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 .
Application Status
The Amendments and Remarks filed 11 August 2026 in response to the Office Action 15 July 2026 are acknowledged and have been entered.
Claims 1-20 and 32-40 are cancelled. Claims 21-31 were initially allowed; however, after further review the claims as written raise issues that were not documented in the prior office action. Therefore, this office action contains rejections that were not necessitated by claim amendments and is a non-final.
Priority
The application claims priority to application 63/388,147 filed 07/11/2022.
Claim Objections
Claims 21, 24-26, 29 and 30 objected to because of the following informalities:
Regarding claims 21 and 24-26, the claims use “small interference RNA” and “small-interference RNA,” whereas the specification defines and consistently discusses the conventional term “small interfering RNA (siRNA).” It would be remedial to provide consistency with the specification and terminology ordinary used in the art, and to amend “small interference RNA” and “small-interference RNA” to “small interfering RNA”.
Regarding claims 21, 29, and 30, the claims use the term “GapmeR”. The specification used the terms “gapmer”, “GapmeR”, “Gapmer” and “gapmeR”. It would be remedial to amend the claims and specification to recite “gapmer” to be consistent with general scientific and medical literature.
Appropriate correction is required.
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 25-27 and 29 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.
Claim 25 recites a small interference RNA having at least 90% sequence identity to “a nucleic acid sequence of SEQ ID NO: 1 or SEQ ID NO:2”. Claim 26 recites “wherein the small interference RNA is a small interference RNA having a nucleic acid sequence of SEQ ID NO: 1 or SEQ ID NO:2.” Claim 27 recites “wherein the KIAA0930 inhibitor is the short-hairpin RNA, wherein the short-hairpin RNA has at least 90% sequence identity to a nucleic acid sequence of SEQ ID NO:8 or SEQ ID NO:9.” Claim 29 likewise recites that the GapmeR of CRISPR Cas9 guide RNA has at least 90% sequence identity to “a nucleotide sequence of” the identified SEQ ID NOs. The recitation of “a nucleic acid sequence of SEQ ID NO: x” encompasses a subsequence comprising two or more consecutive nucleotides of the identified SEQ ID NO. rather than requiring the complete nucleotide sequence identified by that SEQ ID NO. As a result, claims 25-27 and 29 encompass a genus vastly broader that the particular KIAA0930-targeting nucleic acids disclosed and tested in the specification. The specification provides particular KIAA0930-targeting siRNAs corresponding to SEQ ID NOs: 1 and 2, GapmeRs corresponding to SEQ ID NOs: 3-5, CRISPR guide sequences corresponding to SEQ ID NOs 6, 7, and 10, and shRNAs corresponding to SEQ ID NOs: 8 and 9. The specification does not provide a representative number of species across the much broader genus encompassed by the claims, nor does it identify structural characteristics common to substantially all nucleic acids containing or sharing identity with any two-or-more nucleotide subsequence of the disclosed SEQ ID NOs that correlate with inhibition of KIAA0930. Possession of the disclosed complete KIA0930-targeting sequences does not reasonably demonstrate possession of the vastly large genus of nucleic acids that happened to contain, or have sequence to, a short subsequence thereof as these subsequences may also occur in unrelated nucleic acids that would not necessarily hybridize specifically to KIAA0930 or inhibit KIAA0930 expression. Accordingly, the specification does not demonstrate that the Applicant was in possession of the full genus nucleic acid inhibitors encompassed by the claims.
Claims 21-31 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.
Nature of the Invention
Claim 21 is directed to a method of treating cancer cachexia or muscle atrophy in a subject in need thereof by administering an effective amount of a KIA0930 inhibitor selected from a small interference RNA, short-hairpin RNA, GapmeR, or CRISPR Cas9 guide TNA. The nature of the claimed invention is complex because claims 21-31 are directed to therapeutic methods, rather than merely inhibition of KIAA0930 in cultured cells. Successful practice requires that an administered KIAA0930 inhibitor reach the appropriate cells in vivo, sufficiently reduce KIAA0930 expression, and that such reduction result in the claimed therapeutic effect of treating cancer cachexia or muscle atrophy.
Claims 21-31 narrow certain aspects of claim 21, but do not resolve this deficiency. Claim 22 limits treatment to cancer cachexia, while claim 23 broadly encompasses muscle atrophy, including non-cancer causes recognized by the specification. Claims 24-31 narrow the inhibitor type or sequence but still require successful in-vivo administration and a resulting therapeutic effect. Although these limitations reduce the structural breadth of the inhibitor genus, selection of a particular inhibitor species of nucleotide sequence does not itself establish that the inhibitor can be therapeutically administered to a subject in a manner that treats that claimed condition.
Breadth of the claims
The claims are broadly drawn to treatment of any cancer associated cachexia or any form of muscle atrophy, including muscle atrophy not associated with cancer. The claims are broadly drawn to the inhibition of KIAA0930 in any type of cell and are not limited to inhibition of KIAA0930 in tumor cells, The claims are broadly drawn to any route of administration, including local and system administration. The claims broadly encompass the use of any delivery system.
The scope of “muscle atrophy” is particularly broad. The specification itself explains that the muscle atrophy may result from disuse, prolonged inactivity, neurogenic causes, damage to the nervous system, malnutrition, sarcopenia and disease, in addition to cancer-associated wasting [0026]. Thus, the ordinary scope of claim 21, and 23-31, encompass muscle atrophy arising from mechanistically distinct conditions that are not associated with cancer.
Guidance from the specification/State of the Art
The specification demonstrated that suppression of KIAA0930 in cultured cancer cells can affect a cancer-cell-conditioned-medium-induced myotube atrophy phenotype. Applicant tested siRNA, GapmeR, shRNA, and CRISPR-Cas9 methodologies in cancer cells and subsequently exposed C2C12 myotubes to conditioned medium from the manipulated cancer cells [0258; Figs. 5-8]. The specification, however, provides only one animal experiment relevant to cachexia. In that experiment, PANC-1 cells already expressing KIAA0930-targeting shRNA1, shRNA2, or control RNA were inoculated into pancreas in NSG mouse [0255]. After 8 weeks, mice bearing KIAA0930-knockdown PANC-1 cells exhibited increased tibialis anterior (TA) muscle weight and cross-sectional area relative to mice bearing control PANC-1 cells [0255]. The animal was not treated by administering a KIA0930 inhibitor to an existing tumor bearing subject. Rather, the cancer cells were genetically manipulated to reduce KIA0930 before those cells were implanted into the animal. Accordingly, the working example demonstrates that a tumor generated from cells having pre-existing KIAA0930 knockdown produces a reduced cachexic phenotype, bur it does not demonstrate that administration of a KIAA0930 inhibitor to a subject having cancer cachexia or muscle atrophy constitutes an effective therapy. The specification’s experimental methods likewise show that the siRNA, GapmeR, and guide-RNA studies involved transfection of cultured cells, while shRNA was introduced by lentiviral transduction. These methods do not provide a working example of therapeutic administration, dosing, or pharmacological treatment of an already affected subject.
Regarding therapeutic delivery and tissue specificity, the specification discloses that KIAA0930 is not restricted to cancer cells, but rather is expressed in normal tissues, including relatively high expression in adult and fetal brain, bone marrow, and spinal cord [0024]. Yet the claims contain no requirement that KIA0930 inhibition be restricted to tumor, cancer cells, tumor microenvironment, or another defined tissue. The specification does not establish which cells must be inhibited in vivo to obtain the therapeutic effect, which tissues may safely tolerate KIAA0930 inhibition, or whether inhibition in normal KIA0930-expressing tissues affects safety or efficacy. Juliano (Juliano et al. Nucleic acids research 44.14 (2016): 6518-6548) teaches that a central problem for therapeutic oligonucleotides is getting the active oligonucleotide to the tissue of theraprutic interest while minimizing exposure of other tissues, followed by delivery to the correct intracellular compartment [abstract; pg. 6520, col. 1, para 5]. Likewise, Setten (Setten et al. Nature reviews Drug discovery 18.6 (2019): 421-446) teaches that therapeutic RNAi, although capable of sequence-specific silencing, continued to present substantial challenges involving safety and potency. Thus, the specification does not provide guidance reasonably commensurate with the breadth of a method encompassing unrestricted administration of KIAA0930 inhibitors to a subject.
Regarding CRISPR-Cas9 guide-RNA embodiment, Claim 21 identified a “CRISPR Cas9 guide RNA” itself as the KIAA0930 inhibitor, while claims 29 and 31 expressly recite KIAA0930-targeting guide RNA sequences. The working example, however, does not establish that a guide RNA alone inhibits KIA0930. The specification teaches that the guide-RNA experiment was carried out in Cas9 overexpressing HTC116 cells, which were then transfected with KIAA0930-targeting guide RNA [0011]. Therefore, the observed KIA0930 reduction occurred in a cellular environment in which Cas9 was supplied. This is consistent with the known mechanism of CRISPR-Cas9. The specification teaches an RNA-guided endonuclease as an enzyme whose recognition is facilitated by a separate RNA sequence and distinguishes active Cas9 from nuclease-deficient Cas proteins [0067]. Smith (Smith et al. PLoS biology 15.11 (2017): e2003213) teaches that in CRISPR system Cas9 is the nuclease and is programmed by an sgRNA to create a targeted DNA break [pg. 2, para 2]. Mout (Mout et al. Bioconjugate chemistry 28.4 (2017): 880) teaches that gene disruption requires delivery of both Cas9 and sgRNA and identify effective in-vivo delivery of the multiple CRISPR components as a major therapeutic challenge [pg. 2]. Nevertheless, claims 21, 29, and 31 do not require a Cas9 nuclease, Cas9-encoding nucleic acid, dCas9, or any other protein capable of causing KIAA0930 inhibition. Nor does the specification demonstrate therapeutic administration of the claimed guide RNA together with such a component in an animal. According, one of ordinary skill would be required to determine, which Cas9 of Cas9-derived effector is required; the form in which it is to be supplies; how the guide RNA and Cas9 components are delivered to the relevant cells in vivo; the amounts and relative timing required; and whether adequate KIA0930 inhibition can be achieved with acceptable off-target activity based on the teachings of Mout as stated above and Luther (Luther et al. Expert opinion on drug delivery 15.9 (2018): 905-913) who teaches that CRISPR components do not spontaneously enter cytosol or nuclease and that significant barriers remained in translating the technology to effective in-vivo use [pg. 906, col. 2].
Regarding non-cancer muscle atrophy, claim 21 alternatively encompasses treating muscle atrophy and claim 23 limits the method to treating muscle atrophy with requiring cancer. The specification defines muscle atrophy broadly and recognizes multiple non-cancer etiologies, including disuse, prolonged activity, malnutrition, sarcopenia, neurological damage, and disease [0026]. However, every efficacy experiment relied upon for KIA0930 inhibition concerns cancer-associated muscle wasting: cancer-cell conditioned medium, manipulated cancer cells, cancer-cell/stroma-cell interaction, or the pancreatic-cancer xenograft model [0239, 0255, 0256]. The specification does not demonstrate or establish a mechanistic relationship between KIA0930 and muscle atrophy resulting from non-cancer causes. Nor does the specification provide a reasonable basis for predicting that suppression of KIA0930 would treat those different disorders. Accordingly, practicing the full scope of claim 21 and 23 would require screening the KIAA0930 inhibitors across numerous biological distinct causes of muscle atrophy to determine whether KIA0930 is involved and whether inhibition produces a therapeutic effect.
Experimentation Required
In view of the breadth of the claims, the limited therapeutic guidance, the absence of any exampled in which an inhibitor is administered therapeutically to an affected animal, the distinct delivery requirements of the claimed inhibitor classes, the widespread normal-tissue expression of KIA0930, the absence of guidance regarding tissue targeting of safety, and the lack of evidence linking KIA0930 to non-cancer causes of muscle atrophy, practicing the claims over their full scope would require substantial experimentation. Such experimentation would include determining appropriate inhibitor chemistry and delivery system; effective doses; target tissues and cell types; biodistribution; intracellular uptake; degree and duration of KIAA0930 inhibition; systemic versus localized effect; safety of KIAA0930 inhibition in normal tissues; and efficacy across the numerous etiologically distinct forms of muscle atrophy encompassed by the claims.
Taking into consideration the factors outlined above, including the nature of the invention, the breadth of the claims, the state of the art, the guidance provided by the applicant and the specific examples, it is the conclusion that an undue experimentation would be required to make and use the invention as claimed.
Conclusion
No claims allowed.
Any inquiry concerning this communication or earlier communications from the examiner should be directed to TIFFANY N GROOMS whose telephone number is (571)272-3771. The examiner can normally be reached M-F 830-530.
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/TIFFANY NICOLE GROOMS/Examiner, Art Unit 1637
/Jennifer Dunston/Supervisory Patent Examiner, Art Unit 1637
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