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 .
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and the fee set forth in 37 CFR 1.17(e) has been timely paid, the finality of the previous Office action has been withdrawn pursuant to 37 CFR 1.114.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 December 9, 2025 has been entered.
Status of Claims/Rejections
Claims 21-32, 34-35, 37-38, and 40-42 are currently pending and under examination on the merits in the instant application.
Any rejections not repeated in this Office action are withdrawn, and the following rejections are the only rejections applied in this application.
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 21-32, 34-35, 37-38, and 40-42 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 21-32, 34-35, 37-38, and 40-42 recite a broad limitation that each of RNA1, RNA2, RNA3, and RNA4 each “at least six nucleotides in length” in limitations “a)”, “b)”, “c)”, and “d)”, and the claims simultaneously recite narrower limitations that RNA1 and RNA2 are at least 80% homologous to SEQ ID NO:1 and RNA3 and RNA4 are at least 80% homologous to SEQ ID NO:2, wherein both SEQ ID NO:1 and SEQ ID NO:2 are 24 nucleotides in length. Hence, the simultaneous recitation of both the broad and narrower limitations in the same claims renders the claims indefinite because it is unclear whether the limitations introducing more defined, specific structural limitations pertaining to the four RNAs in the newly added “wherein” clause are merely exemplary thus not required, or whether the new limitations are required. If required, it is unclear how the broad limitations in “a)”, “b)”, “c)”, and “d)” help particularly pointing out and distinctly claiming the metes and bounds of the subject matter.
A broad range or limitation together with a narrow range or limitation that falls within the broad range or limitation (in the same claim) may be considered indefinite if the resulting claim does not clearly set forth the metes and bounds of the patent protection desired. See MPEP § 2173.05(c).
Solely in the interest of compact prosecution, the broad limitations “a)”, “b)”, “c)”, and “d)” will not be taken into consideration.
Claims 25-27 each depend from claim 21, which is now amended to recite that RNA1 and RNA2 are each at least 80% homologous to SEQ ID NO:1 and RNA3 and RNA4 are each at least 80% homologous to SEQ ID NO:2. As such, it is scientifically impossible for RNA1, RNA2, RNA3, and RNA4, all of which are 24 nucleotides in length, to satisfy the recited at least 80% sequence identity to SEQ ID NOs:1 and 2 when the RNAs are 10, 15, 19, 30, 40, and 50 nucleotides in length. Hence, claims 25-27 recites structurally impossible/conflicting limitations, thereby rendering the claims indefinite.
Claims 34-35 recite that RNA1 and RNA3 are fully complementary to each other and RNA2 and RNA4 are fully complementary to each other. This “fully complementary” limitation conflicts with the required structural limitation for the presence of “an overhang of the 3’-terminal nucleotide residues of not more than five nucleotides.” That is, an “overhang” requires an unhybridized, non-duplexed sequence, and the presence of the unhybridized, overhanging sequence at the 3’ termini cannot produce “fully complementary” RNA1-RNA3 and RNA2-RNA4. Therefore, claims 34-35 recite structurally conflicting, impossible limitations regarding the oligonucleotide conjugate K, thereby rendering the claims indefinite.
Claim Rejections - 35 USC § 112
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 21-32, 34-35, 37-38, and 40-42 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.
The factors to be considered when analyzing claims for compliance with the written description requirement include, but are not limited to: (A) actual reduction to practice; (B) disclosure of drawings or structural chemical formulas; (C) sufficient relevant identifying characteristics (e.g., complete structure, partial structure, physical and/or chemical properties, structure/function correlation); (D) level of skill and knowledge in the art; and (E) predictability in the art. See MPEP §2163.
Each factor listed above is analyzed below.
(A) actual reduction to practice
The instant specification lacks any actual reduction to practice the instantly claimed in vivo therapeutic method of treating any tumor or any viral infection in a subject comprising administering an oligonucleotide conjugate K. Furthermore, even for the method of claim 42 that is not expressly recited to require a treatment in a subject, the instant specification does not provide an actual reduction to practice the method of claim 42 because the in vitro examples in the instant specification were practiced with RNA species that do not satisfy the claimed structural limitations.
(B) disclosure of drawings or structural chemical formulas
It is noted that all of the exemplified 5’-5’ or 3’-3’ phosphodiester-linked RNAs such as “GFP2_s2n55” comprising SEQ ID NOs:2 and 5, “GFP2_s2n55_as-ppp” comprising SEQ ID NOs:4 and 5, and “GFP2_as2n33” comprising SEQ ID NO:2 and 7 are blunt-ended on both ends thus do not comprise “an overhang of the 3’-terminal nucleotide residues of not more than five nucleotides” as specifically required by the instant claims.
(C) sufficient relevant identifying characteristics
Since the phosphodiester-linked RNAs disclosed in the instant application are all blunt-ended without a 3’ overhang, the specification fails to describe the required structure-function correlation for the genus of oligonucleotide conjugate K structures required to comprise “an overhang of the 3’-terminal nucleotide residues of not more than five nucleotides” in “each of RNA1 and RNA3, and each of RNA2 and RNA4”, wherein RNA1 and RNA2 are each at least 80% identical to SEQ ID NO:1 and RNA3 and RNA4 are each at least 80% identical to SEQ ID NO:2 (emphasis added). Further, even if the blunt-ended phosphodiester-linked RNA species disclosed in the instant application should be deemed to correctly represent the instantly claimed genus of oligonucleotide conjugate K structures with a 3’-overhang in each of RNA1, RNA2, RNA3, and RNA4, the specification fails to adequately describe that the blunt-ended, phosphodiester-linked RNA species have the function of treating any type of tumor or any type viral infection in a subject in vivo as the RNA species are merely tested in chloroquine-treated human PBMCs in vitro, wherein the IFNa inducing activity in vitro shown by a limited number of structural variants is not representative of the instantly claimed in vivo method of treating any tumor or any viral infection in a subject.
(D) level of skill and knowledge in the art
There is no prior art of record filed by applicant or searched by the examiner that teaches that IFNa production activity of an RNA molecule comprising two linked duplexes comprising SEQ ID NO:1 and SEQ ID NO:2 in chloroquine-treated human PBMCs in vitro is an art-recognized model for in vivo therapeutic activity in treating any tumor or any viral infection in a subject. In addition, there is no prior art of record filed by applicant or searched by examiner that teaches that the blunt-ended RNA structures are indicative of 3’-overhang-containing RNA structures in inducing IFNa, thereby treating any tumor/viral infection in a subject via RIG-1 activation.
(E) predictability in the art
Interestingly, the instant specification explicitly demonstrates that the mere incorporation of a 2’-O-methyl modification at the first base (position 1) of SEQ ID NO:10 hybridized with SEQ ID NO:5 (5’-5’ linked RNA) abolishes IFNa-inducing activity, whereas the same modification at the first base (position 1) of SEQ ID NO:9 hybridized with SEQ ID NO:7 (3’-3’ linked RNA) retains IFNa-inducing activity. See Table 4. In addition, the specification discloses that a conjugation of a FAM moiety at the 5’ end of SEQ ID NO:20 SEQ ID NO:5 (5’-5’ linked RNA) does not have IFNa-inducing activity compared to the negative control “Medium”. See Table 5a. Hence, the instant specification itself demonstrates a high level of unpredictability in vitro pertaining to the structural RNA variants encompassed by the instant claims, wherein such in vitro unpredictability is insufficient to support a reasonable level of in vivo predictability of the 3’-overhang-containing oligonucleotide conjugate K structures comprising SEQ ID NOs:1-2 or at least 80% homologs thereof claimed in the instant case.
In fact, it was known in the art that the IFNa-inducing activity of an RNA duplex comprising a 3’ overhang in one strand highly depends on the 3’-overhang sequence (e.g., UUU vs. ACA) such that the RNA duplex comprising the UUU 3’-overhang sequence in one strand induced IFNa at about 7.5 ng/ml, whereas the RNA duplex comprising the ACA 3’-overhang sequence induced IFN-a at about 2.5 ng/ml, thereby demonstrating about a 3-fold difference in IFN-a inducing activity of RNA duplexes having different 3’-overhang sequences. See Figure 9F of Hartmann et al. (WO 2009/141146 A1, of record). Even better, Hartmann further discloses that RNA duplexes having 4 or 5-mer 3’-overhang sequences had “no activity” in inducing IFNa. See Figure 3. Hence, the negative results provided by Hartmann’s un-linked RNA duplexes comprising 3’-overhangs in vitro reasonably suggest a high level of unpredictability pertaining to IFNa-inducing activity that leads to RIG-1 activation for treating any type of tumor or any type of viral infection in a subject in vivo.
In view of the totality of factors (A)-(E) analyzed above, it is concluded that the instant specification clearly fails to adequately describe the instantly claimed in vivo method comprising using the instantly claimed structure of the oligonucleotide conjugate K. Therefore, the instant specification fails to reasonably convey that the instant co-inventors completed and had possession of the claimed subject matter as of the filing date sought in the instant case.
Response to Arguments
Applicant's arguments filed on December 9, 2025 have been fully considered but they are not persuasive. Applicant argues that activation of RIG-1 and IFNa was known to be useful in treating viral infections and cancers by pointing out “Exhibit A” and “Exhibit B”. In response, it is noted that neither “Exhibit A” nor “Exhibit B” teaches the activity of activating RIG-1 and IFNa by the instantly claimed oligonucleotide conjugate K having the claimed structural limitations such as phosphodiester-linked duplexes of SEQ ID NOs:1-2 having 3’-overhangs on all four RNA strands. Further, neither “Exhibit A” nor “Exhibit B” teaches that chloroquine-treated human PBMCs in vitro is an art-recognized model for in vivo therapeutic activity for tumor/viral infection treatment. Hence, the mere knowledge that activation of RIG-1 and IFNa was considered useful for treating cancers and viral infections is not sufficient to support that the instant specification itself describes the claimed in vivo method and demonstrates possession of the claimed method.
Applicant argues that the “particular configurations of oligonucleotide conjugate K were shown to be effective in producing IFNa.” In response, it is noted that the IFNa-inducing oligonucleotides disclosed in the instant specification do not satisfy the structural limitations set forth in the claims as explained in the rejection above, and furthermore, the IFNa-inducing oligonucleotide species do not represent the entire genus of oligonucleotide conjugate K that provides treatment of any tumor and any viral infection in a subject for the reasons explained in the rejection above.
Accordingly, applicant’s arguments are not found persuasive.
Claims 21-32, 34-35, 37-38, and 40-42 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(s) 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 factors to be considered in determining whether undue experimentation is required are summarized In re Wands, 858 F.2d 731,737, 8 USPQ2d 1400, 1404 (Fed. Cir. 1988). The Court in Wands states: “Enablement is not precluded by the necessity for some experimentation such as routine screening. However, experimentation needed to practice the invention must not be undue experimentation. The key word is ‘undue’, not ‘experimentation’.” (Wands, 8 USPQ2d 1404). 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.” These factors include, but are not limited to: (A) The breadth of the claims; (B) The nature of the invention; (C) The state of the prior art; (D) The level of one of ordinary skill; (E) The level of predictability in the art; (F) The amount of direction provided by the inventor; (G) The existence of working examples; and (H) The quantity of experimentation needed to make or use the invention based on the content of the disclosure. See MPEP §2164.
As extensively explained in detail in the written description rejection above, the instant specification contains to actual working example pertaining to the instantly claimed in vivo therapeutic method of treating any tumor/viral infection comprising administering an oligonucleotide conjugate K having the claimed structural limitations, while the levels of the prior art knowledge, skills, and predictability pertaining to the claimed method are deemed extremely low or non-existent. Further, the specification does not provide any necessary information pertaining to the required in vivo therapeutic effect or IFNa inducing activity in a cell mediated by the instantly claimed 3’-overhang-containing oligonucleotide conjugate K structure in spite of the complete lack of relevant prior art knowledge. Hence, in view of the factors (A)-(G) listed above, an undue amount of experimentation would be deemed necessary in order to practice the instantly claimed method.
In view of the totality of factors (A)-(H), it is concluded that the instant specification fails to provide an enabling disclosure commensurate in scope with claims 21-32, 34-35, 37-38, and 40-42.
Conclusion
No claim is allowed.
Any inquiry concerning this communication or earlier communications from the examiner should be directed to DANA H SHIN whose telephone number is (571)272-8008. The examiner can normally be reached Monday-Thursday: 8am - 6:30pm.
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/DANA H SHIN/Primary Examiner, Art Unit 1635
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