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 .
Election/Restrictions
Claims 96-97 were cancelled in the amendment filed on 3/2/26 and remain withdrawn from further consideration pursuant to 37 CFR 1.142(b) as being drawn to a nonelected invention, there being no allowable generic or linking claim.
The non-elected target RNA in claim 90; the non-elected proteins of interest in claim 91; SEQ ID NOs: 1-3, 8-11, 14-16, 152-157, and 160-166 and 177-189 in claim 92; SEQ ID NOs: 80-83, 87-92 and 140-145 in claim 93 were cancelled in the amendment filed on 3/2/26 and remain withdrawn from further consideration pursuant to 37 CFR 1.142(b) as being drawn to a nonelected species, there being no allowable generic or linking claim.
Response to Arguments
Any rejection or objection not reiterated herein has been overcome by amendment. Applicant’s amendments and arguments have been thoroughly reviewed, but are not persuasive to place the claims in condition for allowance for the reasons that follow.
Applicant’s arguments, see pages 10-11, filed 3/2/26, with respect to 103 rejection Gerber taken with Li have been fully considered and are persuasive. The rejection of claims 90-91 has been withdrawn because Gerber teaches DNA construct comprising a sequence encoding a transgene and a sequence encoding an siRNA and not an RNA construct comprising a mRNA encoding IGF1 and Il-1 beta siRNA.
Claim Rejections - 35 USC § 103
The text of those sections of Title 35, U.S. Code not included in this action can be found in a prior Office action.
Claims 78-89 and 94-95 are rejected under 35 U.S.C. 102(a)(1) as being anticipated by Hoge et al. (US 20140200261) taken with Zhao et al. (Am J Physiol Endocrinol Metab 307, E186-E198, 2014).
Hoge teaches making and using modified mRNA (mmRNA) for the alteration of cellular phenotypes and micro environments (pages 1-10 and 324-326). The mmRNA encodes an oncology protein of interest. The mmRNA can be conjugated to another polynucleotide, including siRNA, shRNA, miRNAs, antisense RNA, using a linker, flexible linker (pages 10-11, 166, 178, 186-187 and 216).
Hoge does not teach making a mRNA construct comprising 1) a IL-1 beta siRNA and 2) a mRNA encoding IGF-1, wherein 2) is located upstream or downstream of the siRNA.
However, Zhao studied induction of hepatic growth hormone resistance by endogenous IL-6, TNF-alpha and Il-1beta (pages E186-187 and E195-98). The consequences of GH resistance include postnatal linear growth failure, muscle wasting, poor wound healing and cachexia (E187). “During inflammation, the liver becomes resistant to growth hormones (GH) actions, leading to downregulation of the GH gene IGF-1 and activation of catabolism.” “Consistent with the in vitro observations, neutralization of TNF-alpha and IL-1beta in mouse models of inflammation did not significantly alter SOC3 expression stimulated by inflammation but restored GHR and IGF-1 expression suppressed by inflammation.” “In the inflammatory diseases with maximal inhibition or loss of GHR, removal of TNF-and IL-1beta increases GHR expression, thus restoring IGF-I expression (E198).” Thus, Zhao provides motivation for one of ordinary skill in the art to inhibit IL-1beta, IL6 and TNF-alpha in livers cells to study inflammation and IGF-1 expression.
It would have been prima facie obvious to a person of ordinary skill in the art before the time of the effective filing date to combine the teaching of Hoge taken with Zhao et al. to make a siRNA targeting IL-1 beta and mRNA encoding IGF-1 and combine both sequences in a RNA construct taught by Hoge, wherein the RNA sequence comprising the siRNA is upstream or downstream of the sequence comprising the mRNA, namely to arrive at the claimed invention. See MPEP 2143(I)(C), (D) or (F). One of ordinary skill in the art would have been motivated to combine the teaching to study IGF expression and Il-1beta inhibition in liver cells. Since there are only two options for the siRNA in the RNA construct (downstream or upstream of the mmRNA), it would have been obvious to try either to determine the optimal activity of the siRNA and mRNA. Instant claims 81-83 and 94 are directed to ‘wherein’ clauses (intended use) and do not add any additional structures to the claimed product. Hoge teaches a linker to connect to the mmRNA to another polynucleotide(s), wherein the linker is a flexible linker (paragraphs 98-99, 351, 454, 530 and 845). It would have been obvious to for one of ordinary skill in the art to make the RNA construct comprise two or more the siRNA or two or more the mRNAs to observe an additive effect when studying inflammation in liver cells. One of ordinary skill in the art would have been motivated to make a composition comprising the RNA construct and a pharmaceutically acceptable carrier or diluent to store for future usage or to assist in delivering the RNA construct to a cell.
Therefore the invention as a whole would have been prima facie obvious to one ordinary skill in the art before the effective filing date of the claimed invention to a person having ordinary skill in the art to which the claimed invention pertains.
Double Patenting
The nonstatutory double patenting rejection is based on a judicially created doctrine grounded in public policy (a policy reflected in the statute) so as to prevent the unjustified or improper timewise extension of the “right to exclude” granted by a patent and to prevent possible harassment by multiple assignees. A nonstatutory double patenting rejection is appropriate where the conflicting claims are not identical, but at least one examined application claim is not patentably distinct from the reference claim(s) because the examined application claim is either anticipated by, or would have been obvious over, the reference claim(s). See, e.g., In re Berg, 140 F.3d 1428, 46 USPQ2d 1226 (Fed. Cir. 1998); In re Goodman, 11 F.3d 1046, 29 USPQ2d 2010 (Fed. Cir. 1993); In re Longi, 759 F.2d 887, 225 USPQ 645 (Fed. Cir. 1985); In re Van Ornum, 686 F.2d 937, 214 USPQ 761 (CCPA 1982); In re Vogel, 422 F.2d 438, 164 USPQ 619 (CCPA 1970); In re Thorington, 418 F.2d 528, 163 USPQ 644 (CCPA 1969).
A timely filed terminal disclaimer in compliance with 37 CFR 1.321(c) or 1.321(d) may be used to overcome an actual or provisional rejection based on nonstatutory double patenting provided the reference application or patent either is shown to be commonly owned with the examined application, or claims an invention made as a result of activities undertaken within the scope of a joint research agreement. See MPEP § 717.02 for applications subject to examination under the first inventor to file provisions of the AIA as explained in MPEP § 2159. See MPEP § 2146 et seq. for applications not subject to examination under the first inventor to file provisions of the AIA . A terminal disclaimer must be signed in compliance with 37 CFR 1.321(b).
The filing of a terminal disclaimer by itself is not a complete reply to a nonstatutory double patenting (NSDP) rejection. A complete reply requires that the terminal disclaimer be accompanied by a reply requesting reconsideration of the prior Office action. Even where the NSDP rejection is provisional the reply must be complete. See MPEP § 804, subsection I.B.1. For a reply to a non-final Office action, see 37 CFR 1.111(a). For a reply to final Office action, see 37 CFR 1.113(c). A request for reconsideration while not provided for in 37 CFR 1.113(c) may be filed after final for consideration. See MPEP §§ 706.07(e) and 714.13.
The USPTO Internet website contains terminal disclaimer forms which may be used. Please visit www.uspto.gov/patent/patents-forms. The actual filing date of the application in which the form is filed determines what form (e.g., PTO/SB/25, PTO/SB/26, PTO/AIA /25, or PTO/AIA /26) should be used. A web-based eTerminal Disclaimer may be filled out completely online using web-screens. An eTerminal Disclaimer that meets all requirements is auto-processed and approved immediately upon submission. For more information about eTerminal Disclaimers, refer to www.uspto.gov/patents/apply/applying-online/eterminal-disclaimer.
Claims 78-89 and 94-95 are provisionally rejected on the ground of nonstatutory double patenting as being unpatentable over claims 148-167 of copending Application No. 18192717 in view of Li et al. (Front Immunol. 9:240, pages 1-19, February 2018, of record).
Although the claims at issue are not identical, they are not patentably distinct from each other because both set of claims embrace a composition comprising a RNA construct or a vector encoding the construct wherein the construct comprises a first sequence encoding a cytokine and a second RNA sequence is a siRNA which modulates expression of a gene associated with tumor proliferation or associated with recognition by the immune system, wherein the first sequence is linked to the second sequence via a linker.
The only difference between the instant claims and the claims of ‘717 is the instant claims are limited to a Il-1 beta siRNA and an IGF-1 mRNA.
However, Li et al. teach IL-1 beta plays an important role in inhibiting IGF-1 production in dendritic epidermal T cells (DETCs) in wound-healing response in the skin (pages 1-3). Thus, one of ordinary skill in the art would have been motivated to study IGF-1 and II-1 beta expression in DETCs.
It would have been prima facie obvious to a person of ordinary skill in the art before the time of the effective filing date to combine the ‘717 claims with the teaching of Li for a simple substation to use Il-beta siRNA as the sequence encoding a genetic element that modulates expression of a gene associated with either tumor proliferation or a gene associated with recognition by the immune system and IGF-1 mRNA as the gene encoding a cytokine, namely to arrive at the claimed invention. One of ordinary skill in the art would have been motivated to combine the teaching to study wound healing response in skin.
Furthermore, when a person of ordinary skill in the art looks for the definition of the term linker in the disclosure of '717, they would arrive at page 18, which discloses using a tRNA as the linker. See MPEP 804(II)B1. There are only two sequences in the composition and it would have been a simple substitution to have the second sequence upstream or downstream of the first sequence to optimize the effect of the composition in a cell. It would have been obvious to use more than one siRNA in the composition to observe an additive effect when modulating expression of a target sequence in a cell. It would have been obvious for one of ordinary skill in the art to make a pharmaceutical composition comprising the composition and a pharmaceutically acceptable carrier to assist in delivery of the composition to a cell or for storage for future usage.
This is a provisional nonstatutory double patenting rejection because the patentably indistinct claims have not in fact been patented.
Claims 78-89 and 94-95 are provisionally rejected on the ground of nonstatutory double patenting as being unpatentable over claims 108-130 of copending Application No. 18542975(reference application). Although the claims at issue are not identical, they are not patentably distinct from each other because both set of claims embrace a composition comprising a RNA construct or a vector encoding the construct wherein the construct comprises a first sequence is a mRNA encoding a gene of interest (IGF1) and the second sequence is a siRNA that modulates expression of one or more genes (IL1-beta), wherein the first sequence is linked to the second sequence via a linker. There are only two sequences in the composition and it would have been a simple substitution to have the second sequence upstream or downstream of the first sequence to optimize the effect of the composition in a cell. It would have been obvious to use more than one siRNA in the composition to observe an additive effect when modulating expression of a target sequence in a cell. It would have been obvious for one of ordinary skill in the art to make a pharmaceutical composition comprising the composition and a pharmaceutically acceptable carrier to assist in delivery of the composition to a cell or for storage for future usage.
This is a provisional nonstatutory double patenting rejection because the patentably indistinct claims have not in fact been patented.
Response to Arguments
Applicant's arguments filed 3/2/26 have been fully considered but they are not persuasive because applicant did not address the merits of the provisional NSDP. It is noted that applicant request the rejection be held in abeyance until the claims of either case be deemed allowable.
The amendment to independent claim 78 overcomes the provisionally rejected nonstatutory double patenting as being unpatentable over claims 91-115 of copending Application No. 18542970(reference application) because the claims of ‘970 do not embrace a siRNA targeting IL-beta and an IGF-1 mRNA.
Allowable Subject Matter
Claims 92 and 93 are objected to as being dependent upon a rejected base claim, but would be allowable if rewritten in independent form including all of the limitations of the base claim and any intervening claims. See statement of allowability in office action mailed on 8/28/25, which is incorporated herein.
New claims 98 and 99 are free of the prior art of record and are allowable for the same reasons as claims 92 and 93.
Conclusion
See attached PTO-326 for disposition of claims.
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/BRIAN WHITEMAN/ Primary Examiner, Art Unit 1636