DETAILED ACTION
The examiner for your application at the USPTO has changed. Examiner Abigail VanHorn can be reached at 571-270-3502.
Continued Examination Under 37 CFR 1.114
A request for continued examination under 37 CFR 1.114, including the fee set forth in 37 CFR 1.17(e), was filed in this application after final rejection. Since this application is eligible for continued examination under 37 CFR 1.114, and the fee set forth in 37 CFR 1.17(e) has been timely paid, the finality of the previous Office action has been withdrawn pursuant to 37 CFR 1.114. Applicant's submission filed on June 3 2025 has been entered.
Receipt of Arguments/Remarks filed on June 3 2025 is acknowledged. Claims 1-24, 26, 29-30, 32, 35-36, 40 and 42 were/stand cancelled. Claims 25, 37 and 39 were amended. Claims 25, 27-28, 31, 33-34, 37-39, 41 and 43-44 are pending. Claims 43-44 are withdrawn from further consideration pursuant to 37 CFR 1.142(b) as being drawn to a nonelected invention, there being no allowable generic or linking claim. Election was made without traverse in the reply filed on August 31 2021. Claims 25, 27-28, 31, 33-34, 37-39 and 41 are directed to the elected invention.
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 .
Withdrawn Rejections
The amendments filed June 3 2025 are sufficient to overcome the rejection of Claim(s) 25, 28, 31, 33 and 34 under 35 U.S.C. 103 as being unpatentable over Abe et al. (JP2014143923A, of record) in view of Rossi et al (US 20050244858, of record) Gao et al (Nucleic Acids Research, 1995, Vol. 23, No. 11 2025-2029, of record), and Roy et al., (US 20150307542) and the rejection of claims 27, 37-39, and 41 under 35 U.S.C. 103 as being unpatentable over Abe et al. (JP2014143923A), Rossi et al (US 20050244858), Gao et al (Nucleic Acids Research, 1995, Vol. 23, No. 11 2025-2029), and Roy et al., (US 20150307542) and further in view of Quay et al., (US 20100112687). While m2 as claimed can be 0, the claims require L3 to be bonded to X2 and M2. The claims as amended require for L3 the carbon atom in 5-1, 5-2 or 5-4 to be bonded to a phosphodiester or phosphorothioate at the 5’ or 3’ end of X2 and the oxygen atom of 5-1, 502 or 5-4 to be bonded to M2. This specific structural arrangement is not suggested by the prior art. While Abe et al. suggests a linker falling within the scope of L3, specifically 5-1, see for example Fig. 1 which teaches an optionally substituted C3 phosphate as well as a disulfide which is similar to instantly claimed M2, specifically 6-1 (see for example Fig. 6), Abe et al. does not teach the use of both. Therefore, the arguments and amendments filed June 3 2025 are sufficient to overcome the previous rejections of record.
Drawings
The drawings are 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 numbers for Figures 1-22 are 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.
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 25, 27-28, 31, 33-34, 37-39 and 41 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.
Claims 25, 37 and 39 as currently written are vague and indefinite. Claims 24 and 37 both recite n2 can be 0 and in claim 39 recites m2 can be 0. But the claims also recite that X is bonded to both L1 and L2 in claims 24 and 37; X2 is bonded to both L3 and L4 in claim 39. This creates confusion as to how X or X2 are connected to M or W2 when n2 or m2 is 0.
Claim 33 as currently written is vague and indefinite. The claim recites “wherein the oligonucleotide derivative or salt thereof has at least one targeting compound”. The scope of the claim is unclear. It isn’t clear if this is a further structural element, i.e. the claim should recite the derivative further comprises a targeting compound OR if one of the structures recited in claim 25 is a targeting compound. Furthermore, if this is a further structural element, the claim is indefinite as the claim does not indicate how/where the targeting moiety is connected to the oligonucleotide. Is it on the linear oligonucleotide or the circular oligonucleotide? If the circular then how it is attached?
Claim 39 as currently written is vague indefinite. The last two lines of the claim recites that W1 and W2 are moieties which react with each other to form the circular oligonucleotide. Specific W1 and W2 are claimed in claim 41 which recite -A1-S-S-A2- or -B1-COO-B2. However, claim 37 recites specific M groups which are not encompassed by the structure recited in claim 39 or 41. Therefore, it isn’t clear how cyclization of the compound would result in the structure of claim 37 because the M groups are required in claim 37 but missing from claims 39 and 41.
Claim 41 as currently written is vague and indefinite. The claim recites “COO”, it isn’t clear if Applicants intend for the structure to be C-O-O- OR CO(O) which would indicate an ester. It is noted that claim 31, for example, uses the proper formula for indicating a carbonyl C(O) but the same is not utilized in claim 41.
Claim 41 as currently written is vague and indefinite. Claim 41 recites “wherein the case is excluded where W1 and W2 are -B1-COO-B2 at the same time” in parentheses. The use of parentheses raises the question as to which term is required by the claim. It appears applicants are attempting to exclude W1 and W2 of being -B1-COO-B2- but the presence of the parentheses creates confusion as to if the limitations are required.
Claim 41 is indefinite because it unclear how A1-S-S-A2 or B1-COO-B2 can react to form the cyclic oligonucleotide as required by claim 39. A1, S2 and B2 include alkyl groups which not react together. The instant specification teaches, for example on page 94:
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. This shows that one SH group and another SH group react together to form the cyclic oligonucleotide with a SH-SH but this is not what claim 41 recites. Even when B2 is H which leaves a COOH end group which could be reached with an SH or NH, for example, A1 or S2 doesn’t allow for those as choices unless they are included as an optional substituent. But that means the scope of the claim does not require reactive end groups.
Claims 27-28, 31, 34 and 38 are included in the rejection as they depend on a rejected base claim and they do not clarify the issues.
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 39 and 41 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 reactions to form a cyclic oligonucleotide when W1 and W2 include SH/SH or N3/Alkyne, SH/COOH, does not reasonably provide enablement for W1 and W2 being any moiety and capable of forming the compound of claim 37 or for W1 and W2 being -A1-SS-A2 or -B1-COO-B2 wherein A1, A2, B1 and B2 are all alkyl groups. 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 the invention commensurate in scope with these claims.
To be enabling, the specification of the patent must teach those skilled in the art how to make and use the full scope of the claimed invention without undue experimentation. In re Wright, 999 F.2d 1557, 1561 (Fed. Cir. 1993). Explaining what is meant by “undue experimentation,” the Federal Circuit has stated:
The test is not merely quantitative, since a considerable amount of experimentation is permissible, if it is merely routine, or if the specification in question provides a reasonable amount of guidance with respect to the direction in which the experimentation should proceed to enable the determination of how to practice a desired embodiment of the claimed invention. PPG v. Guardian, 75 F.3d 1558, 1564 (Fed. Cir. 1996).
The factors that may be considered in determining whether a disclosure would require undue experimentation are set forth by In re Wands, 8 USPQ2d 1400 (CAFC 1988) at 1404 where the court set forth the eight factors to consider when assessing if a disclosure would have required undue experimentation. Citing Ex parte Formal, 230 USPQ 546 (BdApls 1986) at 547 the court recited eight factors:
1) the quantity of experimentation necessary,
2) the amount of direction or guidance provided,
3) the presence or absence of working examples,
4) the nature of the invention,
5) the state of the prior art,
6) the relative skill of those in the art,
7) the predictability of the art, and
8) the breadth of the claims.
These factors are always applied against the background understanding that scope of enablement varies inversely with the degree of unpredictability involved. In re Fisher, 57 CCPA 1099, 1108, 427 F.2d 833, 839, 166 USPQ 18, 24 (1970). Keeping that in mind, the Wands factors are relevant to the instant fact situation for the following reasons:
The breadth of the claims and Nature of the Invention
The claim is very broad insofar as it recites any W1 or W2 which reacts to form the cyclic oligonucleotides of claim 37 (claim 39) or W1 and W2 are -A1-SS-A2 or -B1-COO-B2 wherein A1, B1, A2 and B2 are all alkyl. Claim 37 recites that M2 is selected from the group consisting of formula 6-1 to 6-6 whose structure is not encompassed in any of W1, L3, X2, L4 or W2 of formula 7 as recited in claim 39.
The Relative Skill Level, the State of the Prior Art and The Level of
Predictability in the Art
The relative skill of those in the art is high, that of an MD or PHD. Someone with experience in chemical synthesis as well as molecular biology. The state of the art recognizes that disulfide compounds can be used to form circles. See for example Gao et al. (Nucleic Acids Research, 1995, of record). Reactions between azides and alkynes or other click-chemistry reactions are well known. See for example Hein et al. (Pharm Res. 2008).
But reaction of alkyl groups are not suggested in the prior art.
The amount of direction or guidance provided and the presence or absence of working examples
The specification clearly shows various different functional groups which can be reacted together to form the claimed circular oligonucleotide, which include both the linear oligonucleotide as well as the circular oligonucleotide.
Page 94:
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; Page 128:
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However, none of these reactive groups encompass the W1 and W2 as recited in claim 41 or those which would form the circular oligonucleotide as recited in claim 37.
The quantity of experimentation necessary
Because of the known unpredictability of the art, and in the absence of experimental evidence, no one skilled in the art would accept the assertion that the instantly claimed linear oligonucleotide could be used to make the circular oligonucleotide as required by the claim including either the structure recited in claim 37 or using the specifically claimed W1 and W2. Accordingly, the instant claims do not comply with the enablement requirement of §112, since to practice the invention claimed in the patent a person of ordinary skill in the art would have to engage in undue experimentation, with no assurance of success.
Conclusion
In light of the lack of prior art rejections, the examiner notes that claims 43-44 may be eligible for rejoinder. However, pursuant to MPEP 821.04(a): the examiner should withdraw any restriction requirement between the elected invention and any nonelected invention that depends from or otherwise requires all the limitations of an allowable claim. (emphasis added). Claim 43-44 are currently not eligible for rejoinder as they do not require all the limitations of an allowable claims.
Any inquiry concerning this communication or earlier communications from the examiner should be directed to ABIGAIL VANHORN whose telephone number is (571)270-3502. The examiner can normally be reached M-Th 6 am-4 pm EST.
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If attempts to reach the examiner by telephone are unsuccessful, the examiner’s supervisor, Neil 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.
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/ABIGAIL VANHORN/Primary Examiner, Art Unit 1636