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 .
DETAILED ACTION
Claims 1-12 are pending in the instant application.
Priority
Should applicant desire to obtain the benefit of foreign priority under 35 U.S.C. 119(a)-(d) prior to declaration of an interference, a certified English translation of the foreign application must be submitted in reply to this action. 37 CFR 41.154(b) and
41.202(e).
Failure to provide a certified translation may result in no benefit being accorded
for the non-English application. The effective priority date is the filing date of
PCT/EP2021/083126 filed on 11/26/2021 in the absence of a certified translation of
IT102020000028754 filed on 11/27/2020.
.
Objections to the Abstract
The abstract of the disclosure is objected to because of grammatical errors. 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 abstract uses “are” then the singular form of antibody. “Disclosed are an antibody…; the uses of said antibody…; and pharmaceutical compositions containing the antibody”. For multiple antibodies “are an antibody” should be exchanged with ---are antibodies--- and the other singular form of “antibody” should be exchanged with ---antibodies--- throughout.
Objections to the Drawings
The drawings are objected to because in Fig. 16 the x-axis of the graphs “cultore” is misspelled and should be exchanged with ---culture---. 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.
Objections to the Claims
Claim 3 is objected to because of the following informalities: “Complementary” is misspelled in line 3 and should be ---Complementarity---. Appropriate correction is required.
Claim Rejections – 35 USC § 112(a)
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 1-12 are rejected under 35 U.S.C. 112(a) or 35 U.S.C. 112 (pre-AIA ), first paragraph, as failing to comply with the written description requirement. The claim(s) contains subject matter which was not described in the specification in such a way as to reasonably convey to one skilled in the relevant art that the inventor or a joint inventor, or for applications subject to pre-AIA 35 U.S.C. 112, the inventor(s), at the time the application was filed, had possession of the claimed invention.
Regarding instant claim 1, an antibody is claimed to bind CLIC1 based on functional properties without a sequence. Antibody binding to the same antigen, or even the same epitope on that antigen, can be accomplished with an impressively wide variety of antibody structures and no structure activity relationship is identified in the instant disclosure that permits prediction of the antibody sequence based on the claimed functional language. Claims 2 and 5-12 are dependent on claim 1 without narrowing the claims outside of the antibody that is functionally claimed without defined VH and VL CDR sequences.
Regarding instant claim 2, an antibody is claimed based on the epitope to which it binds without a sequence. Antibody binding to the same antigen, or even the same epitope on that antigen, can be accomplished with an impressively wide variety of antibody structures and no structure activity relationship is identified in the instant disclosure that permits prediction of the antibody sequence based on the claimed epitope.
Regarding instant claims 3-4, the claimed antibodies allow variation of the antibody CDR amino acids, but the disclosure does not test variation of the VH and VL CDRs that possess the recited function of binding CLIC1. Variation of the CDR results in unpredictable binding and antibody secretion and the instant disclosure does not test any substitutions of the antibody CDRs or teach a structure activity relationship that permits prediction of the effects of CDR variation.
Regarding instant claims 3-4, the specification does not provide details of possession of an antibody comprising a VH and VL, wherein the VH comprises a VH CDR1-3 of SEQ ID NO:7-9 and the VL comprises a VL CDR1-3 of SEQ ID NO:10-12 or an antibody comprising a VH comprising SEQ ID NO: 15 and ta VL comprising SEQ ID NO:16 other than the sequence and that “Similar results were obtained with the antibody” (specification page 11, lines 8-11).
Regarding instant claim 7 or 9-10, the specification does not have support for an antibody fragment that consists of a single domain antibody that possesses the recited function of binding CLIC1.
Regarding instant claims 10-12, a method of diagnosing inflammation, neurodegenerative diseases or solid tumors is claimed, but the method does not require steps that would enable diagnosis of inflammation, neurodegenerative diseases or solid tumors. Administration of the claimed antibody is not enough to diagnose a disease.
Scope of the claimed genus
Regarding instant claim 1, an antibody is claimed by its functional properties without a sequence, wherein the antibody is claimed to bind CLIC1 and is able to inhibit the chloride ion current mediated by CLIC 1 by at least 90% compared with the inhibition caused by the IAA94 CLIC 1 channel blocker at a concentration of 100 μM, wherein said chloride current is measured by the patch clamp technique in whole-cell configuration on a single glioblastoma cell or in a colorectal cancer cell line. Claims 2 and 5-12 are dependent on claim 1 without narrowing the claims outside of the antibody that is functionally claimed without defined VH and VL CDR sequences.
Regarding instant claim 2, an antibody is claimed based on the epitope to which it binds without a sequence, wherein the antibody is required to recognize a CLIC1 epitope containing the amino acid sequence QVELF.
Regarding instant claims 3-4, an antibody is claimed comprising a VH and VL, wherein the VH comprises a claimed VH sequence or VH CDR1-3 or sequences at least 90% identical and wherein the VL comprises a claimed VL sequence or sequences of VL CDR1-3 or sequences at least 90% identical thereto. The disclosure does not test variation of the claimed VH and VL CDR sequences that possess the recited function of binding CLIC1.
Regarding instant claims 3-4, an antibody is claimed comprising a VH and VL, wherein the VH comprises a VH CDR1-3 of SEQ ID NO:7-9 and the VL comprises a VL CDR1-3 of SEQ ID NO:10-12 or an antibody comprising a VH comprising SEQ ID NO: 15 and a VL comprising SEQ ID NO:16 ;
Regarding instant claims 7 or 9-10, an antibody or fragment thereof is claimed, wherein the antibody fragment is selected from Fab, Fab’, Fab-SH, Fv, scFv, F(ab')2, diabodies or a single domain antibody.
Regarding instant claims 10-12, a method of diagnosing or treating inflammation, neurodegenerative diseases or solid tumors is claimed, wherein the claimed antibody, fragment or composition thereof is administered to the patient.
Summary of Species disclosed in the original specification
MPEP § 2163 states that a “representative number of species” means that the species which are adequately described are representative of the entire genus. Thus, when there is substantial variation within the genus, one must describe a sufficient variety of species to reflect the variation within the genus.
1)-4) The specification identifies two anti-CLIC1 antibodies, wherein one antibody comprised a VH of comprising SEQ ID NO:1-3 and a VL of SEQ ID NO:4-6 and a second antibody comprising a VH of comprising SEQ ID NO:7-9 and a VL of SEQ ID NO:10-12 wherein the CDR sequences are aligned below with Clustal Omega. (https://www.ebi.ac.uk/jdispatcher/msa/clustalo).
Alignment of the CDR regions of the CLIC1 antibodies show each CDR has an unidentical sequence which include amino acid substitutions and gaps. Multiple changes within the CDR region would cause unpredictable binding effects on the claimed antibody target CLIC1 and antibody secretion.
CDRH1 CDRH2 CDRH3 CDRL1 CDRL2 CDRL3
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The specification does not teach a structure activity relationship that would allow CDR residues to be determined that: 1) have the functional property of inhibiting the chloride ion current mediated by CLIC1 by at least 90% compared with the inhibition caused by the IAA94 CLIC 1 channel blocker at a concentration of 100 μM, wherein said chloride current is measured by the patch clamp technique in whole-cell configuration on a single glioblastoma cell line, 2) exhibits specificity with the QVELF epitope; and 3) can be substituted and still maintain binding and antibody secretion or what amino acids that the amino acids within the CDR region can be substituted for.
Further, 4) the specification does not provide details of possession of a class IgG2b antibody containing the heavy chain variable region identified as SEQ ID NO: 15 and the light chain variable region identified as SEQ ID NO:16 other than the sequence provided and that “Similar results were obtained with the antibody (specification page 11, lines 8-11).
Regarding 5), the specification does not test any single domain antibodies.
Regarding 6), the specification does not test diagnosis of inflammation, neurodegenerative diseases or solid tumors with only the required step of administering an antibody, antibody fragment or composition thereof.
As noted below, the art generally accepted that the combination of the CDRs within the VH and VL pair of an antibody were essential for binding specificity. The specification does not describe what residues within the CDRs confer the binding activity claimed and the claim language permits a single domain antibody. Accordingly, the skilled artisan would not be able to discern a structure/function correlation for multivalent peptides other than those comprising all six CDRs.
Given the lack of shared structural properties of the CDR regions, the description of two species of separate CLIC1 antibodies with little overlap, wherein 50% or less of the CDRs overlap, and the fact that the species that were described cannot be considered representative of the broad genus, Applicant was not in possession of the invention as claimed.
State of the Relevant Art
CLIC1 antibodies are known to the prior art, wherein Averaimo taught inhibition of CLIC1 ionic current through the pharmacological blocker IAA94 or a specific anti-CLIC1 antibody directed against its extracellular domain prevents CLIC1-dependent activity of neurite outgrowth induced by cAMP (Averaimo S. et al. (Journal of Neurochemistry, 2014 131(4), 444-456 IDS reference, abstract). No structure activity relationship has been determined that allows an effective CLIC1 antibody comprising a specific CDR sequence to be predicted based on recitation of: 1) functional property limitations for binding the CLIC1 antigen; or 2) a specific epitope of CLIC1.
Antibody binding to the same antigen, or even the same epitope on that antigen, can be accomplished with an impressively wide variety of antibody structures, even when the antibodies are limited to those from a particular source (Gershoni et al., Epitope Mapping, Biodrugs 2007; 21 (3): 145-156pg 146 section 1.1). The skilled artisan therefore understood that antibodies from a variety of different sources may bind the same antigen and even mediate the same functional effects, but differ widely in the details of the structure of their antigen-binding sites, particularly in the amino acid sequence and length of VH-CDR3. Further, it is not possible to predict the amino acid sequence when an epitope is recited, because binding is dictated by the unique interaction between an antibody and its cognate epitope (Blythe et al., Benchmarking B cell epitope prediction: Underperformance of existing methods, Protein Science (2005), 14:246–248 pg. 246). 3D structural analyses of antibody-epitope binding highlighting that the deficiency in the ability to predict the structural features of an antibody when the epitope is disclosed (Schreiber et al., 3D-Epitope-Explorer (3DEX): Localization of Conformational Epitopes within Three-Dimensional Structures of Proteins, Wiley Interscience, 42–44, 60596, pg. 879).
It is well established in the art that the formation of an intact antigen-binding site in an antibody usually requires the association of the complete heavy and light chain variable regions of a given antibody, each of which comprises three CDRs (or hypervariable regions) which provide the majority of the contact residues for the binding of the antibody to its target epitope. E.g., Almagro et. al., Front. Immunol. 2018; 8:1751 (see Section “The IgG Molecule” in paragraph 1 and Figure 1). While affinity maturation techniques can result in differences in the CDRs of the antibody compared to its parental antibody (page 3 “The IgG Molecule, second and third paragraphs), those techniques involve trial-and-error testing and the changes that maintain or improve affinity are not predictable a priori. E.g., id., (page 6 ending paragraph onto page 7).
Chiu ML et al. (Antibodies 2019 8, 55, 1-80) taught the antigen binding of antibodies often results in conformational changes in the contact surface areas of both the antibody and the antigen (page 5, first paragraph). Thus, the prediction of CDR sequence binding to the epitope is difficult to predict. Chiu further taught antibody modeling has been shown to be accurate for the framework region sequences, but CDR modeling requires further development and improvements (page 6, second paragraph). Prediction of the structure of HCDR3 could not be accurately produced when given the Fv structures without their CDR-H3s (page 6, second paragraph). Chiu taught the quality of antibody structure prediction, particularly regarding CDR-H3, remains inadequate, and the results of antibody–antigen docking are also disappointing (page 11, paragraph 2).
In addition to changes within the CDR altering target binding, alterations to the CDR have been shown to dramatically alter antibody secretion. Hasegawa H et al. (mAbs 2017, 9(5) 854-873) taught a pair of human IgG clones with a single amino acid substitution in the variable region was sufficient to alter the efficiency of immunoglobulin biosynthesis (page 866, last sentence left column). Hasegawa taught the 2 mAbs differed only by one amino acid in the LC's CDR1 and that despite the near-identity of their primary sequences, the parental mAb secreted copious amounts of IgG to the culture media, while the variant mAb induced RB phenotypes extensively and secreted 20-fold less IgG (page 866, right column, first paragraph). Importantly, the 2 model IgGs were by no means abnormal or defective as mAbs, but demonstrated a profound impact of a single amino acid substitution on immunoglobulin biosynthesis (page 866, right column, first paragraph).
5) A structure activity relationship for single domain antibodies of CLIC1 have not been described in the art, wherein the sequence of a single domain antibody of CLIC1 can be predicted. Wagner HJ et al. (Int J Mol Sci. 2018 19(11): 3444) taught In the context of nanobodies, universal scaffolds have been identified, enabling the generation of robust or humanized VHH variants but, this strategy has only been applied to graft CDRs to acceptor frames obtained from animals of the same taxonomic family (page 2, last paragraph). Wagner taught the design of nanobody grafts with CDRs derived from conventional antibodies requires careful consideration, because both the heavy and light chain variable domain (VH and VL) form the antigen binding site and are involved in the recognition of the antigenic epitope (page 2, last paragraph). Furthermore, the framework plays an important role in CDR conformation and orientation and distinct framework residues often contribute directly to antigen binding (page 2, last paragraph). Thus, single-domain antibodies are not generally only a VH or VL and antibodies require both the VH and VL.
Additionally, the prior art has taught single variable domains from species with VH and VL antibody pairing is distinct from other species with single domain only antibodies. (Holliger P et al. (Nature Biotechnology 2005 23 1126–1136). Holliger taught despite early excitement concerning the functional activity of single variable heavy domain antibodies, these antibody fragments rarely retained the affinity of the parent antibody and were also poorly soluble and often prone to aggregation (page 1127, left to right column bridging paragraph). Holliger taught while high affinity single variable like domain antibodies are present in camelid, as VhH, and shark, as V-NAR, domains, these single domain antibodies are structurally different, wherein each display long surface loops, often larger than for conventional murine and human antibodies, and are able to penetrate cavities in target antigens, such as enzyme active sites (for example, lysozyme) and canyons in viral and infectious disease biomarkers (page 1127, left to right column bridging paragraph). Holliger taught the structural changes are shown in Fig. 2, wherein superimposition of a human VH domain (Fig. 2b) and a single domain V-NAR(Fig. 2c) has a vastly different CDR3 that does not overlap structurally (Fig. 2d). Holliger taught unlike mouse VH domains, camelid VhH and shark V-NAR domains are in general soluble and can be produced as stable in vitro targeting reagents (page 1127, right column, second paragraph). Holliger did not describe single domain VL antibodies as successful. Thus, single-domain antibodies are not generally only a VH or VL and antibodies and require both the VH and VL, which are distinct from VHH.
Summary
Regarding instant claim 1, the Applicant does not have written description of an antibody is claimed to bind CLIC1 based on functional properties without a sequence. Antibody binding to the same antigen, or even the same epitope on that antigen, can be accomplished with an impressively wide variety of antibody structures and no structure activity relationship is identified in the instant disclosure that permits prediction of the antibody sequence based on the claimed functional language. Claims 2 and 5-12 are dependent on claim 1 without narrowing the claims outside of the antibody that is functionally claimed without defined VH and VL CDR sequences.
Regarding instant claim 2, the Applicant does not have written description of an antibody is claimed based on the epitope to which it binds without a sequence. Antibody binding to the same antigen, or even the same epitope on that antigen, can be accomplished with an impressively wide variety of antibody structures and no structure activity relationship is identified in the instant disclosure that permits prediction of the antibody sequence based on the claimed epitope.
Regarding instant claims 3-4, a genus of species is not present in the instant specification that would demonstrate a structure activity relationship would be known for antibody CDR residues for the recited function of binding the protein target CLIC1. There is a lack of an appropriate number of species with identical or alternative amino acid residues within the CDR binding determinant region that indicate which amino acid residues: i) are essential for binding; ii) can be changed and still allow protein target binding; iii) disrupt protein target binding; and iv) allow antibody secretion. One of skill in the art would reasonably conclude that applicant was not in possession of the claimed antibody.
Regarding instant claims 3-4, the specification does not provide details of possession of an antibody comprising a VH and VL, wherein the VH comprises a VH CDR1-3 of SEQ ID NO:7-9 and the VL comprises a VL CDR1-3 of SEQ ID NO:10-12 or an antibody comprising a VH comprising SEQ ID NO: 15 and ta VL comprising SEQ ID NO:16 other than the sequence and that “Similar results were obtained with the antibody” (specification page 11, lines 8-11).
Regarding instant claim 7 or 9-10, the Applicant does not have written description of an antibody fragment that consists of a single domain antibody and the specification does not have support for an antibody fragment that consists of a single domain antibody that possesses the recited function of binding CLIC1.
Regarding instant claims 10-12, Applicant was not in possession of a method of diagnosing or treating inflammation, neurodegenerative diseases or solid tumors is claimed, wherein the claimed antibody, fragment or composition thereof is administered to the patient with no other required steps.
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.
Claims 1-5 are rejected under 35 U.S.C. 102(a)(1) as being anticipated by Peretti M et al. (Mol Cancer Ther 2018 17 (11): 2451–2461).
Regarding instant claims 1 and 3-5, Peretti taught a custom-made antibody against the last 30 amino acids of the amino terminus (AB-NH2) of CLIC1 (page 2452, right column, Materials and Methods, second paragraph), wherein glioblastoma cancer stem cells were incubated with a custom-made antibody (AB-NH2) directed against the external portion of CLIC1 transmembrane protein (Fig. 3A, picture below)
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Peretti Fig. 3 is identical to instant Fig. 7 of the instant disclosure. The instant specification evidences that the antibody that stained the glioblastoma cells in instant Fig. 7 is named tmCLIC1 (instant specification, page 9, lines 5-6, instant Figure 7) and further evidences that the tmCLIC1omab antibody is an IgG1 class antibody comprising the heavy chain variable region identified as instant SEQ ID NO: 13 and the light chain variable region identified as instant SEQ ID NO:14 and is hereinafter called "tmCLIC1omab" (instant specification, page 11, lines 6-8).
Thus, regarding instant claims 1 and 3-5, the custom-made antibody of Peretti against the last 30 amino acids of the amino terminus (AB-NH2) of CLIC1 is tmCLIC1omab comprising an IgG1 class antibody comprising the heavy chain variable region identical to instant SEQ ID NO: 13 and the light chain variable region identical to instant SEQ ID NO:14, which further comprises a VH comprising VH CDR1-3 of instant SEQ ID NO:1-3 and VL comprising VL CDR1-3 of instant SEQ ID NO:4-6. The tmCLIC1omab antibody would naturally be able to inhibit the chloride ion current mediated by CLIC 1 by at least 90% compared with the inhibition caused by the IAA94 CLIC 1 channel blocker at a concentration of 100 μM, wherein said chloride current is measured by the patch clamp technique in whole-cell configuration on a single glioblastoma cell line.
Regarding instant claim 2, the instant specification evidenced that the antibody tmCLIC1omab exhibits specificity with the QVELF epitope (instant specification, pages 24-25, bridging paragraph).
Peretti taught a method of decreasing glioblastoma cancer stem cell proliferation by administering IAA94 or AB-NH2 to glioblastoma cancer stem cells (Fig 1C).
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.
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.
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.
Claims 1-5, 9-10, and 12 are rejected under 35 U.S.C. 103 as being unpatentable over Peretti M et al. (Mol Cancer Ther 2018 17 (11): 2451–2461).
Peretti teach the limitations of claims 1-5 for the reasons set forth above.
Peretti is described above.
Peretti further taught an effective method of decreasing glioblastoma cancer stem cell proliferation by administering IAA94 or AB-NH2 to glioblastoma cancer stem cells (Fig 1C). Peretti taught CLIC1 membrane protein is crucial and specific for GB CSC proliferation, and is a promising pharmacologic target for successful brain tumor therapies (abstract). Peretti taught the uniqueness of CLIC1 functional expression in CSC membranes makes it a promising potential pharmacologic target for a method of GB treatment (page 2452, right column second paragraph).
Peretti does not teach: 1) a single embodiment of treating a patient with glioblastoma by administering a therapeutic composition CLIC1 antibody comprising AB-NH2, but this is obvious in view of Peretti.
Regarding instant claims 9-10 and 12, it would have been obvious for a person having ordinary skill in the art to take the AB-NH2 CLIC1 antibody of Peretti – and: 1) including it in a therapeutic composition for treatment of the solid tumor glioblastoma in view of Peretti.
This is obvious because: 1) Peretti taught: a) CLIC1 membrane protein is crucial and specific for GB CSC proliferation, and is a promising pharmacologic target for successful brain tumor therapies; b) the uniqueness of CLIC1 functional expression in CSC membranes makes it a promising potential pharmacologic target for a method of GB treatment; and c) an effective method of decreasing glioblastoma cancer stem cell proliferation by administering AB-NH2 to glioblastoma cancer stem cells. Thus, including AB-NH2 in a therapeutic composition for glioblastoma treatment is obvious.
There is a reasonable expectation of success because: 1) Peretti taught: a) CLIC1 membrane protein is crucial and specific for GB CSC proliferation, and is a promising pharmacologic target for successful brain tumor therapies; b) the uniqueness of CLIC1 functional expression in CSC membranes makes it a promising potential pharmacologic target for a method of GB treatment; and c) an effective method of decreasing glioblastoma cancer stem cell proliferation by administering AB-NH2 to glioblastoma cancer stem cells. Thus, including AB-NH2 , which is known to be effective at decreasing glioblastoma proliferation, in a therapeutic composition for treatment of glioblastoma, wherein CLIC1 is known to be a promising target, has a reasonable expectation of success.
Claims 1-6 are rejected under 35 U.S.C. 103 as being unpatentable over Peretti M et al. (Mol Cancer Ther 2018 17 (11): 2451–2461) and Bates A et al. (Antibodies (Basel). 2019 8(2):28).
Peretti teach the limitations of claims 1-5 for the reasons set forth above.
Peretti is described above.
Peretti does not teach: 1) a Fab antibody of CLIC1, but this is obvious in view of Bates.
Bates taught antibody fragments offer several advantages over full-length monoclonal antibodies, particularly a lower cost of goods, and because of their small size they can penetrate tissues, access challenging epitopes, and have potentially reduced immunogenicity (abstract). Bates taught Fabs lack an Fc domain, reducing the risk of immune cell bystander activation and non-specific binding and allowing for easier production (page 5, second paragraph).
Regarding instant claim 6, it would have been obvious for a person having ordinary skill in the art to take the AB-NH2 CLIC1 antibody of Peretti – and: 1) make a Fab antibody fragment in view of Bates.
This is obvious because: 1) Bates taught Fabs lack an Fc domain, reducing the risk of immune cell bystander activation and non-specific binding and allowing for easier production.
There is a reasonable expectation of success because: 1) Bates taught antibody fragments offer several advantages over full-length monoclonal antibodies, wherein Fabs lack an Fc domain, reducing the risk of immune cell bystander activation and non-specific binding and allow for easier production.
Claims 1-5 and 7-8 are rejected under 35 U.S.C. 103 as being unpatentable over Peretti M et al. (Mol Cancer Ther 2018 17 (11): 2451–2461), Sen KI et al. (J. Am. Soc. Mass Spectrom. 2017, 28, 5, 803–810), and Bogdanoff WA et al. (ACS Infect Dis. 2016 Mar 14;2(5):313–321).
Peretti teach the limitations of claims 1-5 for the reasons set forth above.
Peretti is described above.
Peretti does not teach: 1) a nucleic acid encoding a CLIC1 antibody; or 2) an expression vector comprising a nucleic acid encoding a CLIC1 antibody, but this is obvious in view of Sen and Bogdanoff.
Sen taught when monoclonal antibodies against a target of interest are available, but the cDNA or the original cell line is not, de novo protein sequencing is required to recombinantly express these antibodies (abstract). Sen taught an effective method to automatically de novo sequence antibodies using mass spectrometry and the Supernovo software (abstract).
Bogdanoff taught de novo sequencing of an antibody to determine the sequence (page 315, right to left column bridging paragraph). Bogdanoff taught having the antibody heavy chain and light chain amino acid sequences allowed them to engineer a recombinant antibody construct of the antibody, wherein the recombinant construct was further introduced into Drosophila S2 host cells for antibody expression and purification (page 316, left to right column bridging paragraph), wherein the recombinant construct was an expression plasmid that comprised a nucleotide acid molecule that encoded for the antibody sequence, which was stably transfected into Drosophila S2 host cells (page 319, left to right column bridging paragraph).
Regarding instant claims 7-8, it would have been obvious for a person having ordinary skill in the art to take the AB-NH2 CLIC1 antibody of Peretti – and: 1) sequence the antibody and produce a nucleic acid encoding a CLIC1 antibody in view of Sen and Bogdanoff; and 2) insert the nucleic acid encoding a CLIC1 antibody into an expression vector to produce a CLIC1 antibody Bogdanoff.
This is obvious because: 1) Sen taught an effective method to automatically de novo sequence antibodies and de novo protein sequencing is required to recombinantly express these antibodies; and 2) Bogdanoff taught de novo sequencing of an antibody to determine the sequence and effectively engineering a recombinant construct in an expression plasmid that comprised a nucleotide acid molecule that encoded for the antibody sequence, which was stably transfected into Drosophila S2 host cells.
There is a reasonable expectation of success because: 1) Sen taught an effective method to automatically de novo sequence antibodies and de novo protein sequencing is required to recombinantly express these antibodies; and 2) Bogdanoff taught de novo sequencing of an antibody to determine the sequence and effectively engineering a recombinant construct in an expression plasmid that comprised a nucleotide acid molecule that encoded for the antibody sequence, which was stably transfected into Drosophila S2 host cells. Thus, a vector comprising a nucleotide sequence encoding for the AB-NH2 CLIC1 antibody of Peretti for recombinant expression would have a reasonable expectation of success.
Claims 1-4 and 11 are rejected under 35 U.S.C. 103 as being unpatentable over Peretti M et al. (Mol Cancer Ther 2018 17 (11): 2451–2461) and Milton RH et al. (Journal of Neuroscience 5 November 2008, 28 (45) 11488-11499).
Peretti teach the limitations of claims 1-5 for the reasons set forth above.
Peretti is described above.
Peretti does not teach: 1) a single embodiment of treating a patient with glioblastoma by administering a therapeutic composition CLIC1 antibody comprising AB-NH2, but this is obvious in view of Milton.
Milton taught an antibody against the native extracellular N terminus of native CLIC1: 1) effectively reduces the membrane chloride current, wherein after activation of the Aβ-induced current in perforated-patch whole-cell recordings from rat PMG cells perfusion with the CLIC1 antibody significantly reduced the current amplitude (Fig. 6a); and 2) inhibited microglial Aβ-induced ROS production (Fig. 6b). Milton taught ROS generation and the resultant oxidative stress in the CNS are believed to constitute a major mechanism underlying the neurodegeneration in Alzheimer's disease and other disorders (page 11497, right column, Discussion, first paragraph). Milton taught CLIC1 has a specific role in the initiation and facilitation of microglial ROS production and, therefore, represents an ideal and novel therapeutic target to counteract the neurodegeneration in Alzheimer’s disease (page 11498, left to right column bridging paragraph).
Regarding instant claim 11, it would have been obvious for a person having ordinary skill in the art to take the AB-NH2 CLIC1 antibody of Peretti – and: 1) including it in a therapeutic composition for treatment of Alzheimer’s disease in view of Milton.
This is obvious because: 1a) Milton taught ROS generation and the resultant oxidative stress in the CNS are believed to constitute a major mechanism underlying the neurodegeneration in Alzheimer's disease and other disorders; 1b) Milton taught CLIC1 has a specific role in the initiation and facilitation of microglial ROS production and, therefore, represents an ideal and novel therapeutic target to counteract the neurodegeneration in Alzheimer’s disease; and 1c) Milton taught an antibody against the native extracellular N terminus of native CLIC1: i) effectively reduces membrane chloride current after Aβ-induced current; and ii) inhibited microglial Aβ-induced ROS production. Thus, including AB-NH2 in a therapeutic composition for Alzheimer’s disease treatment is obvious.
There is a reasonable expectation of success because: 1a) Milton taught ROS generation and the resultant oxidative stress in the CNS are believed to constitute a major mechanism underlying the neurodegeneration in Alzheimer's disease and other disorders; 1b) Milton taught CLIC1 has a specific role in the initiation and facilitation of microglial ROS production and, therefore, represents an ideal and novel therapeutic target to counteract the neurodegeneration in AD; and 1c) Milton taught an antibody against the native extracellular N terminus of native CLIC1: i) effectively reduces membrane chloride current after Aβ-induced current; and ii) inhibited microglial Aβ-induced ROS production. Thus, including AB-NH2 , which is known to be effective at decreasing microglial ROS production and Aβ-induced current, in a therapeutic composition for treatment of Alzheimer’s disease, wherein CLIC1 is known to be an ideal target, has a reasonable expectation of success.
Conclusion
Claims 1-12 are rejected.
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/J.J.S./Examiner, Art Unit 1643
/JULIE WU/Supervisory Patent Examiner, Art Unit 1643