DETAILED ACTION
The present application, filed on or after March 16, 2013, is being examined under the first inventor to file provisions of the AIA .
This Office action is in response to the communication filed 6-29-26.
Claims 1, 4-6, 9, 12, 13, 20-24, 29-31, 35, 38 and 43 are pending in the instant application.
Response to Arguments and Amendments
Any objections or rejections not repeated in this Office action are hereby withdrawn.
Maintained Rejections/Rejections Necessitated by Amendments
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.
Claim 1 is 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.
Claim 1, second line from the end, recites the limitation “the first ligand B1 and the second ligand B2”. There is insufficient antecedent basis for the limitation “the second ligand B2” in the claim.
Appropriate correction is required.
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, 4-6, 9, 12, 13, 20-24, 29-31, 35, 38 and 43 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 pre-AIA the inventor(s), at the time the application was filed, had possession of the claimed invention for the reasons of record set forth in the Office action mailed 1-28-26 and as set forth below.
Applicant’s Arguments
…The specification explicitly discloses the COMPOUND I formula with the same structural variables and ranges now recited in claim 1. The specification expressly discloses that the first effector moiety A1 "comprise(s) or consist(s) of at least one of any one or more of an oligonucleotide, a nucleic acid and a xeno nucleic acid, preferably selected from anti-sense oligonucleotide (ASO, AON), short interfering RNA (siRNA), microRNA (miRNA), DNA aptamer, RNA aptamer, mRNA, peptide nucleic acid (PNA), phosphoramidate morpholino oligomer (PMO), locked nucleic acid (LNA), bridged nucleic acid (BNA)" and others. (See Specification, page 80).
The specification also explicitly discloses conjugates comprising all three components: an antibody, an oligonucleotide, and a saponin in a single molecule. Specifically, the specification discloses an "Anti-EGFR antibody (- oligonucleotide)(- saponin), wherein the oligonucleotide is any one or more of antisense oligonucleotide, siRNA, antisense BNA, and antisense BNA(HSP27), and wherein the saponin is any one or more of a bisdesmosidic triterpene saponin belonging to the type of a 12, 13-dehydrooleanane with an aldehyde function in position C-23 SO1861, GE1741, SA1641, Quil-A, QS-21, wherein the anti-EGFR antibody preferably is cetuximab.". The same is disclosed for an anti-HER2 antibody (trastuzumab) (See Specification, page 42.
The specification further provides working examples demonstrating actual reduction to practice of representative species within the claimed genus. In Example 1, a trifunctional linker scaffold was designed with specific chemical end groups (DBCO, TCO) for conjugation with SO1861 on one arm and an antisense HSP27BNA oligonucleotide on the other, producing SO1861-L-trifunctional linker-L-HSP27BNA, which was then conjugated via its third arm (maleimide) to cetuximab cysteine residues (see Fig. 16-1). This conjugate was tested in an A431 xenograft mouse tumor model and demonstrated a 40% reduction in HSP27 gene expression compared to mono therapies (see Fig. 1-1), showing that conjugated SO1861 efficiently induces targeted delivery of therapeutic oligonucleotides in tumors, in vivo. In Example 9, SO1861-EMCH was conjugated via cysteine residues to cetuximab with a DAR 3.9 and the antisense HSP27BNA oligonucleotide was conjugated via a labile linker to lysine residues with a DAR 1.8, producing cetuxinab-(Cys-L-SO1861)3,9(Lys-L-HSP27BNA)1,8 which was tested in an A431 xenograft mouse tumor model and showed 40% reduction in HSP27 mRNA expression (see Fig. 2-4). Additionally, Example 3 provides detailed synthesis protocols for the dendron(SO1861)4-BNA oligo conjugate, including specific reagents, conditions, and characterisation data.
The specification thus describes the structural formula of COMPOUND I with all claimed variables, the specific structural classes of each component, explicit disclosure of conjugates combining all three components, and multiple working examples demonstrating actual synthesis and biological activity of representative species both in vitro and in vivo. These disclosures are more than sufficient to convey to one skilled in the art that the inventors had possession of the genus as claimed. The common structural attributes identifying members of the genus, a conjugate of COMPOUND I comprising an oligonucleotide effector moiety, a cell- targeting immunoglobulin, and a covalently bound bisdesmosidic triterpene saponin of the 2,13-dehydrooleanane type are clearly and concisely described throughout the specification.
Response to Applicant’s Arguments
The Breadth of the Claims:
The claims are broadly drawn to compositions comprising therapeutic molecules with the chemical structure of COMPOUND I:
Alm ((-L9w) (L1q-B1n)u ((-L2r-L3s)(-L4v- C)p)t))x, wherein Al is a first effector moiety, B1 is a first ligand, C is one or more bisdesmosidic triterpene saponins, belonging to the type of a 12,13-
dehydrooleanane with an aldehyde function in position C-23 and optionally comprising a glucuronic acid function in a carbohydrate substituent at the C-3 beta OH group of the saponin;
m = 1-32;
n = 1
p= any of 1-128;
L1 is at least one linker for covalently coupling two chemical groups;
L2 is at least one linker for covalently coupling two chemical groups;
L3 is at least one oligomeric or polymeric scaffold for covalently coupling two chemical groups;
L4 is at least one linker for covalently coupling two chemical groups;
L9 is a tri-functional linker for covalently coupling three chemical groups;
q = 0 or 1;
r = 0 or 1;
s = 0 or 1;
t = 0, 1 or 2 if s = 0, and t= any of 0-16 if s = 1;
v = 0 or 1;
w = 1 or 0; and
x = 1-16,
wherein the first effector moiety Al comprises or consists of an oligonucleotide; wherein the first ligand B1 comprises or consists of an immunoglobulin, a binding domain or a binding fragment thereof, or comprises or consists of any one of an antibody, an IgG, a molecule comprising or consisting of a Vhh or Vh domain, a Fab, an scFv, an Fv, a dAb, an F(ab)₂, Fcab fragment, or comprise(s) or consist(s) of at least one non proteinaceous ligand and/or at least one proteinaceous ligand, the ligand for binding to a cell surface molecule, with the proviso that the first and second ligand are the same or are different, which first ligand binds to a tumor cell epitope optionally comprising one of those listed in claim 5 or 6, which first effector molecule optionally comprises a nucleic acid molecule listed in claim 9 or 12, which one or more saponins optionally comprises a saponin listed in claim 13, and is optionally covalently bound to one or more oligomeric or polymeric scaffolds or directly bound to an amino acid residue of the first ligand or first effective molecule or via one or more linkers optionally comprising a cleavable linker.
Contrary to Applicant’s assertions, when all of the variables encompassed by the claims are considered, e.g., when q, r, s, t, v and w are zero, the claims merely recite a single A1 first effector which is an oligonucleotide, a single targeting ligand B1, and 1-128 saponin molecules. In the absence of any linkers, it is unclear how these molecules would be attached.
Teachings in the Art
As stated previously, Fuchs et al (Biomedicines, Vol. 5, No. 14, pages 1-25 (2017)) teach that the mechanism of saponin mediated endosomal escape is not fully understood (last full para on page 17). Fuchs teaches different outcomes are observed of protein based targeted toxins in vitro and in vivo, with low efficacy in animal models. Fuchs attributes the limitations to low entry of the toxin into the target cell’s cytosol, release of the toxin into the cytosol after internalization, and lysosomal degradation. Diverse effects of saponins are due to their wide structural variations. Fuchs teaches that the synergistic effect of toxins and triterpene saponins only applies to certain triterpenoids, and the current need to study the structure activity relationship of the various saponins. The specificity for target cells was lost when certain saponins were used in combination with targeted toxins. Fuchs teaches that the hydroxyl group at C-3 must be a branched sugar chain. Drastic synergistic enhancer effects of saponins and protein toxins require a molecule mass of at least 1600 g/mol (text on pages 1-3).
Fuchs also teaches relevant characteristics of oleanane type triterpenoid saponins. Where the residues at C-3 and C-4 and a sugar chain at C-28 with at least four sugar units were found mandatory to enhance the cytotoxicity of protein toxins (Fig. 1 on page 3). Fuchs also teaches that the isolation of chemically defined triterpene saponins is extremely time-consuming, raw extracts used to isolate saponins are highly complex and comprise hundreds of different and partly very similar triterpene saponin structures. (first para on page 4). At times, portions of saponin molecules remain associated with the cell after extensive washing and cause drastic and long lasting sensitization of the target cells against saporin (second para on page 8). And, while independent of the targeting moiety of the targeted toxin, the saponin mediated enhancement factor of cytotoxic effects is dependent on the target cell line and on the expression and internalization level of the target molecule (bridging para on pages 13-14). Fuchs addresses disparities between in vitro and in vivo efficacy of convincing enhancer effects of saponins for targeted toxins (first para on page 15).
Thakur et al (International J. Biological Macromolecules, Vol. 61, pages 285-294 (2013)) teach that the charge dependent enhancement of saponins was highly specific to type I ribosome inactivating proteins compared to bacterial toxins. Thakur teaches that the surface charge and hydrophobicity of toxin-saponin therapeutics saponins need to be carefully considered for surface design of novel therapeutics, and that the role of charge of the saponins in saponin toxin complexes is incompletely understood (abstract and introduction on page 285, bridging para on pages 290-292).
Ekladious et al (Nature Reviews Vol. 18, pages 273-289 (2019)) (See IDS filed 6-18-21) address the many obstacles hampering polymer drug conjugate therapeutics. Ekladious teaches the problematic heterogeneity of PEG protein conjugates, giving unpredictability due to variability in pharmacokinetics and pharmacodynamics. Ekladious also addresses the stability of self-assembled nanostructures and their dilution in the bloodstream. Ekladious teach the importance of the choice of linker chemistry and the control of drug release in designing effective drug polymers. And Ekladious teaches the gap between preclinical findings and patient data, and the failure of murine models to accurately recapitulate human cancers (See esp. pages 275-277, 282-284, 288-289).
Van Dongen et al (Biomacromolecules, Vol. 15, pages 3215-3234 (2014)) (See IDS filed 6-18-21) disclose the challenges of conjugation in the formation of multivalent polymers for drug delivery and imaging, which challenges include conjugation heterogeneity, scaffold heterogeneity, intended and unintended toxicity, and various influences of multivalency (See esp. pages 3215, 3219, 3221, 3223-3225).
Teachings in the Specification
As stated previously, the specification teaches the following:
Figure 1-1: in vivo HSP27 expression in A431 xenograph ‘nude’ mouse tumor model treated with 30mg/kg cetuximab-Cys-(SO1 861-L-trifunctional linker-L-HSP27BNA), 25 mg/kg Cetuximab-(Lys-L- HSP27BNA)4 or 25 mg/kg Cetuximab-(Cys-L-SO1861).
Figure 2-1: in vitro enhanced HSP27 gene silencing in EGFR expressing A431 cells by treatment with cetuximab-Cys-(SO1861-L-trifunctional —linker-L-HSP27BNA), Cetuximab-(Lys-L-HSP27BNA)4 or Cetuximab-(Cys-L-SO1861).
Figure 3-1: The legends and axes for Figures A, B, C and D are the same. A. cell killing activity in EGFR expressing cells (MDA-MB-468) by cetuximab, cetuxamib + 10 pM cetuximab-saporin, cetuximab-Cys- (dendron(-L-SO1861)4)3,9 and cetuximab-Cys-(dendron(-L-SO1861)4)3,9 + 10pM cetuximab-saporin. B. cell killing activity in HER2 expressing cells (SK-BR-3) by trastuzumab, trastuzumab + 50 pM trastuzumab-saporin, Trastuzumab-Cys-(dendron(-L-SO1861)4)4 and Trastuzumab-Cys-(dendron(-L-SO1861)4)4 + 50 pM trastuzumab-saporin. C. cell killing activity in EGFR expressing cells (HeLa) by cetuximab, cetuxamib + 10 pM cetuximab-saporin, cetuximab-Cys-(dendron(-L-SO1861)*)39 and cetuximab-Cys-(dendron(-L-SO1861)4)3,9 + 10pM cetuximab-saporin. D. cell killing activity in HER2 expressing cells (JIMT-1) by trastuzumab, trastuzumab + 50 pM trastuzumab-saporin, Trastuzumab-Cys-(dendron(-L-SO1861)4)4 and Trastuzumab-Cys-(dendron(-L-SO1861)4)4 + 50 pM trastuzumab-saporin.
Figure 4-1: The legends and axes for Figures A, B, C and D are the same. A. cell killing activity in EGFR**/CD71* cells (MDA-MB-468) of cetuximab, cetuximab + 10 pM CD71mab-saporin, Cetuximab- Cys-(dendron(-L-SO1861)4)3,9, Cetuximab-Cys-(dendron(-L-SO1861)4)3,9 + 10 pM CD7/1mab-saporin , Cetuximab-Lys-(dendron(-L-SO1861)4)4,4 or Cetuximab-Lys-(dendronCL-SO1861)4)4,4 + 10 pM CD7imab-saporin. B. cell killing activity in HER2**/CD71* (SK-BR-3) cell lines of trastuzumab, trastuzumab + 10 pM CD71mab-saporin, trastuzumab-Cys-(dendron(-L-SO1861)4,4, trastuzumab-Cys-(dendron(-L-SO1861)4,4 + 10 pM CD71mab-saporin, trastuzumab-Lys-(dendron(-L-SO1861)4)4,7 or trastuzumab-Lys-(dendron(-L-SO1861)4)4,7 + 10 pM CD71mab-saporin. C. cell killing activity in EGFR*/CD71* cells (CaSki) of cetuximab, cetuximab + 10 pM CD71mab-saporin, Cetuximab-Cys- (dendron-L-SO1861)4)3,9, Cetuximab-Cys- (dendron-L-SO1861)4)3,9 + 10 pM CD71mab-saporin, Cetuximab-Lys-(dendron(-L-SO1861)4)4,4 or Cetuximab-Lys-(dendron(-L-SO1861)4)4,4 + 10 pM CD71mab-saporin. D. cell killing activity in HER2*’/CD71* cells (JIMT-1) of trastuzumab, trastuzumab + 10 pM CD71mab-saporin, trastuzumab-Cys-(dendron(-L-SO1 861)4)4,4, trastuzumab-Cys-(dendron(-L-SO1 861)4)4,4 + 10 pM CD71mab-saporin, trastuzumab-Lys-(dendron(-L-SO1861)4)4,7 or trastuzumab-Lys-(dendron(-L-SO1861)4)4,7+ 10 pM CD71mab-saporin.
Figure 5-1: cell killing activity in HER2 expressing cells (SK-BR-3) of T-DM1, T-DM1 + 25.6 nM trastuzumab or T-DM1 + 5.3 nM trastuzumab-Cys-(dendron(-L-SO1861)4)4.
Figure 6-1: HSP27 gene silencing activity of HSP27BNA-dendron(-L-SO1861)4 compared to the HSP27BNA alone.
Figure 7-1: Schematic representation of release of SO1861 from dendron(-L-SO1861)4 under acidic conditions.
Figure 8-1: The legends and axes for Figures A and B are the same. A. cell killing activity in EGFR expressing A431 cells by the ‘naked’ dendron (Dendron(NEM)4), Dendron(NEM4 + 10 pM EGFdianthin, dendron(-L-SO1861)4 or dendron(L-SO1861)4 + 10 pM EGFdianthin. B cell killing activity in EGFR expressing HeLa cells by the ‘naked’ dendron (Dendron(NEM)4, Dendron(NEM)4 + 10 pM EGFdianthin, dendron-L-SO1861)4 or dendron(L-SO1861)4 + 10 pM EGFdianthin.
Figure 10-1: Schematic representation of the monoclonal antibody-(SO1861-scaffold-antisense BNA oligo) conjugate.
Figure 13-1: Schematic representation of Dendron(-L-SO1861).
Figure 15-1: Schematic representation of SO1861-L-trifunctional linker-L-HSP27BNA.
Figure 17-1: Model scaffold consisting of four molecular arms for saponin binding via a Schiff base (imine) and one arm for click chemistry. The polymeric structure is a pentavalent polyethylene glycol- based dendrimer of the first generation.
Figure 18-1: Cell viability of HER14 cells after treatment with a pentameric dendrimer (pentrimer), the pentrimer in the presence of SA1641, dianthin-EGF, dianthin-EFG in the presence of SA1641, the pentrimer in presence of dianthin-EGF, and the pentrimer in presence of dianthin-EGF as well as SA1641.
Figure 19-1: SO1861 structure with highlighted chemical groups for conjugation of endosomal escape enhancing saponins to a polymeric structure. Highlighted groups are aldehyde (black circle), carboxylic acid (dashed circle), alkene (dashed pentagon), and alcohol (dashed box).
Figure 20-1: A. Standard molecular structure of SO-1861-EMCH conjugate. Maleimide group is marked with a circle. B. 3D model of SO1861-EMCH conjugate. Maleimide group is marked with a circle.
Figure 24-1: Molecular structure of G4-dendron with protected amino groups.
Figure 1-2. Antibody-protein toxin + unconjugated SO1861 vivo study. BT474 tumor bearing mice treated with various concentrations of Trastuzumab-saporin (i.v.) + 1.5 mg/kg unconjugated SO1861…
Figure 2-2. unconjugated saponin-mediated endosomal escape and target cell killing enhancement. A) Cell viability analyses of HeLa cells (EGFR*) treated with SO1861, SO1832, SO1862 (isomer of S01861) or SO1904 with or without 1.5 pM EGFdianthin B) Cell viability analyses of HeLa cells (EGFR*) treated with EGFdianthin and fixed concentrations of SO1861, SO1832, SO1862 (isomer of SO1861) or SO1904. C) Cell viability analyses of HeLa cells (EGFR*) treated with SO1861 or GE1741 with or without 1.5 pM EGFdianthin. D) Cell viability analyses of HeLa cells (EGFR*) treated with various QSmix (saponin mixture from Quillaia Saponaria) with or without 1.5 pM EGFdianthin.
QSmix is a mixture of saponins from an extract Quillaja Saponaria.
Figure 4-2. unconjugated SO1861 versus SO1861-EMCH (labile) versus SO1861-S (stable). … with or without EGFdiantin.
Figure 4-4: HER2 or EGFR targeted protein toxin delivery and cell killing in cancer cells, according to the invention. A. Trastuzumab-(Cys-L-SO1861)3,8(Lys-L-dianthin)1,7.
Figure 5-4: EGFR targeted antisense BNA oligo delivery and gene silencing in cancer cells, according to the invention. A. Cetuximab-(Cys-L-SO1861)3,8(Lys-L-HSP27BNA)3,7.
Figure 6-4: HER2 targeted antisense BNA oligo delivery and gene silencing in cancer cells, according to the invention. Trastuzumab-(Cys-L-SO1 861)*8(Lys-L-HSP27BNA)*5 treatment and controls on SK- BR-3 cells (HER2**).
Figure 12-4: Antibody-SO1861 conjugation procedure. Shown is the coupling reaction of the linking of four moieties of a plant-derived saponin SO1861 to the four cysteines in the light chain of an antibody. First, the disulphide bonds in the IgG are disrupted under influence of exposure to TCEP (Tris(2-carboxyethyl)phosphine); second, the saponin SO1861 comprising a chemical linker bound to it, is added together with trifluoro acetic acid, and four saponin moieties are linked to the IgG. For producing cleavable ‘ready to conjugate’ saponins the aldehyde group of SO1861 was reacted with an EMCH (e- maleimidocaproic acid hydrazide) linker. The hydrazide group of EMCH forms an acid cleavable hydrazone bond with the aldehyde of SO1861. … the EMCH linker presents a maleimide group that is thiol (sulfhydryl group) reactive and thus can be conjugated to thiols of the IgG, i.e. the ligand moiety…
[Emphases added][Citations omitted}.
And, contrary to Applicant’s assertions, the teachings in the specification, of specific multimers and compositions claimed, are not representative of the broad genus of therapeutic molecules encompassed by the claims. The specification fails to provide the requisite guidance for making or using the large genus of multimeric compounds instantly claimed. Since the disclosure fails to describe the common attributes and characteristics concisely identifying members of the proposed genus of multimeric compositions claimed, and because the claimed genus is highly variant, the description provided is insufficient. One of skill in the art would reasonably conclude that the disclosure fails to provide a representative number of species to describe the broad genus instantly claimed.
Thus, Applicant was not in possession of the claimed genus and the instant rejection is properly maintained.
Claim Rejections - 35 USC § 103
In the event the determination of the status of the application as subject to AIA 35 U.S.C. 102 and 103 (or as subject to pre-AIA 35 U.S.C. 102 and 103) is incorrect, any correction of the statutory basis (i.e., changing from AIA to pre-AIA ) for the rejection will not be considered a new ground of rejection if the prior art relied upon, and the rationale supporting the rejection, would be the same under either status.
The following is a quotation of 35 U.S.C. 103 which forms the basis for all obviousness rejections set forth in this Office action:
A patent for a claimed invention may not be obtained, notwithstanding that the claimed invention is not identically disclosed as set forth in section 102, if the differences between the claimed invention and the prior art are such that the claimed invention as a whole would have been obvious before the effective filing date of the claimed invention to a person having ordinary skill in the art to which the claimed invention pertains. Patentability shall not be negated by the manner in which the invention was made.
This application currently names joint inventors. In considering patentability of the claims the examiner presumes that the subject matter of the various claims was commonly owned as of the effective filing date of the claimed invention(s) absent any evidence to the contrary. Applicant is advised of the obligation under 37 CFR 1.56 to point out the inventor and effective filing dates of each claim that was not commonly owned as of the effective filing date of the later invention in order for the examiner to consider the applicability of 35 U.S.C. 102(b)(2)(C) for any potential 35 U.S.C. 102(a)(2) prior art against the later invention.
Claim(s) 1, 4-6, 9, 12, 13, 20-24, 29-31, 35, 38 and 43 is/are rejected under 35 U.S.C. 103 as being unpatentable over Bottger et al (Toxicon, Vol. 73, pages 144-150 (2013)) in view of Gilabert-Oriol et al (Biochem. Pharm., Vol. 97, pages 247-255 (2015)), Gilabert-Oriol et al (Molecular Pharmaceutics, Vol. 10, pages 4347-4357 (2013)), Holmes et al (Informa Healthcare, Vol. 37, No. 1, pages 42-55 (2015)), and Bachran et al (Combined Application of Saponins and Chimeric Toxins, pages 412-420 (2005)) for the reasons of record set forth in the Office action mailed 1-28-26 and as set forth below.
Applicant’s Arguments
Applicant respectfully submits that none of the cited references teaches or suggests the use of an oligonucleotide as the effector moiety in combination with a saponin. The prior art is exclusively directed to protein toxins as effector moieties. Bottger studies the synergistic enhancement of the cytotoxicity of ribosome-inactivating proteins type I (RIP-I) by saponins.. Gilabert-Oriol (2015) conjugates the protein toxin dianthin to therapeutic antibodies and co-applies free SO1861. Gilabert-Oriol (2013) conjugates the protein toxin saporin to trastuzumab and cetuximab via cleavable disulfide bonds, again with free SO1861 co-administered separately. Holmes teaches that saponinum album augments "the cytotoxicity of the type I ribosome-inactivating protein saporin and an EGF-saporin target toxin." A person of ordinary skill in the art would not have had a reasonable expectation of success in substituting an oligonucleotide for a protein toxin, because the prior art teaches that the saponin enhancement effect is specific to certain ribosome-inactivating proteins.
Applicant further submits that none of the cited references teaches covalent conjugation of a saponin within a therapeutic molecule. Bottger studies co-administration of free saponins with free protein toxins and does not teach or suggest covalent conjugation of a saponin to any molecule. Gilabert-Oriol (2015) expressly proposes a combinatorial approach in which "the immunotoxin would be injected subcutaneously at different concentrations in the vicinity of the tumor and SO1861 would be administered subcutaneously in the neck." (See Gilabert-Oriol (2015), page 254). Gilabert-Oriol (2013) similarly co-administers free SO1861 with immunotoxin conjugates. Holmes likewise co-administers saponinum album with saporin-based immunotoxins. The prior art thus uniformly teaches a two-component co-administration system: a free saponin administered separately from a separate antibody-protein toxin conjugate. The prior art does not teach or suggest a single conjugate molecule with a covalently integrated saponin as required by claim 1, as amended.
Additionally, claim 1 as amended specifically requires C to be "an endosomal escape enhancer saponin" defining its function within the conjugate. The prior art provides no teaching that a saponin would retain endosomal escape enhancing function when covalently attached within a conjugate molecule. The prior art's exclusive reliance on free saponin co-administration suggests the opposite: that the saponin needed to be administered separately to perform its membrane-disrupting function. The Examiner has not identified any reference that teaches or suggests covalently linking a saponin to an oligonucleotide-containing conjugate, nor has the Examiner provided any articulated reasoning as to why a person of ordinary skill in the art would have been motivated to do so with a reasonable expectation of success.
The specification further demonstrates unexpected results that support non-obviousness. As disclosed therein, the inventors established that "separately administering to the mice a dose of free saponin and a dose of ADC... did not result in any desired anti-tumor activity such as delayed tumor growth, tumor regression, diminished and slower tumor growth, compared to control animals not treated with the ADC and free saponin." (See Specification, page 166). The free saponin was administered using various routes of administration and various time points, and varying the dose of free saponin did not provide for efficacious anti-tumor activity. By contrast, covalent integration of the saponin within conjugates as claimed achieved effective targeted delivery and gene silencing both in vitro and in vivo. These results are unexpected in view of the prior art, which uniformly teaches co-administration of free saponin as the approach for enhancing toxin efficacy.
Response to Applicant’s Arguments
The claims are broadly drawn to compositions comprising therapeutic molecules with the chemical structure of COMPOUND I:
Alm ((-L9w) (L1q-B1n)u ((-L2r-L3s)(-L4v- C)p)t))x, wherein Al is a first effector moiety, B1 is a first ligand, C is one or more bisdesmosidic triterpene saponins, belonging to the type of a 12,13-
dehydrooleanane with an aldehyde function in position C-23 and optionally comprising a glucuronic acid function in a carbohydrate substituent at the C-3 beta OH group of the saponin;
m = 1-32;
n = 1
p= any of 1-128;
L1 is at least one linker for covalently coupling two chemical groups;
L2 is at least one linker for covalently coupling two chemical groups;
L3 is at least one oligomeric or polymeric scaffold for covalently coupling two chemical groups;
L4 is at least one linker for covalently coupling two chemical groups;
L9 is a tri-functional linker for covalently coupling three chemical groups;
q = 0 or 1;
r = 0 or 1;
s = 0 or 1;
t = 0, 1 or 2 if s = 0, and t= any of 0-16 if s = 1;
v = 0 or 1;
w = 1 or 0; and
x = 1-16,
wherein the first effector moiety Al comprises or consists of an oligonucleotide; wherein the first ligand B1 comprises or consists of an immunoglobulin, a binding domain or a binding fragment thereof, or comprises or consists of any one of an antibody, an IgG, a molecule comprising or consisting of a Vhh or Vh domain, a Fab, an scFv, an Fv, a dAb, an F(ab)₂, Fcab fragment, or comprise(s) or consist(s) of at least one non proteinaceous ligand and/or at least one proteinaceous ligand, the ligand for binding to a cell surface molecule, with the proviso that the first and second ligand are the same or are different, which first ligand binds to a tumor cell epitope optionally comprising one of those listed in claim 5 or 6, which first effector molecule optionally comprises a nucleic acid molecule listed in claim 9 or 12, which one or more saponins optionally comprises a saponin listed in claim 13, and is optionally covalently bound to one or more oligomeric or polymeric scaffolds or directly bound to an amino acid residue of the first ligand or first effective molecule or via one or more linkers optionally comprising a cleavable linker.
Contrary to Applicant’s assertions, when all of the variables encompassed by the claims are considered, e.g., when q, r, s, t, v and w are zero, the claims merely recite a single A1 first effector which is an oligonucleotide, a single targeting ligand B1, and 1-128 saponin molecules. In the absence of any linkers, it is unclear how these molecules would be attached.
In response to applicant’s argument that there is no teaching, suggestion, or motivation to combine the references, the examiner recognizes that obviousness may be established by combining or modifying the teachings of the prior art to produce the claimed invention where there is some teaching, suggestion, or motivation to do so found either in the references themselves or in the knowledge generally available to one of ordinary skill in the art. See In re Fine, 837 F.2d 1071, 5 USPQ2d 1596 (Fed. Cir. 1988), In re Jones, 958 F.2d 347, 21 USPQ2d 1941 (Fed. Cir. 1992), and KSR International Co. v. Teleflex, Inc., 550 U.S. 398, 82 USPQ2d 1385 (2007). In this case, and as stated previously, Gilabert-Oriol teach the conjugation of antibodies to saporin via a cleavable disulfide linker, Gilabert-Oriol teach the formation of immunotoxins comprising the conjugation of antibodies to toxins, and direct the binding of the immunotoxins to cancer specific receptors, providing the combinatorial approach of Cetuximab, Panitumumab, and Trastuzumab by conjugation and coadministration of SO1861, Bachran examines the enhanced uptake and cytotoxicity on target cells after administration of the combination of saponin and a targeted chimeric toxin composed of EGF and saponinum album (SA) conjugates linked via a cleavable adapter, and Holmes teaches EGF saporin-target toxins for optimizing targeted toxins, where the augmentative property of SA on saporin and saporin based immunotoxins were directed against five different cell surface target molecules on human leukemia and lymphoma cells.
Bottger et al (Toxicon, Vol. 73, pages 144-150 (2013)) teach the categorization of saponins. Fifty six saponins were divided into 13 categories, according to their chemical structure and cytotoxic behavior. Bottger analyzed the modifications of bisdesmosidic triterpene saponin, including acetylation of the C3 residue, sugar branching, and C28 residue modifications with various branched and linear sugars on oleanolic acid, hydroxyoleanolic acid, dihydroxyoleanolic acid, trihydroxyoleanolic acid, and dihydroxyoleanan-12-en (Table 1 on page 147) and acetylation of the C23 residue (Fig. 2 on page 149).
Gilabert-Oriol et al (Molecular Pharmaceutics, Vol. 10, pages 4347-4357 (2013)) (See IDS filed 6-18-21) teach the conjugation of antibodies to saporin via a cleavable disulfide linker. The immunoconjugates retained ability to trigger antibody dependent cell mediated cytotoxicity, specifically binding their intended target cell receptor, and having augmented cell killing activity in the presence of triterpenoid saponins. Studies also indicated a specific saponin mediated endolysosomal release of the toxin moiety (see esp. pages 4347-4348, 4351-4355).
Holmes et al (Informa Healthcare, Vol. 37, No. 1, pages 42-55 (2015))(See IDS filed 6-18-21) teach triterpenoid saponin augmentation of saporin based immunotoxin cytotoxicity against human leukemia and lymphoma cells. Holmes teaches that saponinum album (SA) is a complex mixture of triterpenoid saponins which augment the cytotoxicity of type I ribosome inactivating protein saporin. Holmes teaches EGF saporin-target toxins for optimizing targeted toxins. The augmentative property of SA on saporin and saporin based immunotoxins were directed against five different cell surface target molecules on human leukemia and lymphoma cells (see esp. pp 42-45).
Bachran et al (Combined Application of Saponins and Chimeric Toxins, pages 412-420 (2005))(See IDS filed 6-18-21) teach saponins to be a group of plant glycosides consisting of a steroid or triterpenoid aglycone with one or more sugar moieties attached. Bachran examines the enhanced uptake and cytotoxicity on target cells after administration of the combination of saponin and a targeted chimeric toxin composed of EGF and saponinum album (SA) conjugates linked via a cleavable adapter (see esp. pages412-412, 418).
Contrary to Applicant’s assertions, it would have been obvious to construct the various multimeric therapeutic molecules claimed because the prior art of record provides a multitude of the various conjugates. All of the components were provided in the prior art, and the combinations of toxins, saponins, proteins, antibody components, and/or nucleic acids have been amply provided in the combined teachings of Bottger, Gilabert-Oriol, Gilabert-Oriol, Holmes, and Bachran, as set forth above.
For these reasons, the instant invention would have been obvious to one of ordinary skill in the art before the effective filing date of the claimed invention and the instant rejection for obviousness is properly maintained.
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 1, 4-6, 9, 12, 13, 20-24, 29-31, 35, 38 and 43 are provisionally rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1, 2, 5, 7, 11, 13, 14, 17, 23-26 of copending Application No. 17/312,104 (reference application). Although the claims at issue are not identical, they are not patentably distinct from each other because both sets of claims are drawn to compositions comprising therapeutic molecules comprising conjugates comprising an oligonucleotide linked to a cell surface targeting molecule, an effector moiety and at least one covalently bound triterpenoid saponin or bisdesmosidic triterpene saponin.
This is a provisional nonstatutory double patenting rejection because the patentably indistinct claims have not in fact been patented.
Applicant’s Arguments
Applicant's arguments filed 6-29-26 have been fully considered but they are not persuasive.
Applicant argues the following:
With respect to co-pending U.S Application No. 17/312,104, claim 1 recites a conjugate comprising an oligonucleotide covalently linked to at least one saponin, wherein the saponin is a bisdesmosidic triterpene saponin of the 2,13-dehydrooleanane type, covalently bound to the oligonucleotide via at least one linker involving a hydrazone bond. However, U.S. Application No.17/312,104 does not disclose or suggest a single conjugate molecule further comprising a targeting ligand in addition to the oligonucleotide and saponin.
Although claim 26 of U.S. Application No. 17/312,104 previously referred to an antibody- drug conjugate or ligand-drug conjugate, that claim has been withdrawn. Accordingly, the application no longer discloses or claims a construct comprising an oligonucleotide, a saponin, and a targeting ligand within the same molecule.
Response to Applicant’s Arguments
Applicant is correct that claim 1 of Application No. 17/312,104 (hereinafter ‘104) recites a conjugate comprising an oligonucleotide covalently linked to at least one saponin, wherein the saponin is a bisdesmosidic triterpene saponin of the 2,13-dehydrooleanane type, covalently bound to the oligonucleotide via at least one linker involving a hydrazone bond. But, contrary to Applicant’s assertions, claim 26 of the ‘104 application recites an antibody drug conjugate comprising the conjugate of claim 1, or a ligand drug conjugate, which antibody or ligand are targeting ligands. And, contrary to Applicant’s assertions, although claim 26 or the ‘104 application is currently withdrawn, it is still a pending claim and is properly relied upon for the instant double patenting rejection.
Conclusion
Applicant's amendment necessitated the new ground(s) of rejection presented in this Office action. Accordingly, THIS ACTION IS MADE FINAL. See MPEP § 706.07(a). Applicant is reminded of the extension of time policy as set forth in 37 CFR 1.136(a).
A shortened statutory period for reply to this final action is set to expire THREE MONTHS from the mailing date of this action. In the event a first reply is filed within TWO MONTHS of the mailing date of this final action and the advisory action is not mailed until after the end of the THREE-MONTH shortened statutory period, then the shortened statutory period will expire on the date the advisory action is mailed, and any nonprovisional extension fee (37 CFR 1.17(a)) pursuant to 37 CFR 1.136(a) will be calculated from the mailing date of the advisory action. In no event, however, will the statutory period for reply expire later than SIX MONTHS from the mailing date of this final action.
Certain papers related to this application may be submitted to Art Unit 1637 by facsimile transmission. The faxing of such papers must conform with the notices published in the Official Gazette, 1156 OG 61 (November 16, 1993) and 1157 OG 94 (December 28, 1993) (see 37 C.F.R. ' 1.6(d)). The official fax telephone number for the Group is 571-273-8300. NOTE: If Applicant does submit a paper by fax, the original signed copy should be retained by applicant or applicant's representative. NO DUPLICATE COPIES SHOULD BE SUBMITTED so as to avoid the processing of duplicate papers in the Office.
Any inquiry concerning this communication or earlier communications from the examiner should be directed to Jane Zara whose telephone number is (571) 272-0765. The examiner’s office hours are generally Monday-Friday, 10:30am - 7pm. If attempts to reach the examiner by telephone are unsuccessful, the examiner's supervisor, Jennifer Dunston, can be reached on (571)-272-2916. Any inquiry of a general nature or relating to the status of this application should be directed to the Group receptionist whose telephone number is (703) 308-0196.
Information regarding the status of an application may be obtained from the Patent Application Information Retrieval (PAIR) system. Status information for published applications may be obtained from either Private PAIR or Public PAIR. Status information for unpublished applications is available through Private PAIR only. For more information about the PAIR system, see http://pair-direct.uspto.gov. Should you have questions on access to the Private PAIR system, contact the Electronic Business Center (EBC) at 866-217-9197 (toll-free).
Jane Zara
8-6-26
/JANE J ZARA/Primary Examiner, Art Unit 1637
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