only a post-synthesis labeling application.
There is no record of success in implementing repeated cycles of enzymatic incorporation of nucleosides with dual modifications in the art.
The Level of Predictability in the Art
Prior arts do not establish predictability. Since no prior art demonstrated the success in repeated cycles of TiEOS-based incorporation of nucleosides with dual modifications for click chemistry-enabled label conjugations, it is necessary to demonstrate feasibility using working examples. There is very high level of unpredictability in the art.
The Quantity of Experimentation necessarily Needed
In light of the high level of unpredictability in the art, and the minimal direction provided by the inventor for repeated cycles of TiEOS-based incorporation of nucleoside(s) with dual modifications (3’-O-blocking group and a nucleobase modification of either an alkyne or an azide group), the quantity of experimentation necessarily needed to make or use the invention as claimed, especially with respect to the formation of a polynucleotide with predetermined sequences and a plurality of labels based on the disclosure, is considerably high. For example, it would be necessary for one skilled in the art to identify reliable TdT mutant variant with the optimal catalytic properties required for successful synthesis and implementation of orthogonal labeling involving click chemistry. There would be an unreasonable amount of experimentation required.
Conclusion of 35 U.S.C. 112(a) Enablement Analysis
After applying the Wands factors and analysis to claim 19, taking into consideration the factors outlined above, including the nature of the invention, the breadth of the claims, the state of the art, the guidance provided by the applicant and the specific examples, in view of the applicant’s entire disclosure, it is concluded that the specification is not enabled for the full scope as discussed above. Therefore, claim 19 is rejected under 35 U.S.C. §112(a) for failing to disclose sufficient information to enable a person of skill in the art to use the invention commensurate in scope with these claims.
Claims 20-25, 30-32 are also rejected for depending from claim 19 and failing to remedy the lack of enablement therein.
Conclusion
No claims are allowable.
Any inquiry concerning this communication or earlier communications from the examiner should be directed to Delphinus D. Yu whose telephone number (571) 272-1576. The examiner can normally be reached Mon-Thr 7:30am to 4:30pm Fri 10am to 2pm ET.
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, Neil P Hammell can be reached on (571) 270-5919. 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.
/DELPHINUS DOU YI YU/Examiner, Art Unit 1636
/NEIL P HAMMELL/Supervisory Patent Examiner, Art Unit 1636
Prosecution Insights