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 127-130, 134-138, 141, 144-145, and 147-151 are pending in the instant application and being examined on the merit.
Claims 131-133, 139-40, 142-143, and 146 are canceled.
Claims 147-151 are new.
Objections and Rejections Withdrawn
The rejections to claims 131-133, 139-40, 142-143, and 146 are moot in view of claim cancelation.
The objection to claim 127 is withdrawn in view of claim amendment.
The rejections to claims 127-130, 134-138, 141, and 144-145 under 35 USC §112(b) are withdrawn in view of claim amendment.
The rejections to claim 145 under 35 USC §112(a) is withdrawn in view of claim amendment.
The rejections to claims 127-130, 134-138, 141, and 144-145 under 35 USC §103 are withdrawn in view of claim amendment and WO 2019241430 (Jaminet PA et al.) was owned by Applicant.
The rejections to claims 127-130, 134-138, 141, and 144-145 under Nonstatutory Double Patenting are withdrawn in view of claim amendment and WO 2019241430 (Jaminet PA et al.) was owned by Applicant.
New claim rejections
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.
Regarding instant claim 141, the disclosure does not test exchange of all antibody VH and VL regions with one another from separate antibody CDRH1-H3 and CDRL1-L3 outside of 6 CDRs present in the AGX-A03, AGX-A04, AGX-A05, AGX-A07, AGX-A08, AGX-A09, AGX-A11, AGX-A07 H2, H2v1L5v2, AGX-A07 H2L5, AGX-A01 H1L10, AGX-A01, and H1v1L10 clones that possesses the recited function of binding TM4SF1 and are able to be secreted.
Scope of the claimed genus
Claims 141 claim anti-TM4SF1 antibody drug conjugates wherein sequence identifiers of any one of the claimed VH, or VL sequences can be paired together from separate anti-TM4SF1 antibody clones AGX-A03, AGX-A04, AGX-A05, AGX-A07, AGX-A08, AGX-A09, AGX-A11, AGX-A07, H2v1L5v2, AGX-A07 H2L5, AGX-A01 H1L10, AGX-A01, and H1v1L10.
State of the Relevant Art
1) TM4SF1 antibodies are known to the art. The anti-TM4SF1 antibodies produced by clones AGX-A03, AGX-A04, AGX-A05, AGX-A07, AGX-A08, AGX-A09, AGX-A11, AGX-A07 H2, H2v1L5v2, AGX-A07 H2L5, AGX-A01 H1L10, AGX-A01, and H1v1L10 are able to bind TM4SF1 as taught by WO 2019046338 (Jaminet PA et al. IDS reference). Jaminet '338 taught the humanized anti-TM4SF1 hAGX-A01-H1L10 effectively bound HUVEC cells with an EC50 of about 3 nM (Fig. 12-13). Jaminet ‘338 taught hAGX-A01-H1L10 comprised a heavy chain of SEQ ID NO:112 and a light chain of SEQ ID NO:122 (page 116 and 118 Table 2). Jaminet did not demonstrate a structure activity relationship would be known for exchange all VH and VL components of separate antibodies with one another for the recited function of binding the protein target TM4SF1.
At the time of the filing of the instant application, it was well established in the art that the formation of an intact antigen-binding site in an antibody usually required the association of the complete heavy and light chain variable regions of a given antibody, each of which consists of three “complementarity determining regions” (“CDRs”) which provide the majority of the contact residues for the binding of the antibody to its target epitope. E.g., Almagro & Fransson, Frontiers in Bioscience 2008; 13:1619-33 IDS reference; (see Section 3 “Antibody Structure and the Antigen Binding Site” 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, reference of record) 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 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, reference of record) 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).
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.
The specification identifies anti-TM4SF1 antibodies produced by clones AGX-A03, AGX-A04, AGX-A05, AGX-A07, AGX-A08, AGX-A09, AGX-A11, AGX-A07, H2v1L5v2, AGX-A07 H2L5, AGX-A01 H1L10, AGX-A01, and H1v1L10, wherein the antibody sequences are present in Table 2
Alignment of the CDR regions of the TM4SF1 antibodies of the AGX-A03, AGX-A04, AGX-A05, AGX-A07, AGX-A08, AGX-A09, AGX-A11, AGX-A07, H2v1L5v2, AGX-A07 H2L5, AGX-A01 H1L10, AGX-A01, and H1v1L10 clones show the antibody CDRs have several regions that are distinct and have no overlap. Exchange of VH and VL regions would cause unpredictable binding effects on the claimed antibody target TM4SF1 and antibody secretion.
CDRH1 CDRH2 CDRH3 CDRL1 CDRL2 CDRL3
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1) The specification does not have examples of exchange of separate VH and VL species from all antibodies with the SEQ ID NOs identified in instant claim 141 to form antibody or antigen-binding fragments that bind to TM4SF1.
As noted above, the art generally accepted that the combination of the CDRs within the VH and VL pair of an antibody were essential for binding specificity. But the specification does not describe what residues within the CDRs confer the binding activity claimed and the claim language permits pairing of any VH and VL. Accordingly, the skilled artisan would not be able to discern a structure/function correlation for multivalent peptides other than those comprising all six CDRs or antibody or antigen fragment of the TM4SF1 antibody clones present together in AGX-A03, AGX-A04, AGX-A05, AGX-A07, AGX-A08, AGX-A09, AGX-A11, AGX-A07, H2v1L5v2, AGX-A07 H2L5, AGX-A01 H1L10, AGX-A01, and H1v1L10.
Given the lack of shared structural properties of the CDR regions, the description of separate species of anti-TM4SF1 antibodies without testing of the VH and VL exchanges claimed, 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.
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.
Claims 127-130, 134, 144-145, 147-148 and 150-151 are rejected under 35 U.S.C. 103 as being unpatentable over Ma Y et al. (Drug Metabolism and Disposition 2019 47(8) 884-889, IDS reference), WO 2015054427 (Jaminet S-C S et al.), Sciuto TE et al. (Biochem Biophys Res Commun. 2015 Aug 1;465(3):338–343), and Turk V et al. (Biochim Biophys Acta Proteins Proteom. 2011 1824(1):68–88, reference of record).
Regarding instant claim 127, Ma taught carfilzomib (CFZ) is an effective proteasome inhibitor used for oncology indications including treating multiple myeloma (abstract). Ma taught CFZ is a potent cytotoxic agent with an IC50 value in the nanomolar range in various cancer cell lines and was considered as a potential payload for antibody drug conjugates (ADCs); however, the conjugated CFZ to anti-CD22 or anti-HER2 antibody totally abolishes the in vitro potency (abstract). Ma taught in CFZ linked to the ADC, cathepsin B (a lysosomal enzyme) was efficient in liberating CFZ from the ADC by cleavage of the valine-citrulline linker, but the liberated CFZ in the lysosome was inactivated due to further metabolism by lysosomal enzymes (abstract). Ma taught these results suggested that the CFZ-ADC upon uptake and internalization specifically delivers CFZ payload to the lysosomes, where CFZ was inactivated (abstract). Ma taught free CFZ by itself is not as vulnerable and could reach its target (abstract). Ma taught a pharmaceutical composition comprising an anti-HER2 antibody linked to carfilzomib (Fig. 2). Ma taught the structure of the CFZ ADC as
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(Fig. 6).
Ma taught: i) common adverse events induced by CFZ include anemia, hypertension, thrombocytopenia, and pneumonia; ii) like other small molecular cytotoxic agents, CFZ may largely decrease the health-related quality of life for patients in chemotherapy; iii) CFZ was tested as a payload of antibody drug conjugates (ADCs) to investigate the potential of improving its efficacy and safety because ADC technology is a demonstrated strategy to effectively enlarge the therapeutic windows of cytotoxic agents and minimize their side effects (page 884, right column, Introduction, first column)..
Ma does not teach: 1) an ADC comprising an anti-TM4SF1 antibody, a proteasome inhibitor and a linker between the antibody and proteasome inhibitor; 2) treating a disease in a subject comprising administering a pharmaceutical composition of an ADC with a pharmaceutically acceptable excipient, wherein the disease is characterized by abnormal endothelial cell (EC)- cell interactions, wherein the interaction is between an EC-tumor cell, but this is obvious in view of Jaminet ‘427, Sciuto, and Turk.
Regarding instant claims 127, 145, and 147-148, and 150-151, Jaminet ‘427 taught TM4SF1 as a vascular target for treating cancer and that an anti-TM4SF1 antibody 8G4 was progressively internalized into the EC, and, when complexed with a saporin therapeutic agent, caused extensive EC killing (page 20, lines 29-37). Jaminet ‘427 taught administration of an anti-TM4SF1 antibody saporin cytotoxic agent conjugate to cancer and endothelial cells effectively killed cancer and endothelial cells (Figs. 6-7). Jaminet ‘427 taught an anti-TM4SF1 antibody 8G4 was internalized in cells wherein the antibody was endocytosed into the cytoplasm and nucleus (page 41, lines 6-16 and Figs. 5B-5F). Regarding instant claim 144-145, Jaminet ‘427 taught 8G4 comprising pharmaceutical compositions may further include a pharmaceutically acceptable excipient and be formulated for a method of treating a subject having a disorder associated with pathological angiogenesis of cancer (page 32, lines 1-11). Regarding instant claims 144-145, 147-148, and 150-151, Jaminet ‘427 taught a method of treating a subject having a disorder associated with pathological angiogenesis of cancer including administering a therapeutically effective amount of a pharmaceutical composition comprising an anti-TM4SF1 antibody 8G4 (page 32, lines 14-24), wherein the pharmaceutical composition can be internalized into a TM4SF1 -expressing tumor vasculature endothelial cell or a tumor cell following binding to TM4SF1 (page 32, lines 32-34).
Regarding instant claims 127, 145, and 147-148, and 150-151, Sciuto taught: i) TM4SF1 is highly and selectively expressed on the plasma membranes of tumor cells and on tumor-associated endothelium in vivo; ii) TM4SF1 has potential as a dual therapeutic target using an antibody drug conjugate (ADC) approach; and iii) TM4SF1 is an attractive candidate for cancer therapy with antibody-bound toxins that have the capacity to react with either cytoplasmic or nuclear targets in tumor cells or tumor-associated vascular endothelium (abstract). Sciuto taught for ADC to be successful, antibodies reacting with cell surface antigens must be internalized for delivery of associated toxins to intracellular targets (abstract). Regarding instant claim 127, Sciuto taught a monoclonal anti-TM4SF1 antibody, 8G4, is: i) efficiently taken up into cells by uncoated vesicles in a dynamin-dependent, clathrin-independent manner; and ii) transported along microtubules through the cytoplasm and passes through nuclear pores into the nucleus (abstract). Regarding instant claims 127, 145, and 147-148, and 150-151, Sciuto taught TM4SF1, which is highly and selectively expressed on the plasma membranes of tumor cells and tumor-associated endothelium, as an attractive candidate for a method of administering a cancer therapy with antibody-bound toxins that have the capacity to react with either cytoplasmic or nuclear targets in tumor cells or tumor-associated vascular endothelium (abstract). Regarding instant claims 150-151, Sciuto taught TM4SF1 is expressed at low levels on normal vascular endothelium (page 338, left column first paragraph), but highly and selectively expressed on tumor-associated endothelium (abstract).
Turk taught studies have shown that active cathepsins are also localized in other cellular compartments, such as the nucleus, cytoplasm and plasma membrane (page 69, left column, second to last paragraph).
Regarding instant claims 127-130 and 134, it would have been obvious for a person having ordinary skill in the art to take the anti-HER2 antibody ADC conjugated to CFZ with a structure of:
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– and modify it to: 1) exchange the anti-HER2 antibody for an anti-TM4SF1 antibody 8G4 of Jaminet ‘427; and 2)
One would be motivated to exchange the anti-HER2 antibody for the anti-TM4SF1 antibody because an anti-TM4SF1 antibody is internalized via a dynamin-dependent, clathrin-independent manner and transported along microtubules through the cytoplasm and nuclear pores into the nucleus as taught by Sciuto and CFZ is an effective drug as taught by Ma, but CFZ is inactivated in when internalized to the lysosome by an anti-HER2 antibody.
This is further obvious because:
1a) Sciuto taught: i) TM4SF1 is highly and selectively expressed on the plasma membranes of tumor cells and on tumor-associated endothelium in vivo; ii) TM4SF1 has potential as a dual therapeutic target using an antibody drug conjugate (ADC) approach; and iii) TM4SF1 is an attractive candidate for cancer therapy with antibody-bound toxins that have the capacity to react with either cytoplasmic or nuclear targets in tumor cells or tumor-associated vascular endothelium;
1b) Sciuto taught a monoclonal anti-TM4SF1 antibody, 8G4, is: i) efficiently taken up into cells by uncoated vesicles in a dynamin-dependent, clathrin-independent manner; and ii) transported along microtubules through the cytoplasm and passes through nuclear pores into the nucleus;
1c) Jaminet ‘427 taught the anti-TM4SF1 antibody 8G4 is progressively internalized into the endothelial cells and effective at killing endothelial and cancer cells in an ADC further comprising a cytotoxic agent; and
1d) Turk taught studies have shown that active cathepsins are also localized in other cellular compartments, such as the nucleus, cytoplasm and plasma membrane.
There is a reasonable expectation of success because an anti-TM4SF1 MC-vc-PAB-CFZ: 1a) would be targeted to tumor cells and on tumor-associated endothelium and have the capacity to react with either cytoplasmic or nuclear targets in tumor cells or tumor-associated vascular endothelium;
1b) would be efficiently: i) taken up into cells by uncoated vesicles in a dynamin-dependent, clathrin-independent manner; and ii) transported along microtubules through the cytoplasm and pass through nuclear pores into the nucleus;
1c) would be progressively internalized into endothelial and cancer cells and allow for CFZ to be released outside the lysosome;
1d) would release the CFZ from the ADC via cathepsin cleavage of the val-cit-PAB linker in the nucleus, cytoplasm and plasma membrane.
This would produce an anti-TM4SF1 8G4-MC-val-cit-PAB-carfilzomib antibody drug conjugate, wherein the proteasome inhibitor is configured to be potent following nuclear internalization, wherein the linker comprises MC and a C5 alkylene as –[CH2]3-[CH2]2- which meets the claim limitations of instant claims 128-130, wherein linker-carfilzomib structure
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meets the claim limitations of formula (V) in instant claim 127, and structure in instant claim 134.
Regarding instant claims 144-145, 147-148 and 150-151, it would have been obvious for a person having ordinary skill in the art to take the method of Jaminet ‘427 of treating a subject having a disorder associated with pathological angiogenesis of cancer including administering a therapeutically effective amount of a pharmaceutical composition comprising an anti-TM4SF1 antibody 8G4, wherein the anti-TM4SF1 antibody 8G4 can be internalized into a TM4SF1-expressing tumor vasculature endothelial cell or tumor cell, wherein the disease of cancer is characterized by abnormal EC-tumor cell interactions – and: 1) exchange the pharmaceutical composition comprising an anti-TM4SF1 antibody 8G4 for a pharmaceutical composition comprising the anti-TM4SF1 8G4-MC-val-cit-PAB-carfilzomib antibody drug conjugate of Ma, Jaminet ‘427, Sciuto, and Turk above; and 2) administer the ADC in a pharmaceutical composition with a pharmaceutically acceptable excipient as taught by Jaminet ‘427
One would be motivated to: 1) exchange the anti-TM4SF1 antibody 8G4 in the method of Jaminet ‘427 for the anti-TM4SF1 8G4-MC-val-cit-PAB-carfilzomib antibody drug conjugate of Ma, Sciuto, Jaminet ‘427, and Turk because carfilzomib is an effective approved cancer treatment that would be targeted to cancer cells and tumor-associated endothelium; and 2) include a pharmaceutically acceptable excipient in a pharmaceutical composition because administration of the ADC would require an excipient for injection.
This is obvious because: 1a) Ma taught carfilzomib (CFZ) is an effective proteasome inhibitor used for oncology indications including treating multiple myeloma and is a potent cytotoxic agent with an IC50 value in the nanomolar range in various cancer cell lines that was considered as a potential payload for antibody drug conjugates (ADCs); 1b) an anti-TM4SF1 8G4-MC-val-cit-PAB-carfilzomib antibody drug conjugate would: i) efficiently be taken up into cells by uncoated vesicles in a dynamin-dependent, clathrin-independent manner; and ii) transported along microtubules through the cytoplasm and pass through nuclear pores into the nucleus as taught by Sciuto for the anti-TM4SF1 8G4 antibody; 1c) Jaminet ‘427 taught administration of an anti-TM4SF1 antibody ADC effectively killed cancer and endothelial cells that expressed TM4SF1; 2) Jaminet ‘427 taught the anti-TM4SF1 conjugate in a pharmaceutical composition with a pharmaceutically excipient.
There is a reasonable expectation of success because: 1) Ma taught carfilzomib (CFZ) is an effective proteasome inhibitor used for oncology indications including treating multiple myeloma and is a potent cytotoxic agent with an IC50 value in the nanomolar range in various cancer cell lines that was considered as a potential payload for antibody drug conjugates (ADCs); 1b) an anti-TM4SF1 8G4-MC-val-cit-PAB-carfilzomib antibody drug conjugate would be: i) efficiently be taken up into cells by uncoated vesicles in a dynamin-dependent, clathrin-independent manner; and ii) transported along microtubules through the cytoplasm and pass through nuclear pores into the nucleus; 1c) the anti-TM4SF1 antibody- payload conjugates would effectively deliver the payload in the therapeutically important cell types of tumor cells and angiogenic endothelial cells to inhibit tumor growth; and 2) inclusion of a pharmaceutically acceptable excipient in an ADC pharmaceutical composition would require an excipient for injection.
This would produce a method of treating a subject having a disorder associated with pathological angiogenesis of cancer comprising administering a therapeutically effective amount of a pharmaceutical composition comprising an anti-TM4SF1 8G4-MC-val-cit-PAB-carfilzomib antibody drug conjugate and a pharmaceutically acceptable excipient (instant claim 144), wherein the anti-TM4SF1 8G4-MC-val-cit-PAB-carfilzomib antibody drug conjugate can be internalized into a target cell of a TM4SF1-expressing tumor vasculature endothelial cell (instant claim 148) or tumor cell (instant claim 147), wherein the disease of cancer is characterized by abnormal EC-tumor cell interactions (instant claims 150-151) (instant claim 145).
Response to Arguments
Applicant argues the '430 publication is not available as prior art under 35 USC 102. Applicant submits that the '430 publication meets each of the criteria set out in MPEP 2153.0l(a): (1) the May 1, 2020 effective filing date of the instant application is within one year of the December 19, 2019 publication date of the '430 publication; (2) the '430 publication names a joint inventor of the instant application as an inventor; and (3) the' 430 publication does not name any individual as an inventor that is not named as a joint inventor on the instant application. Therefore, the' 430 publication is not prior art under 35 U.S.C. 102(a)(1).
Applicant’s arguments, see page 13, filed 2/9/2026, with respect to ‘430 as prior art have been fully considered and are persuasive. The rejection of claims 127-130, 134, 144-145, 147-148 and 150-151 has been withdrawn.
An updated rejection is above that does not include ‘430.
Claims 127-130, 134-138, 141, 144-145, 147-148 and 150-151 are rejected under 35 U.S.C. 103 as being unpatentable over Ma Y et al. (Drug Metabolism and Disposition 2019 47(8) 884-889 IDS reference), WO 2015054427 (Jaminet S-C S et al.), Sciuto TE et al. (Biochem Biophys Res Commun. 2015 Aug 1;465(3):338–343), and Turk V et al. (Biochim Biophys Acta Proteins Proteom. 2011 1824(1):68–88, reference of record) as applied to claims 127-130, 134, 144-145, 147-148 and 150-151 above, and further in view of WO 2019046338 (Jaminet PA et al. IDS reference).
Ma, Jaminet '427, Sciuto, and Turk are described above.
Ma, Jaminet '427, Sciuto, and Turk did not describe an anti-TM4SF1 antibody comprising a heavy chain of instant SEQ ID NO:112 and a light chain of instant SEQ ID NO:122, but this is obvious in view of Jaminet '338.
Jaminet '338 taught the humanized anti-TM4SF1 hAGX-A01-H1L10 effectively bound HUVEC cells with an EC50 of about 3 nM (Fig. 12-13). Jaminet ‘338 taught hAGX-A01-H1L10 comprised a heavy chain of SEQ ID NO:112 and a light chain of SEQ ID NO:122 (page 116 and 118 Table 2). Jaminet '338 taught the anti-TM4SF1 antibody conjugated to a therapeutic agent to kill or inhibit tumor cells (TCs) and/or tumor vasculature endothelial cells (page 60, [0184]). Jaminet '338 taught humanized antibodies can be important to reduce antigenicity (page 59, [0179]).
Regarding instant claims 135-138 and 141, it would have been obvious for a person having ordinary skill in the art to take the anti-TM4SF1 8G4-MC-val-cit-PAB-carfilzomib of Ma, Jaminet '427, Sciuto, and Turk – and: 1) exchange the anti-TM4SF1 antibody for the humanized anti-TM4SF1 antibody hAGX-A01-H1L10 of Jaminet ‘338 comprising a heavy chain of SEQ ID NO:112 and a light chain of SEQ ID NO:122.
One would be motivated to exchange the anti-TM4SF1 antibody for the anti-TM4SF1 antibody of hAGX-A01-H1L10 because humanized hAGX-A01-H1L10 would cause less antigenicity and has an effective EC50 value of about 3 nM.
This is obvious because: 1a) Jaminet '338 taught the humanized anti-TM4SF1 hAGX-A01-H1L10 effectively bound HUVEC cells with an EC50 of about 3 nM; and 1b) Jaminet '338 taught the anti-TM4SF1 antibody conjugated to a therapeutic agent to kill or inhibit tumor cells (TCs) and/or tumor vasculature endothelial cells
There is a reasonable expectation of success because: 1) the humanized anti-TM4SF1 hAGX-A01-H1L10 effectively bound HUVEC cells.
This would produce an anti-TM4SF1-MC-val-cit-PAB-carfilzomib antibody drug conjugate, wherein the proteasome inhibitor is configured to be potent following nuclear internalization, wherein the anti-TM4SF1 comprises a heavy chain of Jaminet '338 SEQ ID NO:112 and a light chain of Jaminet '338 SEQ ID NO:122 (instant claims 141), which is identical to the heavy chain of instant SEQ ID NO:112 and the light chain of instant SEQ ID NO:122, wherein the VH HCDR1-3 comprises instant SEQ ID NO:115, 116, 118 and the VL LCDR1-3 comprises instant SEQ ID NO: 124, 128, 129, and wherein the heavy chain further contains the IgG1 Fc region of instant SEQ ID NO:87 which contains L234A, L235A, and G237A (instant claims 135-138).
Response to Arguments
Applicant argues the '430 publication is not available as prior art under 35 USC 102. Applicant submits that the '430 publication meets each of the criteria set out in MPEP 2153.0l(a): (1) the May 1, 2020 effective filing date of the instant application is within one year of the December 19, 2019 publication date of the '430 publication; (2) the '430 publication names a joint inventor of the instant application as an inventor; and (3) the' 430 publication does not name any individual as an inventor that is not named as a joint inventor on the instant application. Therefore, the' 430 publication is not prior art under 35 U.S.C. 102(a)(1).
Applicant’s arguments, see page 13, filed 2/9/2026, with respect to ‘430 as prior art have been fully considered and are persuasive. The rejection of claims 127-130, 134, 144-145, 147-148 and 150-151 has been withdrawn.
An updated rejection is above that does not include ‘430.
Claims 127-130, 134, 144-145, 147-148 and 149-151 are rejected under 35 U.S.C. 103 as being unpatentable over Ma Y et al. (Drug Metabolism and Disposition 2019 47(8) 884-889 IDS reference), WO 2015054427 (Jaminet S-C S et al.), Sciuto TE et al. (Biochem Biophys Res Commun. 2015 Aug 1;465(3):338–343), and Turk V et al. (Biochim Biophys Acta Proteins Proteom. 2011 1824(1):68–88, reference of record) as applied to claims 127-130, 134, 144-145, 147-148 and 150-151 above, and further in view of Bae S et al. (Stem Cells Dev 2011 20(2):197-203), Lin C-I et al. (Angiogenesis 2014 17(4):897-907.), and Maffey A et al. (Scientific Reports 2017 7 13162).
Ma, Jaminet '427, Sciuto, and Turk are described above
Ma does not describe the target cell is a mesenchymal stem cell, but this is obvious in view of Bae and Lin.
Regarding instant claim 149, Bae taught TM4SF1 was abundantly expressed on mesenchymal stem cells (MSC) (abstract).
Regarding instant claim 149, Lin taught anti-TM4SF1 monoclonal antibodies effectively eliminated the human vascular component present in Matrigel plugs further comprising human endothelial colony-forming cells (ECFC) and human mesenchymal stem cells (MSC) (abstract).
Regarding 149, Maffey taught interaction between tumor cells and the microenvironment is key in initiation, progression, and invasiveness of cancer and that mesenchymal stem cells (MSCs) are recruited to the sites of developing tumors, thus promoting metastasis formation (abstract). Maffey taught interaction of breast cancer cells with MSCs results in an increased proliferation and metabolic activity of breast cancer cells, partially due to MSC-derived microvesicles that are shed in the tumor microenvironment (abstract).
Regarding instant claims 149, it would have been obvious for a person having ordinary skill in the art to take the method of Ma, Jaminet '427, Sciuto, and Turk above of treating a subject having a disorder associated with pathological angiogenesis of cancer comprising administering a therapeutically effective amount of a pharmaceutical composition comprising an anti-TM4SF1 8G4-MC-val-cit-PAB-carfilzomib antibody drug conjugate and a pharmaceutically acceptable excipient, wherein the anti-TM4SF1 8G4-MC-val-cit-PAB-carfilzomib antibody drug conjugate can be internalized into a target cell of a TM4SF1-expressing tumor vasculature endothelial cell or tumor cell, wherein the disease of cancer is characterized by abnormal EC-tumor cell interactions – and modify the method to: 1) further target mesenchymal stem cells.
One would be motivated to target mesenchymal stem cells because Maffey taught interaction of breast cancer cells with MSCs results in an increased proliferation and metabolic activity of breast cancer cells, partially due to MSC-derived microvesicles that are shed in the tumor microenvironment.
This is obvious because: 1a) Bae taught TM4SF1 was abundantly expressed on mesenchymal stem cells (MSC); 1b) Lin taught anti-TM4SF1 monoclonal antibodies effectively eliminated the human vascular component present in Matrigel plugs further comprising human endothelial colony-forming cells (ECFC) and human mesenchymal stem cells (MSC); and 1c) Maffey taught: i) interaction between tumor cells and the microenvironment is key in initiation, progression, and invasiveness of cancer and that mesenchymal stem cells (MSCs) are recruited to the sites of developing tumors, thus promoting metastasis formation; and ii) interaction of breast cancer cells with MSCs results in an increased proliferation and metabolic activity of breast cancer cells, partially due to MSC-derived microvesicles that are shed in the tumor microenvironment. Thus, it would be obvious to target MSCs which express TM4SF1.
There is a reasonable expectation of success because: 1a) TM4SF1 is abundantly expressed on MSC, so the ADC would effectively target them; 1b) anti-TM4SF1 monoclonal antibodies are known to effectively eliminated the human vascular component present in Matrigel plugs further comprising human endothelial colony-forming cells (ECFC) and human mesenchymal stem cells (MSC); and 1c) Killing tumor MSC would inhibit MSC-dependent proliferation, progression and invasiveness of cancer.
Response to Arguments
Applicant argues the '430 publication is not available as prior art under 35 USC 102. Applicant submits that the '430 publication meets each of the criteria set out in MPEP 2153.0l(a): (1) the May 1, 2020 effective filing date of the instant application is within one year of the December 19, 2019 publication date of the '430 publication; (2) the '430 publication names a joint inventor of the instant application as an inventor; and (3) the' 430 publication does not name any individual as an inventor that is not named as a joint inventor on the instant application. Therefore, the' 430 publication is not prior art under 35 U.S.C. 102(a)(1).
Applicant’s arguments, see page 13, filed 2/9/2026, with respect to ‘430 as prior art have been fully considered and are persuasive. The rejection of claims 127-130, 134, 144-145, 147-148 and 150-151 has been withdrawn.
An updated rejection is above that does not include ‘430.
Conclusion
No claims are allowable
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/J.J.S./Examiner, Art Unit 1643
/Karen A. Canella/Primary Examiner, Art Unit 1643
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