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
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.
Response to Amendments
Applicant’s amendments, corrected Specification, IDS, and response filed Dec. 1, 2025 have been received and entered into the case.
Note to Applicant
In the future, it is requested that the Applicant follows the guidelines set forth under 37 CFR 1.121 when filing amended claim sets, see MPEP 714 section II C. For example, in the amended claim set submitted Dec. 1, 2025, markings to show the changes made to claims 7-9, 11 and 12 should have been included (i.e. strike-through for deleted matter or underlining for added matter). The modifications to these claims do not match the previous claim set filed on Jun. 5, 2025. For example, in claim 7 the phrase “The method of claim 1” was recited in the Jun. 5, 2025 claim set and presently, in the Dec. 1, 2025 claim set the phrase is “The method of any one of claims 1 and 6,”. Similar issues were found in claims 8-9 and 11. In the Jun. 5, 2025 claim set, Claim 12 depended from claim 10 and did not contain all of the steps that are present in the current claim set of Dec. 1, 2025.
Status of the Claims
Claims 1-3 and 6-17 currently pending.
Claims 1 and 6-12 are amended.
Claims 13-17 have been withdrawn from further consideration pursuant to 37 CFR 1.142(b) as being drawn to a nonelected Invention, there being no allowable generic or linking claim.
Claims 4 and 5 are cancelled.
Claims 1-3 and 6-12 have been considered on the merits.
Specification Objections
Specification objections are withdrawn due to amendment.
Claim Objections
The previous objections are withdrawn due to amendment. New claim objections have been added to address the amendments.
The disclosure is objected to because of the following informalities: minor grammatical error in claims.
Claim 12 is objected to because of the following informalities: The periods after the letters denoting the steps need to be removed. For example, in claim 12 in line 3, "a." should be corrected to "a)". In other words, a claim should only contain one period. Please see MPEP 608.01(m).
Claims 8, 9, 10 and 11 are objected to under 37 CFR 1.75(c) as being in improper form because a multiple dependent claim cannot depend from any other multiple dependent claim. See MPEP § 608.01(n). Accordingly, the claims 8, 9, 10, and 11 have not been further treated on the merits. Claim 10 depends from claim 9 and therefore, is included.
Appropriate correction is appreciated.
Claim Rejections - 35 USC § 112
The claim rejections under 35 USC § 112, (a) or first paragraph (pre-AIA ), for written description are withdrawn due to amendment.
The claim rejections under 35 USC § 112, (a) or first paragraph (pre-AIA ), for scope of enablement are withdrawn due to amendment and some of applicant’s arguments were found to be persuasive. Specifically, Applicant argument that “mitochondrial DNA depletion” encompasses multiple disorders that share the same underlying etiology (Remarks pg. 9 para. 2) was persuasive.
Claim Rejections - 35 USC § 103
The claim rejections under 35 USC § 103 are revised due to amendment. New claim rejections under 35 USC § 103 have been added to address the claim amendments.
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 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.
This application currently names joint inventors. In considering patentability of the claims the examiner presumes that the subject matter of the various claims was commonly owned as of the effective filing date of the claimed invention(s) absent any evidence to the contrary. Applicant is advised of the obligation under 37 CFR 1.56 to point out the inventor and effective filing dates of each claim that was not commonly owned as of the effective filing date of the later invention in order for the examiner to consider the applicability of 35 U.S.C. 102(b)(2)(C) for any potential 35 U.S.C. 102(a)(2) prior art against the later invention.
Claims 1-3, 6, 7, and 12 are rejected under 35 U.S.C. 103 as being unpatentable over Hirano et al. (WO 2016/205671 A1)(ref. of record) in view of Warnecke et al. (The Journal of Organic Chemistry, 2009)(ref. of record).
With respect to claims 1 and step c of claim 12, Hirano teaches a method of treating mitochondrial DNA depletion syndromes, including thymidine kinase 2 (Tk2) deficiency, in a subject in need of by administering a therapeutically effective amount of composition containing either deoxythymidine (dT) or deoxycytidine (dC), or a mixture of both (pg. 1 lines 14-22, pg. 4 lines 18-22, pg. 3 lines 30-33 and pg. 7 lines 10-13 and 20-22).
With respect to claims 1 and step c of claim 12, Hirano teaches the composition can be administered parenterally including intravenously and intrathecally (pg. 4 line 31, pg. 12 lines 4-6 and 20-21, pg. 13 lines 20-29).
With respect to step a of claim 12, Hirano teaches that genetic testing can be done to determine the mutation type in the TK2 gene and to diagnosis whether the patient has TK2 deficiency which would be understood to require obtaining a nucleic acid sample from the subject (pg. 11 lines 3-13). With respect to step b of claim 12, Hirano teaches that the administration of the deoxynucleosides starting as soon as the disorder is diagnosed and that the tests for the diagnosis of mitochondrial DNA depletion syndromes including TK2 deficiency are known in the art (pg. 4 line 32 to pg. 6 line 2). With respect to step d of claim 12, Hirano teaches measuring the corresponding mononucleoside plasma levels (pg. 5 lines 28-32).
Hirano does not teach the method where the nucleotides administered are dinucleotides or have structure of Formula 1 as recited in claims 1 and step c of claim 12. Likewise, Hirano does not teach the method where the composition comprises the compound with the formula of claim 2. Hirano does not teach the method where the composition is a mixture and further comprises the compound of formula of claim 3.
However, Warnecke reports that dideoxynucleoside polyphosphates are signaling and regulatory molecules for many different biological functions (pg. 3024 para. 1). Warnecke teaches that there are possible medical applications for dideoxynucleoside polyphosphates (pg. 3024 para. 1-2). Formula I of claim 1 represents dideoxynucleoside polyphosphates. Warnecke teaches synthesis of nucleoside diphosphates and teaches the claimed compounds of claims 1-3 (pg. 3024 para. 2, scheme 1). For instance the compound of claim 2, where R1 is H, R2 is 5-methyl-2H-Δ2-pyrimidine-2,4(3H)-dione, R3 is 4-amino-2H- Δ2-pyrimidine-2-one and R4 is OH, would be correspond to scheme 1 compound 2 of Warnecke where B’ and B are pyrimidines and can be thymine and cytosine. It is noted that 5-methyl-2H-Δ2-pyrimidine-2,4(3H)-dione is another name for thymine and 4-amino-2H- Δ2-pyrimidine-2-one is another name for cytosine. Similarly, the compound of claim 3, where R1 is OH, R2 is 9Δ2-purine-6-amine, R3 is 2-amino-9Δ2-purine-6(1H)-one and R4 is OH, would be correspond to scheme 1 compound 2 of Warnecke where B’ and B are purines and can be adenine and guanine. It is noted that 9Δ2-purine-6-amine is another name for adenine and 2-amino-9Δ2-purine-6(1H)-one is another name for guanine.
Accordingly, at the effective time of filing of the claimed invention, one of ordinary skill in the art would have been motivated to modify the method of Hirano to substitute the composition containing deoxythymidine (dT) or deoxycytidine (dC) with a dideoxynucleoside polyphosphate composed of thymine and cytosine (dT(P2)dC), and to further include a dideoxynucleoside polyphosphate composed of adenine and guanine (dA(P2)dG), as taught by Warnecke for the benefit of treating a mitochondrial DNA depletion syndrome by providing nucleotides. It would have been obvious to one of ordinary skill in the art to modify the composition administered in the method of Hirano to include other sources of nucleotides such as dideoxynucleoside polyphosphates, dT(P2)dC and dA(P2)dG to treat mitochondrial DNA depletion syndromes which are known to be treated by administering nucleotides as taught by Hirano. Additionally, one of ordinary skill in the art would have had a reasonable expectation of success in making such a modification, since dideoxynucleoside polyphosphates with the claimed formula were known as taught by Warnecke and suggested to also have therapeutic value and the administration of nucleotides were a known therapy for mitochondrial DNA depletion syndromes.
Claims 6, 7 and step d of claim 12 contain wherein clauses that recites the intended results of the method rather than requiring an additional step be performed. MPEP 2111.04 states “Claim scope is not limited by claim language that suggests or makes optional but does not require steps to be performed” and that a such a clause ‘"in a method claim is not given weight when it simply expresses the intended result of a process step positively recited.” Therefore since these claims only recite the results of the steps, then art reading on the claimed method will also read on these results since performing the same steps will inherently lead to the same results in the absence of evidence to the contrary including unexpected results. According the method taught by the combined teachings of Hirano and Warnecke would produce the claimed results.
Therefore, the invention as a whole was prima facie obvious to one of ordinary skill in the art at the effective time of filing of the invention, especially in the absence of evidence to the contrary.
Response to Arguments
Applicant's arguments filed Dec. 1, 2025 have been fully considered but they are not persuasive.
With respect to the rejections under 35 U.S.C. § 103, Applicant argues that the claim 1 has been amended to recite the mode of administration of the multinucleotide composition as “parenteral” which has an unexpected technical effect as demonstrated in Example 1, Fig. 3 and para. 0089-0090 of the specification (Remarks pg. 10 para. 2). Specifically, Applicant argues that the example shows that there is higher systemic exposure of the nucleosides d(T) and d(C) when dTppdC or dCppdT are administered parenterally than when the mononucleotides, dCMP and dTMP, are administered orally (Remarks pg. 10 para. 2). Similarly, Applicant argues that neither Hirano or Warnecke teach or suggest formulating the claimed molecules for parental administration (Remarks pg. 10 para. 3). However, these arguments were not found to be persuasive, since Hirano teaches parenterally administration of the deoxynucleosides. Hirano teaches the composition can be administered parenterally including intravenously and intrathecally (pg. 4 line 31, pg. 12 lines 4-6 and 20-21, pg. 13 lines 20-29).
Applicant argues that Hirano describes that oral formulations are preferred due to the ease with which mononucleotides readily dissolve in liquid and Warnecke is focused on the synthesis of multinucleoside polyphosphate molecules (Remarks pg. 10 para. 3). However, this argument was not found to be persuasive, Hirano teaches that “a further preferred form of administration is parental including intravenous administration” (pg. 13 lines 20-21).
Conclusion
No claims are allowed.
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.
Examiner Contact Information
Any inquiry concerning this communication or earlier communications from the examiner should be directed to EMILY ANN CORDAS whose telephone number is (571)272-2905. The examiner can normally be reached on M-F 9:00-5:30 EST.
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/EMILY A CORDAS/Primary Examiner, Art Unit 1632