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
Applicant’s election without traverse of the below-listed species in the reply filed on June 20, 2025 is acknowledged:
Claim 1: Linker;
Claim 4: Saponaria species and SO1861;
Claim 11: CD71;
Claim 13: OKT-9 anti-CD71 monoclonal antibody of the IgG type;
Claim 19: A molecule comprising or consisting of a Vhh or Vh domain;
Claims 26-27: OKT-9 anti-CD71 monoclonal antibody of the IgG type;
Claim 28: AMG-172 (renal cell carcinoma);
Claim 29: Oligonucleotide;
Claim 30: A protein; and
Claims 32 and 39-40: Linker.
Claim Status
Claims 5-6, 9-10, 12, 15, 17-18, 20-25, 31, 33-38, and 41-48 have been cancelled and claims 3-4, 7-8, 11, 13-14, 16, 19, 26-30, 32, and 39-40 have been amended, as requested in the preliminary amendment filed on June 15, 2021. Following the amendment, claims 1-4, 7-8, 11, 13-14, 16, 19, 26-30, 32, and 39-40 are pending in the instant application.
Claims 1-4, 7-8, 11, 13-14, 16, 19, 26-30, 32, and 39-40 are under examination in the instant office action.
Priority
Applicant’s claim for the benefit of a prior-filed application under 35 U.S.C. 119(e) or under 35 U.S.C. 120, 121, 365(c), or 386(c) is acknowledged.
Receipt is acknowledged of certified copies of papers required by 37 CFR 1.55. It is also noted that the claim to foreign priority has been perfected, as the certified copies of the foreign priority documents are in English.
Claims 1-3 have an effective filing date of December 21, 2018 corresponding to NL2022283. Claims 14, 16, and 39-40 have an effective filing date of July 10, 2019 corresponding to NL2023468; it is noted that earlier-filed NL2022283 does not disclose a therapeutic combination of proteinaceous molecules as instantly claimed. Claims 4, 11, 13, 19, 26-30, and 32 have an effective filing date of December 9, 2019 corresponding to PCT/EP2019/084292; it is noted that none of the earlier-filed foreign priority documents disclose all of the species/alternatives instantly claimed in claims 4, 11, 13, 19, 26-30, and 32.
Information Disclosure Statement
The information disclosure statements (IDS) submitted on 06/15/2021, 07/12/2022, 11/14/2022, 03/08/2023, 10/26/2023, 02/26/2024, and 09/03/2024 are in compliance with the provisions of 37 CFR 1.97. Accordingly, the information disclosure statements are being considered by the examiner.
The listing of references in the specification is not a proper information disclosure statement. 37 CFR 1.98(b) requires a list of all patents, publications, or other information submitted for consideration by the Office, and MPEP § 609.04(a) states, "the list may not be incorporated into the specification but must be submitted in a separate paper." Therefore, unless the references have been cited by the examiner on form PTO-892, they have not been considered.
Drawings
The drawings are objected to because the figure labels for Figures 1, 2A-B, 4, 5B-D, 6-17, 21-22, 24, 34, 37-40, 41-42, 43B/D, 44B, 45, 47-56, 58, 60-61, 63-64, 66-87, and 89-90 do match the orientation of the Figures. Furthermore, it is noted that the way in which different parts of the figures are labeled (e.g., A, B, C, etc.) are represented Corrected drawing sheets in compliance with 37 CFR 1.121(d) 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. The figure or figure number of an amended drawing should not be labeled as “amended.” If a drawing figure is to be canceled, the appropriate figure must be removed from the replacement sheet, and where necessary, the remaining figures must be renumbered and appropriate changes made to the brief description of the several views of the drawings for consistency. Additional replacement sheets may be necessary to show the renumbering of the remaining figures. 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.
Specification
Applicant is reminded of the proper content of an abstract of the disclosure.
A patent abstract is a concise statement of the technical disclosure of the patent and should include that which is new in the art to which the invention pertains. The abstract should not refer to purported merits or speculative applications of the invention and should not compare the invention with the prior art.
If the patent is of a basic nature, the entire technical disclosure may be new in the art, and the abstract should be directed to the entire disclosure. If the patent is in the nature of an improvement in an old apparatus, process, product, or composition, the abstract should include the technical disclosure of the improvement. The abstract should also mention by way of example any preferred modifications or alternatives.
Where applicable, the abstract should include the following: (1) if a machine or apparatus, its organization and operation; (2) if an article, its method of making; (3) if a chemical compound, its identity and use; (4) if a mixture, its ingredients; (5) if a process, the steps.
Extensive mechanical and design details of an apparatus should not be included in the abstract. The abstract should be in narrative form and generally limited to a single paragraph within the range of 50 to 150 words in length.
See MPEP § 608.01(b) for guidelines for the preparation of patent abstracts.
Applicant is reminded of the proper language and format for an abstract of the disclosure.
The abstract should be in narrative form and generally limited to a single paragraph on a separate sheet within the range of 50 to 150 words in length. The abstract should describe the disclosure sufficiently to assist readers in deciding whether there is a need for consulting the full patent text for details.
The language should be clear and concise and should not repeat information given in the title. It should avoid using phrases which can be implied, such as, “The disclosure concerns,” “The disclosure defined by this invention,” “The disclosure describes,” etc. In addition, the form and legal phraseology often used in patent claims, such as “means” and “said,” should be avoided.
The abstract of the disclosure is objected to because it exceeds 150 words and includes both legal phraseology and implied phrases. A corrected abstract of the disclosure is required and must be presented on a separate sheet, apart from any other text. See MPEP § 608.01(b).
The use of the terms, for example, Alexa Fluor, Thermo Scientific, Multiskan, DMEM, CellTiter 96, Eppendorf, etc., which are trade names or a marks used in commerce, have been noted in this application. The terms should be accompanied by the generic terminology; furthermore the terms should be capitalized wherever it appears or, where appropriate, include a proper symbol indicating use in commerce such as ™, SM , or ® following the term.
Although the use of trade names and marks used in commerce (i.e., trademarks, service marks, certification marks, and collective marks) are permissible in patent applications, the proprietary nature of the marks should be respected and every effort made to prevent their use in any manner which might adversely affect their validity as commercial marks.
Claim Objections
Claims 2, 13, 19, and 26-28 are objected to as they all recite both a “binding domain” and “binding fragment”. For example claim 2 recites “at least one binding domain of an immunoglobulin and/or at least one binding fragment of an immunoglobulin”. It is specifically noted that “binding domain” and “binding fragment” are defined the same on Page 18 of the instant specification; as such a “binding domain” and “binding fragment” are duplicate embodiments.
Claims 2, 11, and 19 are objected to as they recite abbreviations (e.g., EGF, EGFR, PSMA, etc.) which have not been spelled out upon their initial recitation in the claims.
Claims 2 and 19 are objected to because the claims currently recite “F(ab)2” and “F(ab)2”, respectively, but should read “F(ab’)2”.
Claims 4, 13, 26-28, and 30 are objected to as they contain references to various tables and/or schemes. “Where possible, claims are to be complete in themselves. Incorporation by reference to a specific figure or table ‘is permitted only in exceptional circumstances where there is no practical way to define the invention in words and where it is more concise to incorporate by reference than duplicating a drawing or table into the claim. Incorporation by reference is a necessity doctrine, not for applicant’s convenience.’ Ex parte Fressola, 27 USPQ2d 1608, 1609 (Bd. Pat. App. & Inter. 1993) (citations omitted).” See MPEP 2173.05(s).
Claims 14 and 16 are objected to because they currently recite “[t]herapeutic combination”, but should recite “[a] therapeutic combination”.
Claims 26-28 are objected to because they all recite “molecule binding fragment or -domain thereof”, but should read “molecule binding-fragment or -domain thereof” for consistency throughout the claims.
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 2, 4, 7, 11, 13 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.
Regarding claims 2, 4, 7, 11, 13, 19, 26-30, and 32, the phrases “such as”, “preferably”, and/or “e.g.” render the claims indefinite because it is unclear whether the limitation(s) following such phrases are part of the claimed invention. See MPEP § 2173.05(d). They may or may not be required and the presence of two or more interpretations renders the claims indefinite.
Further regarding claims 4 and 32, the phrase “optionally” renders the claims indefinite as it is unclear as to how many alternatives “optionally” may refer to. Additionally with regard to claim 4, it is noted that the use of “optionally” in lines 16-24 introduces many possible combinations of saponin substituents which compound on each other, and as such the use of “optionally” in this manner introduces a high level of ambiguity to the claim; it becomes unclear which optional substituents may or may not present for any possible structure.
Claim 26 recites the limitation “the second binding site” at lines 4 and 12 and “the second proteinaceous molecule” at line 12. There is insufficient antecedent basis for these limitations in the claim. Therefore it is unclear as to which proteinaceous molecule(s) are intended to be included in the scope of the claim.
Claim 28 recites the limitation “the third proteinaceous molecule” at line 3. There is insufficient antecedent basis for this limitation in the claim. Therefore it is unclear as to which proteinaceous molecule(s) are intended to be included in the scope of the claim.
With regard to claims 14 and 16, the claims are considered indefinite due to the recitation of “therapeutic combination”. The phrase “therapeutic combination” is not explicitly defined in the instant specification, and as such it is unclear as to if claims 14 and 16 are product claims or method claims. Merriam-Webster indicates that “combination” may be used as either a noun, referring to the quality or state of being combined, or a verb, as the act or process of combining. It is unclear as to which interpretation is the intended scope of the instant claims. Furthermore, it is noted that if in the instant claims the recitation of “therapeutic combination” is intended to convey method claims, there are no active method steps recited which further renders the claims indefinite. “Attempts to claim a process without setting forth any steps involved in the process generally raises an issue of indefiniteness under 35 U.S.C. 112(b) or pre-AIA 35 U.S.C. 112, second paragraph. For example, a claim which read: ‘[a] process for using monoclonal antibodies of claim 4 to isolate and purify human fibroblast interferon’ was held to be indefinite because it merely recites a use without any active, positive steps delimiting how this use is actually practiced. Ex parte Erlich, 3 USPQ2d 1011 (Bd. Pat. App. & Inter. 1986).” See MPEP 2173.05(q).
Improper Markush
Claims 11, 13, and 26-30 are rejected on the basis that it contains an improper Markush grouping of alternatives.
See In re Harnisch, 631 F.2d 716, 721-22 (CCPA 1980) and Ex parte Hozumi, 3 USPQ2d 1059, 1060 (Bd. Pat. App. & Int. 1984). A Markush grouping is proper if the alternatives defined by the Markush group (i.e., alternatives from which a selection is to be made in the context of a combination or process, or alternative chemical compounds as a whole) share a “single structural similarity” and a common use. A Markush grouping meets these requirements in two situations. First, a Markush grouping is proper if the alternatives are all members of the same recognized physical or chemical class or the same art-recognized class, and are disclosed in the specification or known in the art to be functionally equivalent and have a common use. Second, where a Markush grouping describes alternative chemical compounds, whether by words or chemical formulas, and the alternatives do not belong to a recognized class as set forth above, the members of the Markush grouping may be considered to share a “single structural similarity” and common use where the alternatives share both a substantial structural feature and a common use that flows from the substantial structural feature. See MPEP § 2117.
The Markush groupings of the binding sites in claim 11, antibodies of claims 13, 26-28, nucleic acids of claim 29, and peptides/proteins/enzymes of claim 30 are improper because the alternatives defined by the Markush grouping do not share both a single structural similarity and a common use for the following reasons: the alternatives listed for the different binding sites, nucleic acids, and peptides/proteins/enzymes within each Markush grouping bind different targets and/or exert unique biological functions; as such their binding sites, active sites, and overall structures must be different. Thus, the listed alternatives for the above-listed Markush groupings lack a common use/function and even if they shared one, there is no common structural feature among all that provides the function making it a substantial structural feature.
To overcome this rejection, Applicant may set forth each alternative (or grouping of patentably indistinct alternatives) within an improper Markush grouping in a series of independent or dependent claims and/or present convincing arguments that the group members recited in the alternative within a single claim in fact share a single structural similarity as well as a common use.
Claim Rejections - 35 USC § 102
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 the appropriate paragraphs of 35 U.S.C. 102 that form the basis for the rejections under this section made in this Office action:
A person shall be entitled to a patent unless –
(a)(1) the claimed invention was patented, described in a printed publication, or in public use, on sale, or otherwise available to the public before the effective filing date of the claimed invention.
(a)(2) the claimed invention was described in a patent issued under section 151, or in an application for patent published or deemed published under section 122(b), in which the patent or application, as the case may be, names another inventor and was effectively filed before the effective filing date of the claimed invention.
Claim(s) 1-3, 14, 16, 30, and 39-40 are rejected under 35 U.S.C. 102(a)(1) and (a)(2) as being anticipated by WO 03/088907 A2 (herein after referred to as "Rosazza")
With regard to claim 1, Rosazza teaches new triterpenoid saponins exemplified by the structure of formula (I), shown below, wherein R1 is a disaccharide comprising sugars which are independently selected from the group consisting of arabinose, glucose and rhamnose; and wherein R2 is a trisaccharide comprising sugars which are independently selected from the group consisting of glucuronic acid, galactose and glucose (Page 9).
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Rosazza further teaches that the compounds of the invention may be linked to one or more molecules which target the compounds to tumor cells, wherein targeting is beneficial in that it can be used to increase the overall levels of a drug at the site of treatment, for example, at tumor sites, while minimizing systemic exposure to the drug (Page 25). The targeting agent may be
directed to components of tumor cells; components of tumor vasculature; components that bind
to, or are generally associated with, tumor cells; components that bind to, or are generally
associated with, tumor vasculature; components of the tumor extracellular matrix or stroma or
those bound therein; and even cell types found within the tumor vasculature (Id.). Malignant cells that make up a tumor may be targeted using a bispecific antibody that has a region capable of binding to a relatively specific marker or antigen of the tumor cell; exemplary anti-tumor antibodies are provided, and it is specifically noted that antibodies for use in these aspects of the invention will preferably recognize antigens that are accessible on the cell-surface and that are preferentially, or specifically, expressed by tumor cells (Pages 26-28). The compounds may be linked to secondary molecules (e.g., antibodies) in any operative manner that allows each region to perform its intended function without significant impairment of biological activity; compounds of the present invention may be directly linked to a second compound or may be linked via a linking group wherein "linker group" is intended one or more bifunctional molecules which can be used to covalently couple the compounds to the agent and do not interfere with biological activity (Page 35). Exemplary approaches for linking compounds of the invention to a secondary molecule are disclosed on Pages 35-39, see also Table 1. As such, Rosazza teaches a proteinaceous molecule comprising a first binding site to a first epitope of a first cell-surface molecule (i.e., anti-tumor antigen antibody specific to tumor antigens specifically presented on the tumor cell surface) wherein at least one saponin is covalently bound (e.g., via a linker) to an amino acid residue of the proteinaceous molecule. As such, Rosazza anticipates instant claims 1-3.
With regard to claims 14 and 16, Rosazza teaches that compounds described herein may be linked to one or more molecules which target the compounds to tumor cells; in common with the chemotherapeutic agents discussed above, it is possible that the use of a targeted compound may be used in combination with a second agent, such as a chemotherapeutic agent, wherein both the first and the second agent be directed to the same or different targets within the tumor environment which could result in additive, greater than additive, or even markedly synergistic results (Page 25; emphasis added). Exemplary targeting agents employed in combination with the compounds of the invention will be those targeting agents that are capable of delivering the active molecules to the tumor region, i.e., capable of localizing within a tumor site; the targeting of the compounds is specifically contemplated to allow for greater effective concentrations in tumor regions without or with the minimization of potential side effects which could be observed with a somewhat wider or systemic distribution of the compounds wherein, specifically, the targeting agent may be directed to components of tumor cells; components of tumor vasculature; components that bind to, or are generally associated with, tumor cells; components that bind to, or are generally associated with, tumor vasculature; components of the tumor extracellular matrix or stroma or those bound therein; and even cell types found within the tumor vasculature (Id.; emphasis added). For certain applications, it is envisioned that the second therapeutic agents used in combination with the compounds described herein will be pharmacologic agents conjugated to antibodies or growth factors, particularly cytotoxic or otherwise anti-cellular agents having the ability to kill or suppress the growth or cell division of endothelial cells (i.e., effector moieties); in general, the invention contemplates the use of any pharmacologic agent, including and in supplement to the compounds described herein, that can be conjugated to a targeting agent, preferably an antibody, and delivered in active form to the targeted tumor cells wherein exemplary anti-cellular agents include chemotherapeutic agents, radioisotopes and cytotoxins (Page 34; emphasis added). Rosazza further teaches suitable pharmaceutical compositions in accordance with the invention, which generally include an amount of the active compound admixed with an acceptable pharmaceutical diluent or excipient, such as a sterile aqueous solution, to give a range of final concentrations, depending on the intended use (Page 43). The invention also provides therapeutic kits comprising the compounds of the invention, wherein the kits will generally contain, in suitable container means, a pharmaceutically acceptable formulation of at least one compound of the invention; the kits also may contain other pharmaceutically acceptable formulations, such as those containing components to target the compounds to distinct regions of a patient where treatment is needed, or any one or more of a range of drugs which may work in concert with the compounds, for example, chemotherapeutic agents, wherein the kits may have a single container means that contains the compounds, with or without any additional components, or they may have distinct container means for each desired agent (Page 44). Thus, Rosazza further teaches therapeutic combinations comprising using a second agent in combination with a compound of the invention (i.e., a first proteinaceous molecule). Said second agent may be an antibody conjugated to a pharmacologic agent (i.e., an effector moiety) wherein said antibody of the second agent may target a different tumor molecule (i.e., second proteinaceous molecule) or it may target the same tumor molecule (i.e., third proteinaceous molecule). It is further noted that Rosazza teaches that each agent may be a separate pharmaceutical composition comprising the active agent (i.e., first, second, or third proteinaceous molecule) and a pharmaceutical diluent or excipient. As such, Rosazza anticipates instant claims 14 and 16.
With regard to claim 30, it is further noted that Rosazza discloses exemplary chemotherapeutic agents (i.e., cytotoxic pharmacological agents/effector moieties) useful in combination therapies; some of the exemplary agents are proteins such as enzymes (e.g., L-asparaginase) and biological response modifiers (e.g., interferon alpha) (Pages 19-24; Table 2). As such, Rosazza anticipates instant claim 30.
With regard to claims 39-40, it is further noted that Rosazza teaches therapeutic kits comprising the compounds of the invention, wherein the kits will generally contain, in suitable container means, a pharmaceutically acceptable formulation of at least one compound of the invention; the kits also may contain other pharmaceutically acceptable formulations, such as those containing components to target the compounds to distinct regions of a patient where treatment is needed, or any one or more of a range of drugs which may work in concert with the compounds, for example, chemotherapeutic agents, wherein the kits may have a single container means that contains the compounds, with or without any additional components, or they may have distinct container means for each desired agent (Page 44). Thus, Rosazza teaches that agents of the invention (i.e., first, second, and/or third proteinaceous molecules) may be formulated together in pharmaceutically acceptable formulations. As such, Rosazza anticipates instant claims 39-40.
Claim(s) 1-3, 14, 19, 29-30, 32, and 39 are rejected under 35 U.S.C. 102(a)(1) and (a)(2) as being anticipated by US 2018/0169255 A1 (herein after referred to as "Gao").
With regard to claims 1-3, Gao teaches conjugate compounds comprising antibodies and fragments thereof engineered with one or more reactive cysteine residues and more specifically to conjugate compounds with therapeutic or diagnostic applications; the conjugate compounds comprise cysteine-engineered antibodies or fragments thereof conjugated, for example, with chemotherapeutic drugs, toxins, and detection labels such as radionuclides or fluorophores (Abstract). A cysteine-engineered antibody or Fc fusion protein of the invention can comprise a Fab, a Fab', a F(ab')2 , a Fd, a single chain Fv or scFv, a disulfide linked Fv, a V-NAR domain, an IgNar, an intrabody, an IgGΔCH2, a minibody, a F(ab')3 , a tetrabody, a triabody, a diabody, a single-domain antibody, DVD-lg, Fcab, mAb2, a (scFv)2, or a scFv-Fc (Paragraph 0178). The cysteine-engineered antibodies or Fc fusion proteins disclosed can be conjugated with any heterologous moiety which can be covalently attached to the cysteine-engineered antibody or Fc fusion protein through a reactive cysteine thiol group wherein a conjugated compound of the invention may be represented by the formula CEP-(L-H)p, wherein CEP is the Cysteine Engineered Protein (i.e., antibody or Fc fusion protein), L is a linker, H is a heterologous moiety, and p is 1, 2, 3, or 4 (Paragraph 0185). The conjugate compounds disclosed comprise at least one heterologous moiety conjugated at one of the engineered cysteines wherein such heterologous moiety is a toxin, and an exemplary toxin includes a saponin (Paragraph 0194). Gao further teaches that the cysteine engineered antibodies of the invention can be capable of binding, preferably specifically, to antigens; such antigens include, for example, tumor-associated antigens (TAA), cell surface receptor proteins and other cell surface molecules (Paragraph 0220). Exemplary molecules that may be specifically bound by and/or incorporated into a conjugate compound comprising a cysteine-engineered antibody or Fc fusion protein and a heterologous moiety are listen on Pages 21-22; some of these molecules include, for example, CD27 ligand (i.e., CD70), CD3, CD19, CD20, CD22, EGFR, EPHA4, MUC1, HER2, HER3, etc., all of which are known tumor-cell surface molecules/receptors. As such, Gao teaches a conjugate (i.e., first proteinaceous molecule) which can comprise (i) a cysteine engineered antibody (i.e., a binding site specific for a first epitope) wherein said antibody may bind a tumor-cell surface molecule/receptor, (ii) a linker, and (iii) a heterologous moiety wherein the linker links the heterologous moiety to the engineered cysteine(s) of the antibody. Additionally, such a conjugate may be represented by the formula CEP-(L-H)p, wherein CEP is the Cysteine Engineered Protein (i.e., antibody or Fc fusion protein), L is a linker, H is a heterologous moiety, and p is 1, 2, 3, or 4 and as such the conjugates may comprise more than one heterologous moiety (e.g., saponin) linked to the engineered cysteines of the antibody. Therefore, Gao anticipates instant claims 1-3 and 32.
With regard to claims 14 and 39, Gao further teaches formulations comprising at least one conjugate compound of the invention formulated together with a diluent, carrier, or excipient and pharmaceutical compositions comprising at least one conjugate compound of the invention formulated together with a pharmaceutically acceptable diluent, carrier, or excipient; such formulations or pharmaceutical compositions can include one or a combination of, for example, but not limited to, two or more different conjugate compounds wherein, for example, a formulation or pharmaceutical composition can comprise a combination of conjugate compounds that bind to different targets, e.g., different epitopes, or that have complementary activities (Paragraph 0266; emphasis added). It is further noted that, as detailed above, Gao teaches various heterologous moieties (i.e., effector moieties) that may be used instead of a saponin (see Pages 15-19). Also provided are a kits which comprise at least one purified conjugate compound in one or more containers; i.e., Gao teaches kits which can comprise more than one conjugate comprised in separate containers (i.e., separate formulations/compositions) As such, Gao teaches therapeutic combinations comprising two different conjugate compounds wherein the conjugate compounds bind to different targets (i.e., the combination comprises a first and second proteinaceous molecule) wherein said conjugates may be comprised within the same composition or may be separate compositions. As such, Gao anticipates instant claims 14 and 39.
With regard to claim 19, Gao teaches that a cysteine-engineered antibody or Fc fusion protein of the invention can comprise a Fab, a Fab', a F(ab')2 , a Fd, a single chain Fv or scFv, a disulfide linked Fv, a V-NAR domain, an IgNar, an intrabody, an IgGΔCH2, a minibody, a F(ab')3 , a tetrabody, a triabody, a diabody, a single-domain antibody (i.e., a VHH), DVD-lg, Fcab, mAb2, a (scFv)2 , or a scFv-Fc (Paragraph 0178; emphasis added). As such, Gao anticipates instant claim 19.
With regard to claims 29-30, it is noted that Gao teaches various heterologous moieties (i.e., effector moieties) that may be used instead of a saponin (see Pages 15-19). Gao teaches that a heterologous moiety may be a protein such as, for example, RNase, DNase I, pokeweed antiviral protein, diphteria toxin, shiga toxin, cholera toxin, Staphylococcal enterotoxin-A, etc. (Paragraph 0195). Gao also teaches that a heterologous moiety may be a nucleic acid selected from DNA, RNA, short interfering RNA (siRNA), microRNA, hairpin or nucleic acid mimetics such as peptide nucleic acids wherein, in certain aspects, the conjugated nucleic acid is at least 10, at least 20, at least 30, at least 40, at least 50 , at least 60 at least 100, at least 200, at least 500, at least 1000, at least 5000, or more base pairs (i.e., may include oligonucleotides) (Paragraph 0212). Thus, Gao teaches conjugates which may comprise effector moieties that are proteins or oligonucleotides. As such, Gao anticipates instant claims 29-30.
Claim Rejections - 35 USC § 103
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.
The factual inquiries for establishing a background for determining obviousness under 35 U.S.C. 103 are summarized as follows:
1. Determining the scope and contents of the prior art.
2. Ascertaining the differences between the prior art and the claims at issue.
3. Resolving the level of ordinary skill in the pertinent art.
4. Considering objective evidence present in the application indicating obviousness or nonobviousness.
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) 4 and 7-8 are rejected under 35 U.S.C. 103 as being unpatentable over WO 03/088907 A2 (herein after referred to as "Rosazza") in view of non-patent literature by Gilabert-Oriol et. al. (Biochemical Pharmacology, 2015, 97, 247-255; herein after referred to as “Oriol”) and non-patent literature by Weng et. al. (Journal of Controlled Release, 2015, 206, 75-90; herein after referred to as “Weng”).
Rosazza teaches new triterpenoid saponins exemplified by the structure of formula (I), shown below, wherein R1 is a disaccharide comprising sugars which are independently selected from the group consisting of arabinose, glucose and rhamnose; and wherein R2 is a trisaccharide comprising sugars which are independently selected from the group consisting of glucuronic acid, galactose and glucose (Page 9).
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Rosazza further teaches that the compounds of the invention may be linked to one or more molecules which target the compounds to tumor cells, wherein targeting is beneficial in that it can be used to increase the overall levels of a drug at the site of treatment, for example, at tumor sites, while minimizing systemic exposure to the drug (Page 25). The targeting agent may be
directed to components of tumor cells; components of tumor vasculature; components that bind
to, or are generally associated with, tumor cells; components that bind to, or are generally
associated with, tumor vasculature; components of the tumor extracellular matrix or stroma or those bound therein; and even cell types found within the tumor vasculature (Id.). Malignant cells that make up a tumor may be targeted using a bispecific antibody that has a region capable of binding to a relatively specific marker or antigen of the tumor cell; exemplary anti-tumor antibodies are provided, and it is specifically noted that antibodies for use in these aspects of the invention will preferably recognize antigens that are accessible on the cell-surface and that are preferentially, or specifically, expressed by tumor cells (Pages 26-28). The compounds may be linked to secondary molecules (e.g., antibodies) in any operative manner that allows each region to perform its intended function without significant impairment of biological activity; compounds of the present invention may be directly linked to a second compound or may be linked via a linking group wherein "linker group" is intended one or more bifunctional molecules which can be used to covalently couple the compounds to the agent and do not interfere with biological activity (Page 35). Exemplary approaches for linking compounds of the invention to a secondary molecule are disclosed on Pages 35-39, see also Table 1. As such, Rosazza teaches a proteinaceous molecule comprising a first binding site to a first epitope of a first cell-surface molecule (i.e., anti-tumor antigen antibody specific to tumor antigens specifically presented on the tumor cell surface) wherein at least one saponin is covalently bound (e.g., via a linker) to an amino acid residue of the proteinaceous molecule. Thus, Rosazza discloses a proteinaceous molecule of instant claim 1. However, with regard to claims 4 and 7-8, it is noted that Rosazza does not explicitly teach that the saponin of the proteinaceous molecule is a bisdesmosidic triterpene saponin isolated from a Saponaria species and belonging to the type of a 12,13-dehydrooleanane with an aldehyde function in position C-23 and a glucuronic acid function in a carbohydrate substituent at the C-3beta-OH group, wherein said saponin is SO1861. These deficiencies are remedied by the combination of Oriol and Weng.
Oriol teaches a study wherein the therapeutic antibodies Cetuximab (anti-EGFR, Erbitux1), Panitumumab (anti-EGFR, Vectibix1) and Trastuzumab (anti-HER2, Herceptin1) were chemically conjugated to the toxin dianthin (i.e., DC, PC, and TC, respectively), and dianthin showed increased cytotoxicity on MCF-7 cells when tested in combination with a glycosylated triterpenoid (SO1861) in a real-time impedance-based cytotoxicity assay; in data obtained by live cell imaging, SO1861 specifically mediated the endo/lysosomal escape of dianthin without disrupting the plasma membrane (Abstract). A cytotoxicity assay performed with DC, DP and DT showed that the three immunotoxins did not cause any cytotoxic effects at concentrations below 10 nM (Fig. 7) and as such it was not possible to calculate the concentration of immunotoxins at which the cell growth was inhibited by 50% (GI50); however, the immunotoxins in combination with SO1861 presented strong cytotoxicity in the three cases down to the range of 1–10 pM (Page 252, Column 2). When DC + SO1861 was applied to cells (Fig. 7a), the GI50 of the immunotoxin on HCT-116 cells (over-expressing EGFR) was decreased to 5.3 pM; in the case of DP (Fig. 7b), the GI50 of the immunotoxin on HCT-116 cells was reduced to 1.5 pM; and in the case of DT (Fig. 7c), the GI50 of the immunotoxin on BT-474 cells (over-expressing HER2) was reduced to 23 pM (Pages 252-253). The modification of therapeutic monoclonal antibodies by chemical conjugation of dianthin and co-application of SO1861 is a novel strategy to enhance the efficacy of therapeutic antibodies wherein immunotoxins constructed with Cetuximab, Panitumumab and Trastuzumab achieved enhanced cytotoxicity in the presence of SO1861 with the corresponding GI50 values of 5.3,1.5 and 23 pM, respectively (Page 255, Column 1, Paragraph 2). However, while Oriol discloses the use of SO1861, it does not explicitly disclose any structural features of the saponin. This is remedied by Weng.
Weng teaches that a natural, plant derived glycoside (SO1861) from Saponaria officinalis L. greatly improves the efficacy of lipid based as well as non-lipid based targeted nanoplexes consisting of a targeted K16 peptide with a nucleic acid binding domain and plasmid-DNA, minicircle-DNA or small interfering RNA (siRNA), wherein SO1861 augments the escape of the genetic cargo out of the intracellular compartments into the cytosol (Abstract). Weng discloses the isolation of SO1861 (see Pages 76-77), and provides the core structure of SO1861, provided in Figure 1 (reproduced below).
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Thus, Weng demonstrates that SO1861 is naturally produced and can be isolated from Saponaria officinalis L., and that SO1861 has an aldehyde function at C-23 (the -CHO group) and a glucuronic acid function at the C-3beta-OH group (the negatively charged group).
Rosazza, Oriol, and Weng are considered to be analogous to the present invention as they are all in the field of saponins and their applications. Thus, it would have been obvious to one of ordinary skill in the art to modify the proteinaceous molecules taught by Rosazza such that the specific saponin used is SO1861, as taught by Oriol and Weng, which can be isolated from a Saponaria species and belongs to the type of a 12,13-dehydrooleanane with an aldehyde function in position C-23 and a glucuronic acid function in a carbohydrate substituent at the C-3beta-OH group because the simple substitution of one known element (i.e., saponin) for another would be expected to obtain predictable results with a reasonable expectation of success. One of ordinary skill in the art would have been motivated to utilize SO1861 as the saponin of the proteinaceous molecule of Rosazza because SO1861 augments the escape of the genetic cargo out of the intracellular compartments into the cytosol, as taught by Weng, and provides a novel strategy to enhance the efficacy of therapeutic antibodies and/or immunotoxins, as taught by Oriol, and thus would have been desirable to enhance the efficacy of the targeted proteinaceous molecules of Rosazza.
Claim(s) 11, 13, and 26-27 is/are rejected under 35 U.S.C. 103 as being unpatentable over WO 03/088907 A2 (herein after referred to as "Rosazza"), Gilabert-Oriol et. al. (Biochemical Pharmacology, 2015, 97, 247-255; herein after referred to as “Oriol”), and non-patent literature by Weng et. al. (Journal of Controlled Release, 2015, 206, 75-90; herein after referred to as “Weng”), as applied to claims 4 and 7-8 above, and in further view of non-patent literature by Greene et. al. (Oncotarget, 2017, 8(63), 107052-107075; herein after referred to as “Greene”) and non-patent literature by Sutherland et. al. (Proc. Natl. Acad. Sci. USA, 1981, 78(7), 4515-4519; herein after referred to as “Sutherland”).
Rosazza further teaches that compounds described herein may be linked to one or more molecules which target the compounds to tumor cells; in common with the chemotherapeutic agents discussed above, it is possible that the use of a targeted compound may be used in combination with a second agent, such as a chemotherapeutic agent, wherein both the first and the second agent be directed to the same or different targets within the tumor environment which could result in additive, greater than additive, or even markedly synergistic results (Page 25; emphasis added). Exemplary targeting agents employed in combination with the compounds of the invention will be those targeting agents that are capable of delivering the active molecules to the tumor region, i.e., capable of localizing within a tumor site; the targeting of the compounds is specifically contemplated to allow for greater effective concentrations in tumor regions without or with the minimization of potential side effects which could be observed with a somewhat wider or systemic distribution of the compounds wherein, specifically, the targeting agent may be directed to components of tumor cells; components of tumor vasculature; components that bind to, or are generally associated with, tumor cells; components that bind to, or are generally associated with, tumor vasculature; components of the tumor extracellular matrix or stroma or those bound therein; and even cell types found within the tumor vasculature (Id.; emphasis added). For certain applications, it is envisioned that the second therapeutic agents used in combination with the compounds described herein will be pharmacologic agents conjugated to antibodies or growth factors, particularly cytotoxic or otherwise anti-cellular agents having the ability to kill or suppress the growth or cell division of endothelial cells (i.e., effector moieties); in general, the invention contemplates the use of any pharmacologic agent, including and in supplement to the compounds described herein, that can be conjugated to a targeting agent, preferably an antibody, and delivered in active form to the targeted tumor cells wherein exemplary anti-cellular agents include chemotherapeutic agents, radioisotopes and cytotoxins (Page 34; emphasis added). Rosazza further teaches suitable pharmaceutical compositions in accordance with the invention, which generally include an amount of the active compound admixed with an acceptable pharmaceutical diluent or excipient, such as a sterile aqueous solution, to give a range of final concentrations, depending on the intended use (Page 43). The invention also provides therapeutic kits comprising the compounds of the invention, wherein the kits will generally contain, in suitable container means, a pharmaceutically acceptable formulation of at least one compound of the invention; the kits also may contain other pharmaceutically acceptable formulations, such as those containing components to target the compounds to distinct regions of a patient where treatment is needed, or any one or more of a range of drugs which may work in concert with the compounds, for example, chemotherapeutic agents, wherein the kits may have a single container means that contains the compounds, with or without any additional components, or they may have distinct container means for each desired agent (Page 44). Thus, Rosazza further teaches therapeutic combinations comprising using a second agent in combination with a compound of the invention (i.e., a first proteinaceous molecule). Said second agent may be an antibody conjugated to a pharmacologic agent (i.e., an effector moiety) wherein said antibody of the second agent may target a different tumor molecule (i.e., second proteinaceous molecule) or it may target the same tumor molecule (i.e., third proteinaceous molecule). It is further noted that Rosazza teaches that each agent may be a separate pharmaceutical composition comprising the active agent (i.e., first, second, or third proteinaceous molecule) and a pharmaceutical diluent or excipient. Thus, Rosazza also discloses a therapeutic combination of instant claim 16. It is also specifically noted that Rosazza teaches applications of proteinaceous molecules of the invention, including the treatment of hyperproliferative disorders comprising administering pharmaceutical compositions of the invention (which comprise saponin compounds/conjugates) wherein the hyperproliferative disorder is cancer, such as renal cancer (see Page 7). Additionally, compounds of the invention may be linked to one or more molecules which target the compounds to tumor cells, wherein targeting is beneficial in that it can be used to increase the overall levels of a drug at the site of treatment, for example, at tumor sites, while minimizing systemic exposure to the drug (Page 25). However, with regard to claims 11, 13, and 26-27, it is noted that Rosazza, Oriol, and Weng do not explicitly teach that the first epitope of the first cell-surface molecule to which the first binding site of the first and/or second proteinaceous molecule binds is a tumor-cell specific first epitope of a tumor-cell specific receptor, wherein the tumor-cell specific receptor is CD71 and the binding site comprises OKT-9 anti-CD71 antibody of the IgG type. These deficiencies are remedied by the combination of Greene and Sutherland.
Greene teaches the expression and prognostic significance of the primary iron uptake protein, transferrin receptor 1 (TfR1/CD71/TFRC), in renal cell carcinoma (RCC patients) wherein TfR1 levels in RCC tumors, particularly clear cell RCC, were significantly associated with adverse clinical prognostic features (anemia, lower body mass index, smoking), worse tumor pathology (size, stage, grade, multifocality, sarcomatoid dedifferentiation) and worse survival outcomes, including after adjustments for tumor pathology (Abstract). Results of this study support an important role for TfR1 in RCC progression and identify TfR1 as a novel RCC biomarker and therapeutic target (Id.). Thus, Greene demonstrates that CD71 is associated with RCC and is a potential therapeutic target.
Sutherland teaches that a murine monoclonal antibody (OKT9) raised against human leukemic cells binds to a wide variety of leukemia and tumor cell lines; radio-labeled transferrin bound to its receptors can be specifically precipitated by the monoclonal OKT9, although the latter does not bind transferrin itself, indicating that the antigenic structure defined by this antibody is likely to be the transferrin receptor (Abstract). The monoclonal OKT9 antibody utilized in the study is an IgG1 antibody (Page 4515, Antisera and Cell Labeling). The OKT9 antibody antigen is neither tumor-specific nor "onco-fetal" because several normal cell types, including bone marrow normoblasts and myelocytes, express the determinant; preliminary studies also indicate that the antigen is present on hemopoietic progenitor cells (BFU-E, CFUE) and muscle myoblasts (unpublished observations) and the antigen is not demonstrable on normal (pediatric or adult) thymocytes, blood lymphocytes, or erythrocytes but can be induced on lymphoid cells by mitogenic ligands (Page 4518, Discussion). Flow cytofluorimetry and sorting indicates that in leukemic cells, fetal tissue, and normal bone marrow, antigen expression is strongly correlated with proliferation though not with a specific cycle phase (Id.). Definitive evidence that OKT9 recognizes the transferrin receptor came from experiments in which OKT9 was shown to specifically precipitate iodinated transferrin bound to its cell-surface receptor (but not to bind to transferrin itself, Fig. 5); the presence