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 .
Status of Claims
Claims 1-20 are currently pending and under examination on the merits in the instant application.
Drawings
The drawings in FIG. 1A-1C and 2 are objected to as failing to comply with 37 CFR 1.84(p)(5) because they include the following reference character(s) not mentioned in the description: multiple numerical values such as “10”, “100”, “210”, and “212”; “xxx”; “(C1)”, “(C2)”, “(C3)”; and/or “S”. Corrected drawing sheets in compliance with 37 CFR 1.121(d), or amendment to the specification to add the reference character(s) in the description in compliance with 37 CFR 1.121(b) 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. 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 Objections
Claim 4 is objected to because of the following informalities: “14th upstream from” in line 1 should be “14th upstream position from” or “14th position upstream from”. Appropriate correction is required.
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 1-20 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 1-20 recite a “method of administering”. However, there is no limitation pertaining to the recipient to whom the “administering” is performed. Hence, the “administering” step recited in claims 1-20 is deemed incomplete as the step omits the recipient of the “administering” recited in the claims.
Claims 1-20 recite one or more arms comprising “a dicer independent loop sequence”. The term/phrase “dicer independent loop sequence” is neither art-recognized (i.e., no prior art in applicant’s IDS discloses this term) nor clearly defined in the specification/claims in the instant application. As such, the required sequence cannot be clearly ascertained. For examination purpose, the term/phrase will be interpreted as any loop structure-forming sequence that is not cleaved by the dicer enzyme thus being independent of the dicer enzyme.
Claims 1-20 recite one or more arms comprising “a dicer independent loop-closing sequence”. The term/phrase “dicer independent loop-closing sequence” is neither art-recognized (i.e., no prior art in applicant’s IDS discloses this term) nor clearly defined in the specification/claims in the instant application. As such, the required sequence cannot be clearly ascertained. For examination purpose, the term/phrase will be interpreted as the flanking sequence that is immediately adjacent to the dicer independent loop sequence, which is a loop sequence that is independent of the dicer enzyme.
Claims 1-20 recite that the method requires one or more arms comprising “a corresponding complement sequence.” It is unclear what the aforementioned sequence should be “corresponding” to as the claims recite at least two different sequences (“a dicer independent loop sequence” and “a dicer independent loop-closing sequence”) preceding “a corresponding complement sequence.” For examination purpose, “a corresponding complement sequence” will be interpreted as a sequence that is complementary to both the dicer independent sequence and the flanking sequence that is immediately adjacent to the dicer independent loop sequence, which is the interpretation for the “dicer independent loop-closing sequence” as explained above.
Claims 2 and 12 each recite “an Ago2 cleavage sequence”. This term/phrase is not an art-recognized term/phrase, nor is it clearly defined in the specification or in the claims. For examination purpose, the “Ago2 cleavage sequence” will be interpreted as “Ago2 cleavage site”, which is an art-recognized term.
Claims 2 and 12 each recite “a corresponding seed sequence”. It is unclear what the “seed sequence” should be corresponding to as there is no clearly identified sequence to which the seed sequence should correspond. In addition, the term “seed sequence” is at best described in relation to “microRNA mimic” or “miRNA” in the instant specification, which is consistent with the prior art knowledge. See for instance Ely et al. (Nucleic Acids Research, 2009, 37:e91, applicant’s citation). However, there is no “microRNA” or “miRNA” recited prior to or concurrent with the recitation of “a corresponding seed sequence”. Hence, it is unclear what the “corresponding seed sequence” should be.
Claims 2 and 12 each recite “a MID domain tight interaction.” The term/phrase “MID domain tight interaction” is neither art-recognized (i.e., no prior art in applicant’s IDS discloses this term) nor clearly defined in the specification/claims in the instant application. As such, the metes and bounds pertaining to the term/phrase “MID domain tight interaction” cannot be clearly ascertained, thereby rendering the structure of the polycistronic RNAi scaffold indefinite.
In addition, it is unclear how an “interaction” can possibly be deemed as a structural element that constitutes the claimed structure of “the polycistronic RNAi scaffold”. For examination purpose, the aforementioned term will be interpreted as a “MID domain”.
Claims 3 and 13 recite “thirteen unpaired-base pairs” in line 3. It is unclear how “base pairs” can be “unpaired”. That is, the term “pair” or “pairs” in “base pairs” means that two complementary bases are paired or hybridized with each other. As such, the limitation “unpaired” contradicts the meaning of “base pairs”. For examination purpose, “base pairs” will be interpreted as “bases”.
Claims 6 and 16 recite “highly complementary” in line 3. The word “highly” is a relative term that is not defined in the specification or in the claims. Hence, the requisite degree pertaining to “highly” cannot be clearly ascertained.
Claims 9-10 each recite the limitation "the administration" in line 1. There is insufficient antecedent basis for this limitation in the claims.
Claim 19 recites “wherein each of the one or more arms is administered independently.” It is noted that claim 19 is directed to a method that administers “a combinatorial RNAi molecule via a polycistronic RNAi scaffold” that comprises “one or more arms disposed on the polycistronic RNAi scaffold”. That is, claim 19 requires administration of a single polycistronic RNAi scaffold comprising one or more arms. As such, the “one or more arms” on the single polycistronic RNAi scaffold cannot be administered separately or independently from each other; rather, the multiple arms can only be concurrently administered as a single molecule. Hence, claim 19 recites conflicting limitations pertaining to the administering of the one or more arms, thereby rendering the claim indefinite.
Claim 20 recites “a series of motifs, the series of motifs configured to facilitate an efficient RNAi maturation process.” It is noted that neither the claim nor the specification clearly defines/identifies what the “motifs” or “series of motifs” that facilitate an efficient RNAi maturation process are. Hence, the structure/sequence of the claimed polycistronic RNAi scaffold cannot be clearly ascertained.
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 1-20 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 instant claims are broadly and generically drawn to a method that administers a single RNAi molecule or a combinatorial RNAi molecule via a polycistronic RNAi scaffold comprising one or more arms, each arm being an individual RNAi substrate, which comprises several “sequences” generically recited by mere names in the claims, except the specifically recited “UG” at the 14th position upstream from the 5’ Drosha cleavage site and the “UGAU” hairpin loop sequence.
The instant specification at best appears to describe a prophetic method that administers “NPM198/34a/29b/608” to cells in vitro or to mice in vivo (see paragraphs 0034-0035, 0039, and 0041) and actual working examples that administer “a single miR-198 containing arms” (or “NPM198”) to mice as shown in Figures 8 and 9A-F or a single “NPM198”, “NPM34a”, and “NPM29b” to cells in vitro as shown in Figures 3-7. However, there is no adequate description pertaining to the exact structures of “NPM198/34a/29b/608”, “NPM198”, “NPM34a”, and “NPM29b” “in such full, clear, concise, and exact terms” as required by §112(a). As such, one of ordinary skill in the art cannot readily envisage the nucleotide sequences of the actual RNAi scaffolds or miRNA-containing arms that are administered in the working examples of the instant application as there is no clear identification of nucleotide sequences pertaining to each of “NPM198/34a/29b/608”, “NPM198”, “NPM34a”, and “NPM29b”. Again, the instant specification fails to describe the process of making the claimed polycistronic RNAi scaffold that is required to be administered in the claimed methods “in such full, clear, concise, and exact terms” as required by 35 U.S.C. 112(a) as the 14-page long specification contains substantially no sufficient information in detail pertaining to each of the elements/sequences required to constitute the claimed polycistronic RNAi scaffold.
Furthermore, even if there were a clear, full disclosure of the nucleotide sequences pertaining to the four species mentioned in the instant specification, the four species are not deemed a representative number of substantial structural variants within the claimed genus, which again, merely recite the word “sequence” for multiple elements without clearly identifying the actual nucleotide “sequence” for each of the recited elements of the RNAi scaffold.
Note that the written description requirement for a claimed genus may be satisfied through sufficient description of a representative number of species. A “representative number of species” means that the species which are adequately described are representative of the entire genus. Thus, when there is substantial variation within the genus, one must describe a sufficient variety of species to reflect the variation within the genus…(“[A] patentee of a biotechnological invention cannot necessarily claim a genus after only describing a limited number of species because there may be unpredictability in the results obtained from species other than those specifically enumerated.”)” (emphasis added). See MPEP §2163.
In view of the foregoing, it is concluded that the instant specification fails to adequately describe the claimed subject matter in such a way to reasonably convey that the instant co-inventors had possession of the methods using RNAi scaffolds other than the specifically enumerated by mere names “NPM198/34a/29b/608”, “NPM198”, “NPM34a”, and “NPM29b”, not SEQ ID NOs, as of the filing date sought in the instant case.
Relevant Teachings
As set forth in the §112(b) rejections above, claims 1-20 are replete with indefinite claim language, which renders the precise structure of the claimed polycistronic RNAi scaffold indeterminable. In addition, the instant specification is not any more descriptive of the claimed structure as the specification merely discloses verbatim limitations as recited in the claims without any detailed sequence information pertaining to each “sequence” recited in the claims as explained in the §112(a) rejection above. Taken together, it is impossible for the examiner to make any proper interpretation of the claimed subject matter, especially regarding the structural limitations that constitute the claimed polycistronic RNAi scaffold, thereby preventing the examiner from performing appropriate prior art search and examination. However, for the completeness of the record, the examiner notes the following prior art references, U.S. Patents, and a copending Application, which appear relevant to the claimed subject matter.
1. Wu et al. (US 2017/0240899 A1) teach the following polycistronic RNAi scaffold structures in FIG. 1C and also show the cleavage of the two strands in FIG. 7 as reproduced below.
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2. Tong et al. (US 2011/0286979 A1) teach Dicer-independent processing of stem-loop shRNA in FIG. 1A as below.
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3. Couto (US 2013/0030042 A1) discloses a polycistronic RNAi scaffold, miR17-92 cluster, and the modified scaffold having the arm sequences replaced with a desired RNAi substrate sequences in Figure 10 as shown below.
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4. Hannon et al. (US 2012/0021516 A1) disclose a polycistronic RNAi scaffold comprising miR-144 and miR-451, wherein miR-144 comprises the terminal hairpin loop sequence comprising 5’-UGAU. See FIG. 4C reproduced below.
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5. Yang et al. (PNAS, 2010, 107:15163-15168) show the Ago2 cleavage site, Drosha cleavage sites, the 4-nt terminal loop, the lower stem sequence pertaining to human miR-451 in Figure 2A as shown below.
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6. Bofill-De Ros et al. (Cell Reports, 2019, 26:447-459) teach that the lower stem and flanking sequences play a role in Drosha cleavage fidelity and efficiency. See the entire reference including Figures 3 and 5.
7. Harwig et al. (PLOS ONE, 2017, 12(8):e0183269) teach Ago2 loading process that involves “MID” or “Ago2 MID domain” for the subsequent Ago2 cleavage of the 3’ strand between the 10th and 11th position. See pages 1-3 including Figure 1.
8. Zhu et al. (US 2010/0068814 A1) teach pre-miR-30-based artificial polycistronic RNAi scaffolds. See the entire reference including Figures 1 and 6.
9. U.S. Patent No. 8,987,224 B2 claims a method “comprising the step of delivering to the individual an effective amount of a composition that increases the level of microRNA-198 molecules”, which comprise “microRNA-198, a microRNA-198 mimic, or a modified microRNA-198.”
10. U.S. Patent No. 9,546,365 B2 claims a method “comprising the step of delivering to the individual an effective amount of a composition that increases the level of microRNA-198 molecules”, which comprise “microRNA-198, a microRNA-198 mimic, or a modified microRNA-198.”
11. U.S. Patent No. 11,008,573 B2 claims a method “comprising the step of delivering to the individual an effective amount of a composition that increases the level of microRNA-198 molecules”, which comprise “microRNA-198, a microRNA-198 mimic, or a modified microRNA-198.”
12. U.S. Patent No. 12,134,769 B2 claims a method “comprising the step of delivering to the individual an effective amount of a composition comprising an agent that increases the level of microRNA-198 molecules”, which comprise “microRNA-198, a microRNA-198 mimic, or a modified microRNA-198.”
13. Application No. 18/902,545 claims a method “comprising the step of delivering to the individual a composition comprising an effective amount of an agent that increases the level of microRNA-198 molecules”, which comprise “microRNA-198, a microRNA-198 mimic, or a modified microRNA-198.”
Conclusion
No claim is allowed.
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/DANA H SHIN/Primary Examiner, Art Unit 1635