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 .
The amendment filed 7/20/2026 has been entered. Claims 1, 3, 4, and 7 have been amended. Claim 8 has been added. Claims 1-8 are pending. After review and reconsideration, the finality of the office action of 3/18/2026 is withdrawn in favor of the new rejections below.
The rejection of claims 1-7 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112(a) or 35 U.S.C. 112 (pre-AIA ), first paragraph, as failing to comply with the written description requirement is withdrawn in light of applicant’s amendments deleting “variants” of p50.
The rejection of claims 1-4 and 6 under 35 U.S.C. 102(a)(1) as being anticipated by Bancel et al (WO2013/151672); and
the rejection of claims 1-4, 6 and 7 as being unpatentable over Bancel et al
is withdrawn in light of applicant’s amendment deleting reference to at least about 95% homologous to p50 and requiring that the p50 sequence comprises or consists of, SEQ ID NO:3.
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- 8 are rejected under 35 U.S.C. 112(a) or 35 U.S.C. 112 (pre-AIA ), first paragraph, because the specification, while being enabling for a method of treating cancer in a subject comprising administering to said subject a therapeutically effective amount of at least one of (i) an expression vector encoding the amino acid sequence of p50 consisting of the amino acid sequence of SEQ ID NO:3; (ii) an expression vector comprising a nucleic acid sequence encoding KPC1; (iii) a vector expressing siRNA specific for KPC2 and (iv) a complex comprising siRNA specific for KPC2; does not reasonably provide enablement for a method of treating cancer in a subject comprising administering to said subject a therapeutically effective amount of at least one of
(i) p50 protein consisting of the amino acid sequence of SEQ ID NO:3;
(ii) a fused protein comprising the amino acid sequence of p50 consisting of the amino acid sequence of SEQ ID NO:3,
(iii) KPC1 protein;
(iv) a fused protein comprising KPC1,
(v) a siRNA speciic to KPC2 fused to a protein, or
(vi) a complex comprising p50 or a p50 fusion; a complex comprising KPC1 or r a KPC1 fusion; or a complex comprising a siRNA fusion protein. The specification does not enable any person skilled in the art to which it pertains, or with which it is most nearly connected, to make and use the invention commensurate in scope with these claims.
KPC1 is an intracellular protein (Kravtsova-Ivantsiv et al, Cell, 2015, Vol. 161, pp. 333-347, see graphical abstract on cover page). In order for KPC1 to reach the cytoplasm where it can contribute to the ubiquitination and subsequent proteasomal processing of NFkB1 and degradation to p50, the exogenously administered KPC1 must cross the cell membrane to have access to the cytoplasm. The art teaches that some proteins, mainly transcription factors, can shuttle within the cell, and from one cell to another (Heitz et al, British Journal of Pharmacology, 2009, Vol. 157, pp. 195-206, see page 196, lines 1-4 under the heading “Cell-penetrating peptide families”) and that cationic peptides can cross the cell membrane (Heitz et al, ibid, page 196, lines 20-26), as well as other peptides designed to cross the cell membrane (Heitz et al, ibid, page 196, Table 1). KPC1 is not a transcription factor, nor does it structurally resemble any of the peptides described by Heitz et al. There is no expectation that KPC1 alone, or in a complex will cross the cell-membrane and reach the cytoplasm to exert a positive effect on the production of p50.
The p50 protein produced by intracellular processing of p105 pairs as a dimer with a unidentified transcriptional partner to regulate transcription which results in tumor suppression (Kravtsova-Ivantsiv et al, ibid, see graphical abstract on cover page). There is no evidence in the specification, or art of record to indicate that p50 as a monomer or dimer can shuttle from one cell to another. Thus, there is no expectation that administered p50 protein can cross the external cell membrane. It is noted that the specification uses cell free extracts or cells transformed in vitro to demonstrate the relationship between KPC1, KPC2 and p50. The specification provides no objective evidence that tumor cells in a subject can take up the administered KPC1 protein, KPC1 fusion protein administered p50 protein or p50 fusion protein. There is no expectation that p50 protein alone, or in a complex will cross the cell-membrane and reach the cytoplasm to exert a negative effect on transcription to suppress tumor growth. There is no expectation that KPC1 protein alone, or in a complex will cross the cell-membrane and reach the cytoplasm to exert a negative effect on transcription to suppress tumor growth.
When given the broadest reasonable interpretation, the fusion protein can be any protein, polypeptide or peptide. Heitz et al (British Journal of Pharmacology, 2009, Vol. 157, pp. 195-206) teach that conjugation of a cell penetrating peptide to a cargo attained by chemical cross-linking or fusion provides for the intracellular delivery of the conjugate (page 197, first column, lines 1-19) Heitz et al teach that that the conjugate may be stable or cleavable and the type of linkage chemistry and nature of the spacer have to be considered with respect to the stability of the cargo (page 197, first column, lines 24-29). Heitz et al teach that the covalent CPP technology is limited from a chemical point of view and risks altering the biological activity of the cargo(page 197, first column, lines 39-41). Heitz et al teach that for most CPPs the cellular uptake mechanisms still needs to be confirmed and remains controversial (page 197, lines 15-17 under the heading “Cellular uptake mechanism of cell-penetrating peptides”). Heitz et al teach that evidence for several routes of entry have been reported, and therefore for therapeutic purposes the challenge remains in identifying the route yielding a biological response which may not be the predominant route of entry and to correlated the uptake pathway with the biological response associated with a specific cargo. Thus, one of skill in the art would reasonably conclude that the particular paring of a cargo protein or cargo siRNA with a particular CPP would have to be empirically tested and verified to intracellularly transport the cargo. Further, the specification provides no contemplation as to the nature of the fused protein encompassed by the claims. A cell penetrating peptide is only a member of the genus of proteins encompassed by the fusion proteins of the claims.
The claims are drawn in part to a method of treating cancer in a subject comprising administering a therapeutically effective amount of a fusion protein comprising siRNA targeting KPC2 to the subject or administering siRNA targeting KPC2 to the subject.. When given the broadest reasonable interpretation, the protein portion of the siRNA fusion can be any protein. The art teaches that due to the inability of siRNA to pass through the cellular membrane, the primary success of siRNA applications depends upon suitable vectors to deliver the siRNA intracellulary (Reischl and Zimmer, Nanomedicine, 2009, Vol. 5, pp. 8-20, lines 2-7 of the abstract), and that cellular entrance is further limited by the size of the applied siRNA (ibid, lines 6-7of the abstract). The art teaches examples of siRNA complexes which improve target gene silencing and tumor accumulation (Gary et al, ACSnano, 2011, Vol. 5, pp. 3493-3505, abstract). The art teaches that fusions of siRNA with ligands or antibodies can provide targeting and internalization of an administered siRNA resulting in decreased expression of the targeted gene (Ford and Toloue, WIREs RNA, 2010, Vol. 1, pp. 341-350, see page 345, under “Cancer or disease Targeting Using Antibody Conjugates” and “Targeted Delivery Technology”) and avoidance of accumulation of the siRNA in non-targeted cells and tissues, such as liver and lung after intravenous administration (Chin et al , WO2013/110681, see page 3, lines 19-20) and lung, liver, kidney and brain after intravenous or intrathecal administration (Divita et al, WO2012/137150). However, the specification provides no contemplation as to the nature of the fused protein encompassed by the claims. A cell penetrating peptide is only a member of the large genus of proteins encompassed by the fusion proteins of the claims.
Given the lack of teachings or guidance regarding the issues above, one of skill in the art would be subject to undue experimentation in order to carry out the broadly claimed methods.
All other rejections and/or objections as set forth or maintained in the prior Office action are withdrawn.
Any inquiry concerning this communication or earlier communications from the examiner should be directed to KAREN A CANELLA whose telephone number is (571)272-0828. The examiner can normally be reached M-F 10-6:30.
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KAREN A. CANELLA
Examiner
Art Unit 1643
/Karen A. Canella/Primary Examiner, Art Unit 1643
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