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 .
Claims 49-58, 60 and 65-71 are pending and being acted upon in this Office Action.
Priority
Receipt is acknowledged of papers submitted under 35 U.S.C. 119(a)-(d), which papers have been placed of record in the file.
Specification
The substitute specification filed on February 23, 2026 has been entered.
Objection and Rejection Withdrawn
The objection to the abstract and the specification are withdrawn in view of the abstract and substitute specification filed on February 23, 2026.
The objection to claims 49, 59 and 62 is withdrawn in light of the claim amendment.
The rejection of claims 49, 53-54, 58, 60 and 62 under 35 U.S.C. 112(b) or 35 U.S.C. 112 (pre-AIA ), second paragraph is withdrawn in view of the claim amendment.
Double Patenting
The nonstatutory double patenting rejection is based on a judicially created doctrine grounded in public policy (a policy reflected in the statute) so as to prevent the unjustified or improper timewise extension of the “right to exclude” granted by a patent and to prevent possible harassment by multiple assignees. A nonstatutory double patenting rejection is appropriate where the claims at issue are not identical, but at least one examined application claim is not patentably distinct from the reference claim(s) because the examined application claim is either anticipated by, or would have been obvious over, the reference claim(s). See, e.g., In re Berg, 140 F.3d 1428, 46 USPQ2d 1226 (Fed. Cir. 1998); In re Goodman, 11 F.3d 1046, 29 USPQ2d 2010 (Fed. Cir. 1993); In re Longi, 759 F.2d 887, 225 USPQ 645 (Fed. Cir. 1985); In re Van Ornum, 686 F.2d 937, 214 USPQ 761 (CCPA 1982); In re Vogel, 422 F.2d 438, 164 USPQ 619 (CCPA 1970); and In re Thorington, 418 F.2d 528, 163 USPQ 644 (CCPA 1969).
A timely filed terminal disclaimer in compliance with 37 CFR 1.321(c) or 1.321(d) may be used to overcome an actual or provisional rejection based on a nonstatutory double patenting ground provided the reference application or patent either is shown to be commonly owned with this application, or claims an invention made as a result of activities undertaken within the scope of a joint research agreement. A terminal disclaimer must be signed in compliance with 37 CFR 1.321(b).
The USPTO internet Web site contains terminal disclaimer forms which may be used. Please visit http://www.uspto.gov/forms/. The filing date of the application will determine what form should be used. A web-based eTerminal Disclaimer may be filled out completely online using web-screens. An eTerminal Disclaimer that meets all requirements is auto-processed and approved immediately upon submission. For more information about eTerminal Disclaimers, refer to http://www.uspto.gov/patents/process/file/efs/guidance/eTD-info-I.jsp.
Claims 49-58 and 60 are rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1, 11, 13, 14 and 17 of U.S. Patent No. 12,552,866 (previously 17/436,629). Although the claims at issue are not identical, they are not patentably distinct from each other because the patent and claims teach the claimed conjugates, see Summary in particular. In particular the issued claims are generic with respect to the therapeutic moiety wherein the therapeutic moiety is conjugated to same binding molecule whereas instant claims limited the therapeutic moiety to Rho-kinase inhibitor, a JAK-2 inhibitor, a neprilysin inhibitor or a angiotensin II receptor antagonist (specie).
Issued claim 1 recites a multiparatopic antibody comprising at least two single variable antibody domains, independently from one another, able to specifically bind to platelet-derived growth factor receptor beta (PDGFRB),
wherein: the first single variable antibody domain comprises a CDR 1 sequence according SEQ ID NO: 11, a CDR 2 sequence according to SEQ ID NO: 13 and a CDR 3 sequence according to SEQ ID NO: 15; and
wherein the second single variable antibody domain comprises: a CDR 1 sequence according SEQ ID NO: 67, a CDR 2 sequence according to SEQ ID NO: 69 and a CDR 3 sequence according to SEQ ID NO: 71, or
a CDR 1 sequence according SEQ ID NO: 83, a CDR 2 sequence according to SEQ ID NO: 85 and a CDR 3 sequence according to SEQ ID NO: 87, or
a CDR 1 sequence according SEQ ID NO: 155, a CDR 2 sequence according to SEQ ID NO: 157 and a CDR 3 sequence according to SEQ ID NO: 159, which corresponds to part of instant claim 49
2. The antibody according to claim 1, wherein the second single variable antibody domain comprises a CDR 1 sequence according SEQ ID NO: 155, a CDR 2 sequence according to SEQ ID NO: 157 and the CDR 3 sequence according to SEQ ID NO: 159, which corresponds to instant claim 50.
3. The antibody according to claim 1, wherein the at least two single variable antibody domains are of VHH-type.
4. The antibody according to claim 1, wherein the at least two single variable antibody domains are humanized or camelized.
5. The antibody, according to claim 1, wherein the first single variable antibody domain comprises or consists of SEQ ID NO: 9 (SP02P), and wherein the second single variable antibody domain comprises or consists of any one of SEQ ID NOs: SEQ ID NO: 65 (SP12P), SEQ ID NO: 81 (SP14P) and SEQ ID NO: 153 (SP26P), which corresponds to instant claim 51.
6. The antibody according to claim 1, wherein the first single variable antibody domain comprises or consists of SEQ ID NO: 9 (SP02P) and wherein the second single variable antibody domain comprises or consists of SEQ ID NO: 153 (SP26P), which corresponds to instant claim 51.
7. The antibody according to claim 1, wherein the antibody is a biparatopic antibody, which corresponds to instant claim 55.
8. The antibody according to claim 1, further comprising a half-life extender, which corresponds to instant claim 58.
9. The antibody according to claim 1, wherein the at least two single variable antibody domains are separated by a linker amino acid sequence, which corresponds to instant claim 5 6.
10. The antibody according to claim 1, further comprising an N-terminal or a C-terminal cysteine or histidine residue, which corresponds to instant claim 57.
11. A multiparatopic binding molecule comprising the antibody according to claim 1 and further comprising at least one diagnostic or therapeutic molecule (genus), which corresponds to instant claim 1.
12. The binding molecule according to claim 9, wherein the therapeutic or diagnostic molecule are bound to at least one single variable antibody domain of the antibody by a linker and/or spacer.
13. The binding molecule according to claim 9, wherein the therapeutic molecule is a kinase inhibitor (subgenus), which corresponds to instant claim 1 (species).
14. The binding molecule according to claim 9, wherein the therapeutic molecule is a toxin.
17. The binding molecule according to claim 9, comprising a diagnostic molecule, wherein the diagnostic molecule is an imaging agent, which corresponds to instant claim 1.
Applicant requests that the rejection be held in abeyance until indication by the Office of allowable claims in one of the co-pending applications.
As such, the rejection is maintained.
Rejections necessitated by the amendment filed February 23, 2026
Claim rejections under - 35 U.S.C. 112
The following is a quotation 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 35 U.S.C. 112 (pre-AIA ), first paragraph:
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 49-58, 60 and 65-71 are rejected under 35 U.S.C. 112(a) or 35 U.S.C. 112 (pre-AIA ), first paragraph, as failing to comply with the written description requirement. The claim(s) contains subject matter which was not described in the specification in such a way as to reasonably convey to one skilled in the relevant art that the inventor or a joint inventor, or for pre-AIA the inventor(s), at the time the application was filed, had possession of the claimed invention.
MPEP § 2163 lists factors that can be used to determine if sufficient evidence of possession has been furnished in the disclosure of the Application. These include: (1) Actual reduction to practice, (2) Disclosure of drawings or structural chemical formulas, (3) Sufficient relevant identifying characteristics (such as: i. Complete structure, ii. Partial structure, iii. Physical and/or chemical properties, iv. Functional characteristics when coupled with a known or disclosed, and correlation between function and structure), (4) Method of making the claimed invention, (5) Level of skill and knowledge in the art, and (6) Predictability in the art. “Disclosure of any combination of such identifying characteristics that distinguish the claimed invention from other materials and would lead one of skill in the art to the conclusion that the applicant was in possession of the claimed species is sufficient.” MPEP § 2163.
MPEP § 2163 states that the written description requirement for a claimed genus may be satisfied through sufficient description of a representative number of species by actual reduction to practice, or by disclosure of relevant, identifying characteristics, i.e., structure or other physical and/or chemical properties, by functional characteristics coupled with a known or disclosed correlation between function and structure, or by a combination of such identifying characteristics, sufficient to show the applicant was in possession of the claimed genus.
Claim 49 encompasses a binding molecule comprising at least one diagnostic or therapeutic moiety, and at least two single variable domains of a heavy-chain-only antibody (VHH), each one able to specifically bind to a platelet-derived growth factor receptor beta (PDGFRB) that is expressed on a fibrogenic effector cell identifiable by the expression of alpha smooth muscle actin and/or stress fibers discernable by immune fluorescence microscopy,
wherein a first one of the at least two single variable domains comprises a CDR 1 sequence according SEQ ID NO: 11, a CDR 2 sequence according to SEQ ID NO: 13 and a CDR 3 sequence according to SEQ ID NO: 15; and
wherein a second one of the at least two single variable domains comprises:
A. a CDR 1 sequence according SEQ ID NO: 67, a CDR 2 sequence according to SEQ ID NO: 69 and a CDR 3 sequence according to SEQ ID NO: 71, or
B. a CDR 1 sequence according SEQ ID NO: 83, a CDR 2 sequence according to SEQ ID NO: 85 and a CDR 3 sequence according to SEQ ID NO: 87, or
C. a CDR 1 sequence according SEQ ID NO: 155, a CDR 2 sequence according to SEQ ID NO: 157 and a CDR 3 sequence according to SEQ ID NO: 159; or
wherein a first one of the at least two single variable domains comprises at least one single variable antibody domain comprising a CDR 1 sequence according to SEQ ID NO: 67, a CDR 2 sequence according to SEQ ID NO: 69 and a CDR 3 sequence according to SEQ ID NO: 71; and
wherein a second one of the at least two single variable domains comprises a CDR 1 sequence according SEQ ID NO: 83, a CDR 2 sequence according to SEQ ID NO: 85 and a CDR 3 sequence according to SEQ ID NO: 87;
wherein the first one and/or the second one of the at least two single variable domains comprises at most 4 amino acids that have been conservatively substituted per any one of the CDR sequences, independently,
wherein the diagnostic or therapeutic moiety is conjugated to the remainder of the binding molecule comprising at least two single variable domains of a heavy-chain-only antibody (VHH),
wherein the diagnostic moiety is an imaging agent, and/or wherein the therapeutic moiety is any Rho-kinase inhibitor, any JAK-2 inhibitor, any neprilysin inhibitor, or any Angiotensin II Receptor antagonist.
Claim 50 encompasses the binding molecule according to claim 49, wherein the first one of the at least two single variable domains comprises a CDR 1 sequence according SEQ ID NO: 11, a CDR 2 sequence according to SEQ ID NO: 13 and a CDR 3 sequence according to SEQ ID NO: 15;and wherein the second one of the at least two single variable domains comprises a CDR 1 sequence according SEQ ID NO: 155, a CDR 2 sequence according to SEQ ID NO:157 and a CDR 3 sequence according to SEQ ID NO: 159,wherein any one of the first one and/or of the second one of the at least two single variable domains comprises at most 4 amino acids that have been conservatively substituted per any one of the CDR sequences, independently.
Claim 51 encompasses the binding molecule according to claim 50, wherein the first one of the at least two single variable domains comprises or consists of a VHH sequence according to SEQ ID NOs: 9 (SPO2P), and wherein the second one of the at least two single variable domains comprises or consists of a VHH sequence according to any one of SEQ ID NOs: 153 (SP26P).
Claim 52 encompasses the binding molecule according to claim 49, wherein any one of the first one and/or of the second one of the at least two single variable domains comprises at most 3 amino acids that have been conservatively substituted per any one of the CDR sequences, independently.
Claim 53 encompasses the binding molecule according to claim 49, wherein any one of the first one and/or of the second one of the at least two single variable domains comprises at most 2 amino acids that have been conservatively substituted per any one of the CDR sequences, independently.
Claim 54 encompasses the binding molecule according to claim 49, wherein any one of the first one and/or of the second one of the at least two single variable domains comprises at most 1 amino acids that has been conservatively substituted per any one of the CDR sequences, independently.
Claim 55 encompasses the binding molecule according to claim 49, wherein the binding molecule is biparatopic.
Claim 56 encompasses the binding molecule according to claim 49, wherein the at least two single variable domains are separated by a linker amino acid sequence.
Claim 57 encompasses the binding molecule according to claim 49, wherein the binding molecule comprises an N-terminal or a C-terminal cysteine residue.
Claim 58 encompasses the binding molecule according to claim 491, wherein the binding molecule comprises a half-life extender that provide the binding molecule with increased half-life compared to a binding molecule without a half-life extender.
Claim 60 encompasses the binding molecule according to claim 49, wherein the therapeutic molecule moiety is able to inhibit any one or more of contractile activity, fibrogenic activity, chemotactic activity and pro-inflammatory activity of the fibrogenic effector cell.
Claim 65 encompasses a method of preventing and/or treating a disease or disorder associated with or characterized by the upregulation of PDGFRB expression, said method comprising the administration of a binding molecule comprising at least one diagnostic or therapeutic moiety, and at least two single variable domains of a heavy-chain-only antibody (VHH), each one able to specifically bind to a platelet-derived growth factor receptor beta (PDGFRB) that is expressed on a fibrogenic effector cell identifiable by the expression of alpha smooth muscle actin and/or stress fibers discernable by immune fluorescence microscopy,
wherein a first one of the at least two single variable domains comprises a CDR 1 sequence according SEQ ID NO: 11, a CDR 2 sequence according to SEQ ID NO: 13 and a CDR 3 sequence according to SEQ ID NO: 15; and
wherein a second one of the at least two single variable domains comprises:
A. a CDR 1 sequence according SEQ ID NO: 67, a CDR 2 sequence according to SEQ ID NO: 69 and a CDR 3 sequence according to SEQ ID NO: 71, or
B. a CDR 1 sequence according SEQ ID NO: 83, a CDR 2 sequence according to SEQ ID NO: 85 and a CDR 3 sequence according to SEQ ID NO: 87, or
C. a CDR 1 sequence according SEQ ID NO: 155, a CDR 2 sequence according to SEQ ID NO: 157 and a CDR 3 sequence according to SEQ ID NO: 159; or
wherein a first one of the at least two single variable domains comprises at least one single variable antibody domain comprising a CDR 1 sequence according to SEQ ID NO: 67, a CDR 2 sequence according to SEQ ID NO: 69 and a CDR 3 sequence according to SEQ ID NO: 71; and
wherein a second one of the at least two single variable domains comprises a CDR 1 sequence according SEQ ID NO: 83, a CDR 2 sequence according to SEQ ID NO: 85 and a CDR 3 sequence according to SEQ ID NO: 87;
wherein the first one and/or the second one of the at least two single variable domains comprises at most 4 amino acids that have been conservatively substituted per any one of the CDR sequences, independently,
wherein the diagnostic or therapeutic moiety is conjugated to the remainder of the binding molecule comprising at least two single variable domains of a heavy-chain-only antibody (VHH),
wherein the diagnostic moiety is an imaging agent, and/or wherein the therapeutic moiety is any Rho-kinase inhibitor, any JAK-2 inhibitor, any neprilysin inhibitor, or any Angiotensin II Receptor antagonist.
Claim 66 encompasses the method of preventing and/or treating according to claim 65, wherein the disease or disorder associated with or characterized by the upregulation of PDGFRB expression is any one or more of: liver fibrosis, cirrhosis, lung fibrosis, renal fibrosis, systemic sclerosis/scleroderma, inflammatory bowel disease and a cancer relating to a (sclerosing) malignant tumor.
Claim 67 encompasses the method of preventing and/or treating according to claim 66, wherein preventing and/or treating is preventing and/or treating a (secondary) clinical manifestation that is attributable to liver fibrosis, cirrhosis, lung fibrosis, renal fibrosis, systemic sclerosis/scleroderma, inflammatory bowel disease or a cancer relating to a (sclerosing) malignant tumor.
Claim 68 encompasses the method of preventing and/or treating according to claim 67, wherein the (secondary) clinical manifestation is portal hypertension in liver fibrosis and/or in cirrhosis, or pulmonary hypertension in pulmonary fibrosis.
Claim 69 encompasses the method of preventing and/or treating according to claim 67, wherein the prevention and/or the treatment of a (secondary) clinical manifestation is the prevention and/or treatment of an acute complication of the (secondary) clinical manifestation.
Claim 70 encompasses the method of preventing and/or treating according to claim 69, wherein the acute complication of the (secondary) clinical manifestation is any one or more of: esophageal bleeding in portal hypertension and/or cardiovascular failure, and/or pulmonary failure in pulmonary hypertension.
Claim 71 encompasses the method of preventing and/or treating a disease or disorder associated with or characterized by the upregulation of PDGFRB expression of claim 65, wherein the preventing and/or treating is preventing and/or treating any breast cancer, lung cancer, colon cancer or prostate cancer.
Applicant is not in possession of a method of preventing any disease or disorder associated with or characterized by the upregulation of PDGFRB expression (claims 65-71), such as liver fibrosis, cirrhosis, lung fibrosis, renal fibrosis, systemic sclerosis/scleroderma, inflammatory bowel disease and any cancer relating to a (sclerosing) malignant tumor, any secondary clinical manifestation that is attributable to liver fibrosis, cirrhosis, lung fibrosis, renal fibrosis, systemic sclerosis/scleroderma, inflammatory bowel disease or a cancer relating to a (sclerosing) malignant tumor, pulmonary hypertension in pulmonary fibrosis, oesophageal bleeding in portal hypertension and/or cardiovascular failure, and/or pulmonary failure in pulmonary hypertension, any breast cancer, lung cancer, colon cancer or prostate cancer by administrating any diagnostic wherein the diagnostic agent is any imaging agent or any therapeutic moiety such as any Rho-kinase inhibitor, any JAK-2 inhibitor, any neprilysin inhibitor or any angiotensin II receptor antagonist, wherein the at least one diagnostic or therapeutic moiety is conjugated to at least two single variable domains of a heavy-chain-only antibody (VHH), each one able to specifically bind to a platelet-derived growth factor receptor beta (PDGFRB) that is expressed on a fibrogenic effector cell identifiable by the expression of alpha smooth muscle actin and/or stress fibers discernable by immune fluorescence microscopy,
wherein a first one of the at least two single variable domains comprises a CDR 1 sequence according SEQ ID NO: 11, a CDR 2 sequence according to SEQ ID NO: 13 and a CDR 3 sequence according to SEQ ID NO: 15; and
wherein a second one of the at least two single variable domains comprises:
A. a CDR 1 sequence according SEQ ID NO: 67, a CDR 2 sequence according to SEQ ID NO: 69 and a CDR 3 sequence according to SEQ ID NO: 71, or
B. a CDR 1 sequence according SEQ ID NO: 83, a CDR 2 sequence according to SEQ ID NO: 85 and a CDR 3 sequence according to SEQ ID NO: 87, or
C. a CDR 1 sequence according SEQ ID NO: 155, a CDR 2 sequence according to SEQ ID NO: 157 and a CDR 3 sequence according to SEQ ID NO: 159; or
wherein a first one of the at least two single variable domains comprises at least one single variable antibody domain comprising a CDR 1 sequence according to SEQ ID NO: 67, a CDR 2 sequence according to SEQ ID NO: 69 and a CDR 3 sequence according to SEQ ID NO: 71; and
wherein a second one of the at least two single variable domains comprises a CDR 1 sequence according SEQ ID NO: 83, a CDR 2 sequence according to SEQ ID NO: 85 and a CDR 3 sequence according to SEQ ID NO: 87;
wherein the first one and/or the second one of the at least two single variable domains comprises at most 4 amino acids that have been conservatively substituted per any one of the CDR sequences, independently,
wherein the diagnostic or therapeutic moiety is conjugated to the remainder of the binding molecule comprising at least two single variable domains of a heavy-chain-only antibody (VHH),
wherein the diagnostic moiety is an imaging agent, and/or wherein the therapeutic moiety is any Rho-kinase inhibitor, any JAK-2 inhibitor, any neprilysin inhibitor, or any Angiotensin II Receptor antagonist.
The specification discloses:
[0309] The 18 unique hPDGFRB binders from libraries 1 and 2, and the 11 unique rPDGFRB binders from libraries 3 and 4 (Example 2.2, FIGS. 5 and 6) were produced and purified as described in examples 3 and 4. Then, the apparent affinities were determined with binding assays on hPDGFRB-ECD and rPDGFRB-ECD, respectively, the setup described in example 5.1 Results are summarized in FIGS. 5 and 6 for the hPDGFRB and rPDGFRB VHHs, respectively.
[0310] High affine binders to hPDGFRB-ECD or rPDGFRB-ECD were subsequently assessed for binding to SCC VII cells transfected with hPDGFRB and rPDGFRB, respectively. As shown in FIG. 9, the VHHs obtained from libraries 1 and 2 displayed affinity to SCC-hPDGFRB cells, and VHHs obtained from libraries 3 and 4 displayed good binding to SCC-rPDGFRB cells.
Example 6: Determination of VHHs Binding to Non-Overlapping Receptor Epitopes to Allow Construction of Biparatopic VHH Constructs
[0312] Similar as to in example 6.1, competition assays were performed to identify unique hPDGFRB- or rPDGFRB binders. Across 10 PDGFRB-binding VHHs obtained from libraries 1 and 2 (e.g. the VHH raised against hPDGFRB), four main groups were identified being first SP01P, SP02P, SP07P and SP13P, second SP05P, SP08P and SP10P, third SP12P and SP20P and finally SP14P. All VHH within each of the first three groups mutually competed. Across the three groups, and the lone VHH SP14P, no competition was observed demonstrating that VHH had been raised against at least four different epitopes of the hPDGFRB: those of SP02P, SP05P, SP12P, and SP14P (FIG. 5 rightmost column, exemplary binding curves using SP02P as the reporter VHH are shown in FIG. 11A). Similarly, across the VHH obtained from libraries 3 and 4 (e.g. the VHH raised against rPDGFRB), SP26P showed to have a unique epitope compared to SP27P, SP28P, SP30P, SP31P and SP36P (FIG. 6).
Example 7: Construction and Characterization of Biparatopic VHHs
[0314] The design of biparatopic constructs was led by the following critical traits: First, the constructs must be based on VHH with non-overlapping epitopes (the biparatopic design). Second, the constructs must bind with similar affinity to human- and rodent ligands as this would result in constructs suitable for preclinical as well as clinical pharmaceutical development. Finally, the constructs must display a meaningful in vivo plasma half-life in order to ensure meaningful in vivo exposure.
7.2 PDGFRB
[0319] Based on their high affinity and binding to non-overlapping hPDGFRB epitopes, various biparatopic constructs were prepared based on VHHs SP02P, SP12P SP14P, SP26P and SP28P. The constructs were produced as described in example 7.1. and subjected to binding assay. All constructs based on VHH that had been raised against hPDGFRB (SP02P, SP12P SP14P) showed high affinity for hPDGFRB. The construct SP26P-SP28P, based on VHH raised against rPDGFRB, displayed the lowest affinity for hPDGFRB (FIG. 15A). Contrary, SP26P-SP28P displayed high affinity for rPDGFRB and low affinity for hPDGFRB (FIG. 15B).
[0320] In an effort to pursue a species cross-reactive construct, the VHHs SP02P and SP26P were combined in a biparatopic construct, as these were shown to bind different epitopes (FIG. 11B; SP02P does not compete with binding of fluorescently labelled SP26P to cells expressing PDGFRB). As Shown in FIG. 15C), the binding affinity of this construct for both hPDGFRB and rPDGFRB are below 5 nM. Furthermore, whereas binding of the monomeric VHHs SP02P and SP26P varied across murine PDGFRB ectodomain (mPDGFRB-ECD), rPDGFRB-ECD and hPDGFRB-ECD, the biparatopic construct SP02P-SP26P displayed high affinity regardless of the species. These observations make SP02P (or similar VHH) and SP26P (or similar VHH) particularly promising for use in the present invention. FIG. 15D displays binding of IRDye800-conjugated SP02P-SP26P, and corresponding monomeric VHHs SP02P and SP26P, to murine PDGFRB ECD (left panel), rat PDGFRB ECD (middle panel), or human PDGFRB ECD (right panel).
Example 8: Improving In Vivo Pharmacokinetics in Rats of 13F11-13E8 Through Addition of an Albumin Binding Domain
[0321] The in vivo pharmacokinetic properties of 13F11-13E8-ABD (F11E8-ABD; with ABD) and 13F11-13E8 (F11E8; without ABD) were compared in healthy Sprague-Dawley rats. In brief, rats were dosed intravenously with approximately 3 mg/kg body weight and blood samples were taken at different time points and the concentration of the VHH constructs were determined using an ELISA on immobilized hIGF2R-ECD. The peak serum level (C.sub.max) of 13F11-13E8-ABD exceeded 1000 nM as shown in FIG. 13C. With approximately 20 nmoles infused into the animal, and an estimated serum volume of 10 mL, this C.sub.max would correspond to approximately 50% of the infused dose still being in circulation one hour after dosing demonstrating good bioavailability. On the other hand, 13F11-13E8 was rapidly cleared from circulation and could not be detected anymore within two hours after injection (FIG. 13C). To further confirm the functionality of the ABD, biodistribution of F11E8-ABD and F11E8 were assessed by means of Positron Emission Tomography (PET). In brief, the constructs were radio-labelled with the positron emitter .sup.89Zr-desferral according to Verel et al (J Nucl Med. 2003; 44:1271-1281), and administered intravenously to rats after which biodistribution was assessed on subsequent time points by whole-body PET. As evident from FIG. 13D, F11E8 swiftly accumulated in the kidneys (upper panels, arrows) illustrating renal excretion. In contrast, the extended serum half-life of F11E8-ABD allowed it to accumulate in the liver (lower panels, arrow).
Example 9: Synthesis and Analytical Characterization of Lx Semi-Final Complexes and Maleimide Functionalized Moieties with Small Molecule Kinase Inhibitors: Y27632, Pacritinib, Sacubitril (at), Losartan
9.1. Structures of Y27632-Lx (Semi-Final Moieties) SFMs and Y27632 Maleimide Functionalized Moieties that can be Utilized in the Context of the Present Invention.
9.1.3. Synthesis and Analytical Characterization of Mal-PEG.SUB.4.-Val-Cit-PAB-Y27632 (1e)
9.1.4. Synthesis and Analytical Characterization of Mal-Val-Cit-PAB-Y27632 (1f)
10.2. Conjugation of a Maleimide Functionalized Moieties to a Binding Molecule
11.2. PDGFRB VHH
To determine the rate of internalization of the VHH construct SP02P-SP26P, kinetic internalization assays on hPDGFRB expressing SCC cells and LX-2 cells were performed using a similar method as described for the IGF2R constructs in example 11.1. Internalization of SP02P-SP26P was observed in SCC-hPDGFRB cells (left panel of FIG. 19) as well as in LX-2 cells (right panel of FIG. 19).
[0369] To confirm improved internalization of biparatopic VHH constructs compared to the monomeric individual VHH components, kinetic internalization assays were performed using SCC-rPGDFRB and on SCC-hPDGFRB cells, using a similar method as described for the IGF2R constructs in example 11.1. The biparatopic construct SP02P-SP26P internalized 5-10 fold faster when compared to the corresponding monomeric VHH SP02 and SP26 (FIG. 20; left panel for cells expressing rat PDGFRB, right panel for cells expressing human PDGFRB).
Example 14: Detection of PDGFRB in the Cirrhotic Rat Liver
To evaluate whether SP02-SP26-ABD bound to PDGFRB as (over-) expressed in the cirrhotic liver, various cryo-sections of tissues (liver, kidney, spleen, heart, ileum, brain) obtained from both healthy (SHAM) and cirrhotic (BDL) rats (preparation procedure as outlined in example 15) were stained with SP02-SP26-ABD conjugated to Alexa Fluor 647 (SP02-SP26-ABD-A647, conjugation method as described in example 10.2.). Staining was performed with 50 nM SP02-SP26-ABD-AF647 during overnight incubation at 4° C. Subsequently, the sections were washed and stained with DAPI, mounted with mowiol mounting medium (Merck), and imaged on a Zeiss LSM700 laser scanning confocal microscope with a 20× objective. SP02-SP26-ABD-AF647 strongly stains activated fibroblasts in the cirrhotic liver whereas in the normal liver only background signal was detected (FIG. 23). In the tissues other than the liver, no upregulation of PDGFRB was observed. These observations demonstrate binding of the VHH construct to rPDGFRB in its biological context, and confirm selective over-expression of PDGFRB by activated fibroblasts, in line with what is reported elsewhere (see example 1).
Regarding the therapeutic moiety is a Rho-kinase inhibitor, a JAK-2 inhibitor, a neprilysin inhibitor or a angiotensin II receptor antagonist (claims 49, 65 and dependent claims thereof), the specification does not describe any and all possible Rho-kinase inhibitor, a JAK-2 inhibitor, a neprilysin inhibitor or a angiotensin II receptor antagonists. The specification does not describe the chemical structure-identifying information about all possible Rho-kinase inhibitors, JAK-2 inhibitors, neprilysin inhibitors or angiotensin II receptor antagonists. The specification does not describe a representative number of species falling within the scope of the genus or structural common to the members of the genus so the one of skill in the art can visualize or recognize the member of the genus of the actual claimed Rho-kinase inhibitor, a JAK-2 inhibitor, a neprilysin inhibitor or a angiotensin II receptor antagonists conjugated to the claimed binding molecule.
Clayton (Front. Cell and Dev. Biol 8(222): 1-12, 2020; PTO 892) teaches although significant effort has been made to develop ROCK (Rho-kinase) inhibitors for cancer intervention, the vast majority of compounds have not progressed to clinical trials. The ATP competitive ROCK inhibitorsY-27632 and fasudil have been used extensively as tool compounds and have been shown to inhibit cancer cell migration in various in vitro cancer models (Wei et al., 2016). Todate, only one ROCK inhibitor has progressed into clinical trials for cancer treatment. AT13148 is an orally available multi-AGC kinase inhibitor that was identified through a fragment-based screen and was found to potently inhibit ROCK1 and ROCK2 (Yap et al., 2012). AT13148 was shown to have anti-tumor effects in pre-clinical models of pancreatic (Rath et al., 2018), breast, prostate and uterine cancer (Yap et al., 2012) and was well tolerated in a phase I clinical trial in patients with advanced solid tumors (NCT01585701) (Kumar et al., 2014), see p. 7-8, in particular. Clayton concludes that the role of Rho GTPases as key regulators of cell migration and invasion has been recognized for decades, yet few compounds targeting Rho GTPase signaling networks have been developed beyond an early preclinical stage. Due to the challenges of inhibiting Rho GTPase activation directly, targeting Rho GTPase effectors remains the most promising approach. Whilst PAK and ROCK inhibitors have progressed to phase I clinical trials, further work is needed to elucidate the context-dependent roles of Rho GTPase effectors and to identify compensatory feedback networks which may limit the success of these targeted therapies. Genome sequencing of human tumors has identified several mutations in Rho GTPases, yet the functional and clinical significance of many of these mutants remain poorly understood, see p. 9, in particular.
One of skilled in the art cannot predict which inhibitor of Rho-kinase, JAK-2, or neprilysin, or angiotensin II antagonist conjugated to the claimed binding molecule is effective for preventing or treating which disease associated with or characterized by the upregulation of PDGFRB expression such as such as liver fibrosis, cirrhosis, lung fibrosis, renal fibrosis, systemic sclerosis/scleroderma, inflammatory bowel disease and any cancer relating to a (sclerosing) malignant tumor, any secondary clinical manifestation that is attributable to liver fibrosis, cirrhosis, lung fibrosis, renal fibrosis, systemicsclerosis/scleroderma, inflammatory bowel disease or a cancer relating to a (sclerosing) malignant tumor, pulmonary hypertension in pulmonary fibrosis, oesophageal bleeding in portal hypertension and/or cardiovascular failure, and/or pulmonary failure in pulmonary hypertension, any breast cancer, lung cancer, colon cancer or prostate cancer.
When a patent claims a genus using functional language to define a desired result, “the specification must demonstrate that the applicant has made a generic invention that achieves the claimed result and do so by showing that the applicant has invented species sufficient to support a claim to the functionally-defined genus.” AbbVie Deutschland GmbH & Co., KG v. Janssen Biotech, Inc., 759 F.3d 1285, 1299 (Fed. Cir. 2014) (quoting Ariad, 598 F.3d at 1349).
Regarding preventing any disease or disorder associated with or characterized by the upregulation of PEGFRB (claims 65-71), there is no objective evidence of the claimed method could prevent any and all disease or disorder associated with or characterized by the upregulation of PGGFRB expression by administration of any of the claimed conjugate. It is unpredictable which disease above can be prevented with the claimed conjugates wherein the disease or disorder associated with or characterized by the upregulation of PDGFRB expression.
For example, Gura et al (Science, 278:1041-1042, 1997; PTO 892) who discusses the potential shortcomings of potential anti-cancer agents including extrapolating from in-vitro to in-vivo protocols, the problems of drug testing in knockout mice, and problems associated with clonogenic assays. Indeed, since formal screening began in 1955, thousands of drugs have shown activity in either cell or animal models, but only 39 that are used exclusively for chemotherapy, as opposed to supportive care, have won approval from the FDA (page 1041, 1st column) wherein the fundamental problem in drug discovery for cancer is that the model systems are not predictive.
Even assuming the method is treating any disease or disorder associated with or characterized by the upregulation of PDGFRB expression (claims 65-71), there are no in vivo working examples. A method of preventing and/or treating disease in the absence of in vivo working examples is unpredictable.
For example, Strop et al (of record, Chemistry and Biology 20: 161-167, 2013; PTO 892) teach drug position can have a significant effect on linker stability and antibody pharmacokinetics. The site of conjugation on the drug and antibody can influence ADC properties differently in mice and rats, highlighting potential pitfalls of examining efficacy in mouse xenograft models and toxicity in rats or nonhuman primates, see abstract, p 166, p. 168 right col, in particular.
Nejadmoghaddam (of record, Avicenna Journal of Medical Biotechnology 2(1): 3-23, 2019; PTO 892) discusses major obstacles of antibody-drug conjugates include off-target toxicity, tumor marker selection, antibody specificity, adequately affinity and receptor-mediated internalization are major aspects of choice, cytotoxic payload (e.g., up to 7 drugs per antibody), cytotoxic payload linkage strategy, aqueous solubility, non-immunogenic and stability in storage and bloodstream, see entire document, abstract, p. 15, in particular.
As such, one of ordinary skill in the art would reasonably conclude that Applicant was not in possession of the genus of conjugates set forth in claims 49-58 and 60 for preventing and/or treating any disease or disorder associated with or characterized by the upregulation of PEGFRB as set forth in claims 65-71 at the time of filing.
Vas-Cath Inc. v. Mahurkar, 19 USPQ2d 1111, makes clear that “applicant must convey with reasonable clarity to those skilled in the art that, as of the filing date sought, he or she was in possession of the invention. The invention is, for purposes of the written description inquiry, whatever is now claimed.” (See page 1117.) The specification does not “clearly allow persons of ordinary skill in the art to recognize that [he or she] invented what is claimed.” (See Vas-Cath at page 1116.).
Adequate written description requires more than a mere statement that it is part of the invention and reference to a potential method for isolating it. See Fiers v. Revel, 25 USPQ2d 1601, 1606 (CAFC 1993) and Amgen Inc. v. Chugai Pharmaceutical Co. Ltd., 18 USPQ2d 1016.
One cannot describe what one has not conceived. See Fiddles v. Baird, 30 USPQ2d 1481, 1483. In Fiddles v. Baird, claims directed to mammalian FGF’s were found unpatentable due to lack of written description for the broad class. The specification provided only the bovine sequence. Thus, the specification fails to describe these DNA sequences.
For genus claims, an adequate written description of a claimed genus requires more than a generic statement of an invention's boundaries. A patent must set forth either a representative number of species falling within the scope of the genus or structural features common to the members of the genus. Kubin, Exparte, 83 USPQ2d 1410 (Bd. Pat. App. & Int. 2007); Ariad Pharms., Inc. v. Eli Lilly& Co., 598 F.3d 1336, 1350 (Fed. Cir. 2010).
Therefore, only a conjugated binding molecule comprising a first and a second heavy-chain-only antibody (VHH), each VHH specifically binds to a human platelet-derived growth factor receptor beta (PDGFRb) that is expressed on a fibrogenic effector cell identifiable by the expression of alpha smooth muscle actin and/or stress fibers discernable by immune fluorescence microscopy, wherein the binding molecule is conjugated to a diagnostic agent or a therapeutic agent, wherein the first VHH comprising
a CDR 1 sequence according SEQ ID NO: 11, a CDR 2 sequence according to SEQ ID NO: 13 and a CDR 3 sequence according to SEQ ID NO: 15;and wherein the second VHH comprising a CDR 1 sequence according SEQ ID NO: 67, a CDR 2 sequence according to SEQ ID NO: 69 and a CDR 3 sequence according to SEQ ID NO: 71, or a CDR 1 sequence according SEQ ID NO: 83, a CDR 2 sequence according to SEQ ID NO: 85 and a CDR 3 sequence according to SEQ ID NO: 87, or a CDR 1 sequence according SEQ ID NO: 155, a CDR 2 sequence according to SEQ ID NO: 157 and a CDR 3 sequence according to SEQ ID NO: 159; or wherein the first VHH comprising a CDR 1 sequence according to SEQ ID NO: 67, a CDR 2 sequence according to SEQ ID NO: 69 and a CDR 3 sequence according to SEQ ID NO: 71; and wherein the second VHH comprises a CDR 1 sequence according SEQ ID NO: 83, a CDR 2 sequence according to SEQ ID NO: 85 and a CDR 3 sequence according to SEQ ID NO: 87; wherein the first and the second VHH comprises at most 4 amino acids that have been conservatively substituted per any one of the CDR sequences, independently, and wherein the therapeutic agent is Y27632, pacritinib, sacubitril, or losartan for a method of treating fibrosis associated with the upregulation of PDGFRB expression, and wherein the diagnostic agent is Alexa fluor 647 for a method of detecting disease or disorder associated with or characterized by the upregulation of PDGFRB expression, but not the full breadth of the claims meets the written description provision of 35 U.S.C. § 112, first paragraph. Applicant is reminded that Vas-Cath makes clear that the written description provision of 35 U.S.C. § 112 is severable from its enablement provision (see page 1115).
Applicants’ arguments filed February 23, 2026 have been fully considered but are not found persuasive.
Applicants’ position is claim 49 has been amended. Applicant submits that the Examiner's interpretation requiring only the specific
compounds Y27632, pacritinib, sacubitril, losartan, and Alexa Fluor 647 is unduly narrow. The specification explicitly describes these categories or genera of therapeutic and diagnostic moieties, demonstrating that the inventors possessed the claimed invention at the genus level. The specific compounds cited by the Examiner are merely exemplary species within the broader genera that are explicitly disclosed and claimed. The amendments to claim 49 now recite the diagnostic moiety as "an imaging agent" and the therapeutic moiety as one "selected from a Rho- kinase inhibitor, a JAK-2 inhibitor, a neprilysin inhibitor, or an Angiotensin II receptor antagonist," which directly corresponds to the explicit disclosure in the specification.
Accordingly, the amendments bring the claims into conformance with the written description requirement, and Applicant respectfully requests withdrawal of the rejection of claims 49-64 under 35 U.S.C. § 112(a).
In response, the amendment to claim 49 is acknowledged.
In response to the argument that the specification explicitly describes the therapeutic moiety is "selected from a Rho-kinase inhibitor, a JAK-2 inhibitor, a neprilysin inhibitor, or an Angiotensin II receptor antagonist", the specification does not describe any and all possible Rho-kinase inhibitors, JAK-2 inhibitors, neprilysin inhibitors or a angiotensin II receptor antagonists. The specification does not describe the chemical structure-identifying information about all possible Rho-kinase inhibitors, JAK-2 inhibitors, neprilysin inhibitors or a angiotensin II receptor antagonists. The specification does not describe a representative number of species falling within the scope of the genus or structural common to the members of the genus so the one of skill in the art can visualize or recognize the member of the genus of the actual claimed Rho-kinase inhibitor, a JAK-2 inhibitor, a neprilysin inhibitor or a angiotensin II receptor antagonists conjugated to the claimed binding molecule.
Clayton (Front. Cell and Dev. Biol 8(222): 1-12, 2020; PTO 892) teaches although significant effort has been made to develop ROCK (Rho-kinase) inhibitors for cancer intervention, the vast majority of compounds have not progressed to clinical trials. The ATP competitive ROCK inhibitorsY-27632 and fasudil have been used extensively as tool compounds and have been shown to inhibit cancer cell migration in various in vitro cancer models (Wei et al., 2016). Todate, only one ROCK inhibitor has progressed into clinical trials for cancer treatment. AT13148 is an orally available multi-AGC kinase inhibitor that was identified through a fragment-based screen and was found to potently inhibit ROCK1 and ROCK2 (Yap et al., 2012). AT13148 was shown to have anti-tumor effects in pre-clinical models of pancreatic (Rath et al., 2018), breast, prostate and uterine cancer (Yap et al., 2012) and was well tolerated in a phase I clinical trial in patients with advanced solid tumors (NCT01585701) (Kumar et al., 2014), see p. 7-8, in particular. Clayton concludes that the role of Rho GTPases as key regulators of cell migration and invasion has been recognized for decades, yet few compounds targeting Rho GTPase signaling networks have been developed beyond an early preclinical stage. Due to the challenges of inhibiting Rho GTPase activation directly, targeting Rho GTPase effectors remains the most promising approach. Whilst PAK and ROCK inhibitors have progressed to phase I clinical trials, further work is needed to elucidate the context-dependent roles of Rho GTPase effectors and to identify compensatory feedback networks which may limit the success of these targeted therapies. Genome sequencing of human tumors has identified several mutations in Rho GTPases, yet the functional and clinical significance of many of these mutants remain poorly understood, see p. 9, in particular.
One of skilled in the art cannot predict which inhibitor of Rho-kinase, JAK-2, or neprilysin, or angiotensin II antagonist conjugated to the claimed binding molecule is effective for preventing or treating which disease associated with or characterized by the upregulation of PDGFRB expression such as such as liver fibrosis, cirrhosis, lung fibrosis, renal fibrosis, systemic sclerosis/scleroderma, inflammatory bowel disease and any cancer relating to a (sclerosing) malignant tumor, any secondary clinical manifestation that is attributable to liver fibrosis, cirrhosis, lung fibrosis, renal fibrosis, systemicsclerosis/scleroderma, inflammatory bowel disease or a cancer relating to a (sclerosing) malignant tumor, pulmonary hypertension in pulmonary fibrosis, oesophageal bleeding in portal hypertension and/or cardiovascular failure, and/or pulmonary failure in pulmonary hypertension, any breast cancer, lung cancer, colon cancer or prostate cancer (claims 65-71).
When a patent claims a genus using functional language to define a desired result, “the specification must demonstrate that the applicant has made a generic invention that achieves the claimed result and do so by showing that the applicant has invented species sufficient to support a claim to the functionally-defined genus.” AbbVie Deutschland GmbH & Co., KG v. Janssen Biotech, Inc., 759 F.3d 1285, 1299 (Fed. Cir. 2014) (quoting Ariad, 598 F.3d at 1349).
Regarding preventing any disease or disorder associated with or characterized by the upregulation of PEGFRB (claims 65-71), there is no objective evidence of the claimed method could prevent any and all disease or disorder associated with or characterized by the upregulation of PGGFRB expression by administration of any of the claimed conjugate. It is unpredictable which disease above can be prevented with the claimed conjugates wherein the disease or disorder associated with or characterized by the upregulation of PDGFRB expression.
For example, Gura et al (Science, 278:1041-1042, 1997; PTO 892) who discusses the potential shortcomings of potential anti-cancer agents including extrapolating from in-vitro to in-vivo protocols, the problems of drug testing in knockout mice, and problems associated with clonogenic assays. Indeed, since formal screening began in 1955, thousands of drugs have shown activity in either cell or animal models, but only 39 that are used exclusively for chemotherapy, as opposed to supportive care, have won approval from the FDA (page 1041, 1st column) wherein the fundamental problem in drug discovery for cancer is that the model systems are not predictive.
Even assuming the method is treating any disease or disorder associated with or characterized by the upregulation of PDGFRB expression (claims 65-71), there are no in vivo working examples. A method of preventing and/or treating disease in the absence of in vivo working examples is unpredictable.
For example, Strop et al (of record, Chemistry and Biology 20: 161-167, 2013; PTO 892) teach drug position can have a significant effect on linker stability and antibody pharmacokinetics. The site of conjugation on the drug and antibody can influence ADC properties differently in mice and rats, highlighting potential pitfalls of examining efficacy in mouse xenograft models and toxicity in rats or nonhuman primates, see abstract, p 166, p. 168 right col, in particular.
Nejadmoghaddam (of record, Avicenna Journal of Medical Biotechnology 2(1): 3-23, 2019; PTO 892) discusses major obstacles of antibody-drug conjugates include off-target toxicity, tumor marker selection, antibody specificity, adequately affinity and receptor-mediated internalization are major aspects of choice, cytotoxic payload (e.g., up to 7 drugs per antibody), cytotoxic payload linkage strategy, aqueous solubility, non-immunogenic and stability in storage and bloodstream, see entire document, abstract, p. 15, in particular.
As such, one of ordinary skill in the art would reasonably conclude that Applicant was not in possession of the genus of conjugates set forth in claims 49-58 and 60 for preventing and/or treating any disease or disorder associated with or characterized by the upregulation of PEGFRB as set forth in claims 65-71 at the time of filing.
An adequate written description must contain enough information about the actual makeup of the claimed products – “a precise definition, such as structure, formula, chemic name, physical properties of other properties, of species falling with the genus sufficient to distinguish the gene from other materials”, which may be present in “functional terminology when the art has established a correlation between structure and function” (Amgen page 1361).
Further, “A sufficient description of a genus . . . requires the disclosure of either a representative number of species falling within the scope of the genus or structural features common to the members of the genus so that one of skill in the art can "visualize or recognize" the members of the genus.” See AbbVie, 759 F.3d at 1297, reiterating Eli Lilly, 119 F.3d at 1568-69.
Adequate written description requires more than a mere statement that it is part of the invention and reference to a potential method of isolating it. The compound itself is required. See Fiers v. Revel, 25 USPQ2d 1601 at 1606 (CAFC 1993) and Amgen Inc. v. Chugai Pharmaceutical Co. Ltd., 18 USPQ2d 1016 (Fed. Cir. 1991). One cannot describe what one has not conceived. See Fiddes v. Baird, 30 USPQ2d 1481 at 1483 (BPAI 1993). In Fiddes, claims directed to mammalian FGFs were found to be unpatentable due to lack of written description for that broad class. The specification provided only the bovine sequence.
For these reasons, the rejection is maintained.
Claims 49-58, 60 and 65-71 are rejected under 35 U.S.C. 112(a) or 35 U.S.C. 112 (pre-AIA ), first paragraph, because the specification, while being enabling for a conjugated binding molecule comprising at least one diagnostic or therapeutic moiety conjugated to a first and a second heavy-chain-only antibody (VHH), each VHH specifically binds to a human platelet-derived growth factor receptor beta (PDGFRb) that is expressed on a fibrogenic effector cell identifiable by the expression of alpha smooth muscle actin and/or stress fibers discernable by immune fluorescence microscopy, wherein the binding molecule is conjugated to a diagnostic agent or a therapeutic agent, wherein the first VHH comprising a CDR 1 sequence according SEQ ID NO: 11, a CDR 2 sequence according to SEQ ID NO: 13 and a CDR 3 sequence according to SEQ ID NO: 15;and wherein the second VHH comprising a CDR 1 sequence according SEQ ID NO: 67, a CDR 2 sequence according to SEQ ID NO: 69 and a CDR 3 sequence according to SEQ ID NO: 71, or a CDR 1 sequence according SEQ ID NO: 83, a CDR 2 sequence according to SEQ ID NO: 85 and a CDR 3 sequence according to SEQ ID NO: 87, or a CDR 1 sequence according SEQ ID NO: 155, a CDR 2 sequence according to SEQ ID NO: 157 and a CDR 3 sequence according to SEQ ID NO: 159; or wherein the first VHH comprising a CDR 1 sequence according to SEQ ID NO: 67, a CDR 2 sequence according to SEQ ID NO: 69 and a CDR 3 sequence according to SEQ ID NO: 71; and wherein the second VHH comprises a CDR 1 sequence according SEQ ID NO: 83, a CDR 2 sequence according to SEQ ID NO: 85 and a CDR 3 sequence according to SEQ ID NO: 87; wherein the first and the second VHH comprises at most 4 amino acids that have been conservatively substituted per any one of the CDR sequences, independently wherein the therapeutic agent is Y27632, pacritinib, sacubitril, or losartan for a method of treating fibrosis, and wherein the diagnostic agent is Alexa fluor 647 for detecting liver fibrosis, does not reasonably provide enablement for any binding molecule as set forth in claims 65-71. The specification does not enable any person skilled in the art to which it pertains, or with which it is most nearly connected, to make/use the invention commensurate in scope with these claims.
Enablement is considered in view of the Wands factors (MPEP 2164.01(a)). These factors include, but are not limited to: (A) The breadth of the claims; (B) The nature of the invention; (C) The state of the prior art; (D) The level of one of ordinary skill; (E) The level of predictability in the art; (F) The amount of direction provided by the inventor; (G) The existence of working examples; and (H) The quantity of experimentation needed to make or use the invention based on the content of the disclosure. . In re Wands, 858 F.2d 731, 737, 8 USPQ2d 1400, 1404 (Fed. Cir. 1988).
Claim 49 encompasses a binding molecule comprising at least one diagnostic or therapeutic moiety, and at least two single variable domains of a heavy-chain-only antibody (VHH), each one able to specifically bind to a platelet-derived growth factor receptor beta (PDGFRB) that is expressed on a fibrogenic effector cell identifiable by the expression of alpha smooth muscle actin and/or stress fibers discernable by immune fluorescence microscopy,
wherein a first one of the at least two single variable domains comprises a CDR 1 sequence according SEQ ID NO: 11, a CDR 2 sequence according to SEQ ID NO: 13 and a CDR 3 sequence according to SEQ ID NO: 15; and
wherein a second one of the at least two single variable domains comprises:
A. a CDR 1 sequence according SEQ ID NO: 67, a CDR 2 sequence according to SEQ ID NO: 69 and a CDR 3 sequence according to SEQ ID NO: 71, or
B. a CDR 1 sequence according SEQ ID NO: 83, a CDR 2 sequence according to SEQ ID NO: 85 and a CDR 3 sequence according to SEQ ID NO: 87, or
C. a CDR 1 sequence according SEQ ID NO: 155, a CDR 2 sequence according to SEQ ID NO: 157 and a CDR 3 sequence according to SEQ ID NO: 159; or
wherein a first one of the at least two single variable domains comprises at least one single variable antibody domain comprising a CDR 1 sequence according to SEQ ID NO: 67, a CDR 2 sequence according to SEQ ID NO: 69 and a CDR 3 sequence according to SEQ ID NO: 71; and
wherein a second one of the at least two single variable domains comprises a CDR 1 sequence according SEQ ID NO: 83, a CDR 2 sequence according to SEQ ID NO: 85 and a CDR 3 sequence according to SEQ ID NO: 87;
wherein the first one and/or the second one of the at least two single variable domains comprises at most 4 amino acids that have been conservatively substituted per any one of the CDR sequences, independently,
wherein the diagnostic or therapeutic moiety is conjugated to the remainder of the binding molecule comprising at least two single variable domains of a heavy-chain-only antibody (VHH),
wherein the diagnostic moiety is an imaging agent, and/or wherein the therapeutic moiety is any Rho-kinase inhibitor, any JAK-2 inhibitor, any neprilysin inhibitor, or any Angiotensin II Receptor antagonist.
Claim 50 encompasses the binding molecule according to claim 49, wherein the first one of the at least two single variable domains comprises a CDR 1 sequence according SEQ ID NO: 11, a CDR 2 sequence according to SEQ ID NO: 13 and a CDR 3 sequence according to SEQ ID NO: 15;and wherein the second one of the at least two single variable domains comprises a CDR 1 sequence according SEQ ID NO: 155, a CDR 2 sequence according to SEQ ID NO:157 and a CDR 3 sequence according to SEQ ID NO: 159,wherein any one of the first one and/or of the second one of the at least two single variable domains comprises at most 4 amino acids that have been conservatively substituted per any one of the CDR sequences, independently.
Claim 51 encompasses the binding molecule according to claim 50, wherein the first one of the at least two single variable domains comprises or consists of a VHH sequence according to SEQ ID NOs: 9 (SPO2P), and wherein the second one of the at least two single variable domains comprises or consists of a VHH sequence according to any one of SEQ ID NOs: 153 (SP26P).
Claim 52 encompasses the binding molecule according to claim 49, wherein any one of the first one and/or of the second one of the at least two single variable domains comprises at most 3 amino acids that have been conservatively substituted per any one of the CDR sequences, independently.
Claim 53 encompasses the binding molecule according to claim 49, wherein any one of the first one and/or of the second one of the at least two single variable domains comprises at most 2 amino acids that have been conservatively substituted per any one of the CDR sequences, independently.
Claim 54 encompasses the binding molecule according to claim 49, wherein any one of the first one and/or of the second one of the at least two single variable domains comprises at most 1 amino acids that has been conservatively substituted per any one of the CDR sequences, independently.
Claim 55 encompasses the binding molecule according to claim 49, wherein the binding molecule is biparatopic.
Claim 56 encompasses the binding molecule according to claim 49, wherein the at least two single variable domains are separated by a linker amino acid sequence.
Claim 57 encompasses the binding molecule according to claim 49, wherein the binding molecule comprises an N-terminal or a C-terminal cysteine residue.
Claim 58 encompasses the binding molecule according to claim 491, wherein the binding molecule comprises a half-life extender that provide the binding molecule with increased half-life compared to a binding molecule without a half-life extender.
Claim 60 encompasses the binding molecule according to claim 49, wherein the therapeutic molecule moiety is able to inhibit any one or more of contractile activity, fibrogenic activity, chemotactic activity and pro-inflammatory activity of the fibrogenic effector cell.
Claim 65 encompasses a method of preventing and/or treating a disease or disorder associated with or characterized by the upregulation of PDGFRB expression, said method comprising the administration of a binding molecule comprising at least one diagnostic or therapeutic moiety, and at least two single variable domains of a heavy-chain-only antibody (VHH), each one able to specifically bind to a platelet-derived growth factor receptor beta (PDGFRB) that is expressed on a fibrogenic effector cell identifiable by the expression of alpha smooth muscle actin and/or stress fibers discernable by immune fluorescence microscopy,
wherein a first one of the at least two single variable domains comprises a CDR 1 sequence according SEQ ID NO: 11, a CDR 2 sequence according to SEQ ID NO: 13 and a CDR 3 sequence according to SEQ ID NO: 15; and
wherein a second one of the at least two single variable domains comprises:
A. a CDR 1 sequence according SEQ ID NO: 67, a CDR 2 sequence according to SEQ ID NO: 69 and a CDR 3 sequence according to SEQ ID NO: 71, or
B. a CDR 1 sequence according SEQ ID NO: 83, a CDR 2 sequence according to SEQ ID NO: 85 and a CDR 3 sequence according to SEQ ID NO: 87, or
C. a CDR 1 sequence according SEQ ID NO: 155, a CDR 2 sequence according to SEQ ID NO: 157 and a CDR 3 sequence according to SEQ ID NO: 159; or
wherein a first one of the at least two single variable domains comprises at least one single variable antibody domain comprising a CDR 1 sequence according to SEQ ID NO: 67, a CDR 2 sequence according to SEQ ID NO: 69 and a CDR 3 sequence according to SEQ ID NO: 71; and
wherein a second one of the at least two single variable domains comprises a CDR 1 sequence according SEQ ID NO: 83, a CDR 2 sequence according to SEQ ID NO: 85 and a CDR 3 sequence according to SEQ ID NO: 87;
wherein the first one and/or the second one of the at least two single variable domains comprises at most 4 amino acids that have been conservatively substituted per any one of the CDR sequences, independently,
wherein the diagnostic or therapeutic moiety is conjugated to the remainder of the binding molecule comprising at least two single variable domains of a heavy-chain-only antibody (VHH),
wherein the diagnostic moiety is an imaging agent, and/or wherein the therapeutic moiety is any Rho-kinase inhibitor, any JAK-2 inhibitor, any neprilysin inhibitor, or any Angiotensin II Receptor antagonist.
Claim 66 encompasses the method of preventing and/or treating according to claim 65, wherein the disease or disorder associated with or characterized by the upregulation of PDGFRB expression is any one or more of: liver fibrosis, cirrhosis, lung fibrosis, renal fibrosis, systemic sclerosis/scleroderma, inflammatory bowel disease and a cancer relating to a (sclerosing) malignant tumor.
Claim 67 encompasses the method of preventing and/or treating according to claim 66, wherein preventing and/or treating is preventing and/or treating a (secondary) clinical manifestation that is attributable to liver fibrosis, cirrhosis, lung fibrosis, renal fibrosis, systemic sclerosis/scleroderma, inflammatory bowel disease or a cancer relating to a (sclerosing) malignant tumor.
Claim 68 encompasses the method of preventing and/or treating according to claim 67, wherein the (secondary) clinical manifestation is portal hypertension in liver fibrosis and/or in cirrhosis, or pulmonary hypertension in pulmonary fibrosis.
Claim 69 encompasses the method of preventing and/or treating according to claim 67, wherein the prevention and/or the treatment of a (secondary) clinical manifestation is the prevention and/or treatment of an acute complication of the (secondary) clinical manifestation.
Claim 70 encompasses the method of preventing and/or treating according to claim 69, wherein the acute complication of the (secondary) clinical manifestation is any one or more of: oesophageal bleeding in portal hypertension and/or cardiovascular failure, and/or pulmonary failure in pulmonary hypertension.
Claim 71 encompasses the method of preventing and/or treating a disease or disorder associated with or characterized by the upregulation of PDGFRB expression of claim 65, wherein the preventing and/or treating is preventing and/or treating any breast cancer, lung cancer, colon cancer or prostate cancer.
Enablement is not commensurate in scope with preventing any disease or disorder associated with or characterized by the upregulation of PDGFRB expression (claims 65-71), such as liver fibrosis, cirrhosis, lung fibrosis, renal fibrosis, systemic sclerosis/scleroderma, inflammatory bowel disease and any cancer relating to a (sclerosing) malignant tumor, any secondary clinical manifestation that is attributable to liver fibrosis, cirrhosis, lung fibrosis, renal fibrosis, systemicsclerosis/scleroderma, inflammatory bowel disease or a cancer relating to a (sclerosing) malignant tumor, pulmonary hypertension in pulmonary fibrosis, oesophageal bleeding in portal hypertension and/or cardiovascular failure, and/or pulmonary failure in pulmonary hypertension, any breast cancer, lung cancer, colon cancer or prostate cancer by administrating any diagnostic wherein the diagnostic agent is any imaging agent or any therapeutic moiety such as any Rho-kinase inhibitor, any JAK-2 inhibitor, any neprilysin inhibitor or any angiotensin II receptor antagonist, wherein the at least one diagnostic or therapeutic moiety is conjugated to at least two single variable domains of a heavy-chain-only antibody (VHH), each one able to specifically bind to a platelet-derived growth factor receptor beta (PDGFRB) that is expressed on a fibrogenic effector cell identifiable by the expression of alpha smooth muscle actin and/or stress fibers discernable by immune fluorescence microscopy,
wherein a first one of the at least two single variable domains comprises a CDR 1 sequence according SEQ ID NO: 11, a CDR 2 sequence according to SEQ ID NO: 13 and a CDR 3 sequence according to SEQ ID NO: 15; and
wherein a second one of the at least two single variable domains comprises:
A. a CDR 1 sequence according SEQ ID NO: 67, a CDR 2 sequence according to SEQ ID NO: 69 and a CDR 3 sequence according to SEQ ID NO: 71, or
B. a CDR 1 sequence according SEQ ID NO: 83, a CDR 2 sequence according to SEQ ID NO: 85 and a CDR 3 sequence according to SEQ ID NO: 87, or
C. a CDR 1 sequence according SEQ ID NO: 155, a CDR 2 sequence according to SEQ ID NO: 157 and a CDR 3 sequence according to SEQ ID NO: 159; or
wherein a first one of the at least two single variable domains comprises at least one single variable antibody domain comprising a CDR 1 sequence according to SEQ ID NO: 67, a CDR 2 sequence according to SEQ ID NO: 69 and a CDR 3 sequence according to SEQ ID NO: 71; and
wherein a second one of the at least two single variable domains comprises a CDR 1 sequence according SEQ ID NO: 83, a CDR 2 sequence according to SEQ ID NO: 85 and a CDR 3 sequence according to SEQ ID NO: 87;
wherein the first one and/or the second one of the at least two single variable domains comprises at most 4 amino acids that have been conservatively substituted per any one of the CDR sequences, independently,
wherein the diagnostic or therapeutic moiety is conjugated to the remainder of the binding molecule comprising at least two single variable domains of a heavy-chain-only antibody (VHH),
wherein the diagnostic moiety is an imaging agent, and/or wherein the therapeutic moiety is any Rho-kinase inhibitor, any JAK-2 inhibitor, any neprilysin inhibitor, or any Angiotensin II Receptor antagonist.
The specification discloses:
[0309] The 18 unique hPDGFRB binders from libraries 1 and 2, and the 11 unique rPDGFRB binders from libraries 3 and 4 (Example 2.2, FIGS. 5 and 6) were produced and purified as described in examples 3 and 4. Then, the apparent affinities were determined with binding assays on hPDGFRB-ECD and rPDGFRB-ECD, respectively, the setup described in example 5.1 Results are summarized in FIGS. 5 and 6 for the hPDGFRB and rPDGFRB VHHs, respectively.
[0310] High affine binders to hPDGFRB-ECD or rPDGFRB-ECD were subsequently assessed for binding to SCC VII cells transfected with hPDGFRB and rPDGFRB, respectively. As shown in FIG. 9, the VHHs obtained from libraries 1 and 2 displayed affinity to SCC-hPDGFRB cells, and VHHs obtained from libraries 3 and 4 displayed good binding to SCC-rPDGFRB cells.
Example 6: Determination of VHHs Binding to Non-Overlapping Receptor Epitopes to Allow Construction of Biparatopic VHH Constructs
[0312] Similar as to in example 6.1, competition assays were performed to identify unique hPDGFRB- or rPDGFRB binders. Across 10 PDGFRB-binding VHHs obtained from libraries 1 and 2 (e.g. the VHH raised against hPDGFRB), four main groups were identified being first SP01P, SP02P, SP07P and SP13P, second SP05P, SP08P and SP10P, third SP12P and SP20P and finally SP14P. All VHH within each of the first three groups mutually competed. Across the three groups, and the lone VHH SP14P, no competition was observed demonstrating that VHH had been raised against at least four different epitopes of the hPDGFRB: those of SP02P, SP05P, SP12P, and SP14P (FIG. 5 rightmost column, exemplary binding curves using SP02P as the reporter VHH are shown in FIG. 11A). Similarly, across the VHH obtained from libraries 3 and 4 (e.g. the VHH raised against rPDGFRB), SP26P showed to have a unique epitope compared to SP27P, SP28P, SP30P, SP31P and SP36P (FIG. 6).
Example 7: Construction and Characterization of Biparatopic VHHs
[0314] The design of biparatopic constructs was led by the following critical traits: First, the constructs must be based on VHH with non-overlapping epitopes (the biparatopic design). Second, the constructs must bind with similar affinity to human- and rodent ligands as this would result in constructs suitable for preclinical as well as clinical pharmaceutical development. Finally, the constructs must display a meaningful in vivo plasma half-life in order to ensure meaningful in vivo exposure.
7.2 PDGFRB
[0319] Based on their high affinity and binding to non-overlapping hPDGFRB epitopes, various biparatopic constructs were prepared based on VHHs SP02P, SP12P SP14P, SP26P and SP28P. The constructs were produced as described in example 7.1. and subjected to binding assay. All constructs based on VHH that had been raised against hPDGFRB (SP02P, SP12P SP14P) showed high affinity for hPDGFRB. The construct SP26P-SP28P, based on VHH raised against rPDGFRB, displayed the lowest affinity for hPDGFRB (FIG. 15A). Contrary, SP26P-SP28P displayed high affinity for rPDGFRB and low affinity for hPDGFRB (FIG. 15B).
[0320] In an effort to pursue a species cross-reactive construct, the VHHs SP02P and SP26P were combined in a biparatopic construct, as these were shown to bind different epitopes (FIG. 11B; SP02P does not compete with binding of fluorescently labelled SP26P to cells expressing PDGFRB). As Shown in FIG. 15C), the binding affinity of this construct for both hPDGFRB and rPDGFRB are below 5 nM. Furthermore, whereas binding of the monomeric VHHs SP02P and SP26P varied across murine PDGFRB ectodomain (mPDGFRB-ECD), rPDGFRB-ECD and hPDGFRB-ECD, the biparatopic construct SP02P-SP26P displayed high affinity regardless of the species. These observations make SP02P (or similar VHH) and SP26P (or similar VHH) particularly promising for use in the present invention. FIG. 15D displays binding of IRDye800-conjugated SP02P-SP26P, and corresponding monomeric VHHs SP02P and SP26P, to murine PDGFRB ECD (left panel), rat PDGFRB ECD (middle panel), or human PDGFRB ECD (right panel).
Example 8: Improving In Vivo Pharmacokinetics in Rats of 13F11-13E8 Through Addition of an Albumin Binding Domain
[0321] The in vivo pharmacokinetic properties of 13F11-13E8-ABD (F11E8-ABD; with ABD) and 13F11-13E8 (F11E8; without ABD) were compared in healthy Sprague-Dawley rats. In brief, rats were dosed intravenously with approximately 3 mg/kg body weight and blood samples were taken at different time points and the concentration of the VHH constructs were determined using an ELISA on immobilized hIGF2R-ECD. The peak serum level (C.sub.max) of 13F11-13E8-ABD exceeded 1000 nM as shown in FIG. 13C. With approximately 20 nmoles infused into the animal, and an estimated serum volume of 10 mL, this C.sub.max would correspond to approximately 50% of the infused dose still being in circulation one hour after dosing demonstrating good bioavailability. On the other hand, 13F11-13E8 was rapidly cleared from circulation and could not be detected anymore within two hours after injection (FIG. 13C). To further confirm the functionality of the ABD, biodistribution of F11E8-ABD and F11E8 were assessed by means of Positron Emission Tomography (PET). In brief, the constructs were radio-labelled with the positron emitter .sup.89Zr-desferral according to Verel et al (J Nucl Med. 2003; 44:1271-1281), and administered intravenously to rats after which biodistribution was assessed on subsequent time points by whole-body PET. As evident from FIG. 13D, F11E8 swiftly accumulated in the kidneys (upper panels, arrows) illustrating renal excretion. In contrast, the extended serum half-life of F11E8-ABD allowed it to accumulate in the liver (lower panels, arrow).
Example 9: Synthesis and Analytical Characterization of Lx Semi-Final Complexes and Maleimide Functionalized Moieties with Small Molecule Kinase Inhibitors: Y27632, Pacritinib, Sacubitril (at), Losartan
9.1. Structures of Y27632-Lx (Semi-Final Moieties) SFMs and Y27632 Maleimide Functionalized Moieties that can be Utilized in the Context of the Present Invention.
9.1.3. Synthesis and Analytical Characterization of Mal-PEG.SUB.4.-Val-Cit-PAB-Y27632 (1e)
9.1.4. Synthesis and Analytical Characterization of Mal-Val-Cit-PAB-Y27632 (1f)
10.2. Conjugation of a Maleimide Functionalized Moieties to a Binding Molecule
11.2. PDGFRB VHH
To determine the rate of internalization of the VHH construct SP02P-SP26P, kinetic internalization assays on hPDGFRB expressing SCC cells and LX-2 cells were performed using a similar method as described for the IGF2R constructs in example 11.1. Internalization of SP02P-SP26P was observed in SCC-hPDGFRB cells (left panel of FIG. 19) as well as in LX-2 cells (right panel of FIG. 19).
[0369] To confirm improved internalization of biparatopic VHH constructs compared to the monomeric individual VHH components, kinetic internalization assays were performed using SCC-rPGDFRB and on SCC-hPDGFRB cells, using a similar method as described for the IGF2R constructs in example 11.1. The biparatopic construct SP02P-SP26P internalized 5-10 fold faster when compared to the corresponding monomeric VHH SP02 and SP26 (FIG. 20; left panel for cells expressing rat PDGFRB, right panel for cells expressing human PDGFRB).
Example 14: Detection of PDGFRB in the Cirrhotic Rat Liver
To evaluate whether SP02-SP26-ABD bound to PDGFRB as (over-) expressed in the cirrhotic liver, various cryo-sections of tissues (liver, kidney, spleen, heart, ileum, brain) obtained from both healthy (SHAM) and cirrhotic (BDL) rats (preparation procedure as outlined in example 15) were stained with SP02-SP26-ABD conjugated to Alexa Fluor 647 (SP02-SP26-ABD-A647, conjugation method as described in example 10.2.). Staining was performed with 50 nM SP02-SP26-ABD-AF647 during overnight incubation at 4° C. Subsequently, the sections were washed and stained with DAPI, mounted with mowiol mounting medium (Merck), and imaged on a Zeiss LSM700 laser scanning confocal microscope with a 20× objective. SP02-SP26-ABD-AF647 strongly stains activated fibroblasts in the cirrhotic liver whereas in the normal liver only background signal was detected (FIG. 23). In the tissues other than the liver, no upregulation of PDGFRB was observed. These observations demonstrate binding of the VHH construct to rPDGFRB in its biological context, and confirm selective over-expression of PDGFRB by activated fibroblasts, in line with what is reported elsewhere (see example 1).
However, the specification does not teach how to prevent any and all disease or disorder associated with or characterized by the upregulation of PDGFRB expression by administering the claimed conjugates above to any subject, including healthy subject. There are no in vivo working example. It is unpredictable which disease above, particularly cancer, can be prevented with the claimed conjugates wherein the disease or disorder associated with or characterized by the upregulation of PDGFRB expression.
For example, Gura et al (Science, 278:1041-1042, 1997; PTO 892) who discusses the potential shortcomings of potential anti-cancer agents including extrapolating from in-vitro to in-vivo protocols, the problems of drug testing in knockout mice, and problems associated with clonogenic assays. Indeed, since formal screening began in 1955, thousands of drugs have shown activity in either cell or animal models, but only 39 that are used exclusively for chemotherapy, as opposed to supportive care, have won approval from the FDA (page 1041, 1st column) wherein the fundamental problem in drug discovery for cancer is that the model systems are not predictive.
Even assuming the method is treating any disease or disorder associated with or characterized by the upregulation of PDGFRB expression (claims 65-71), there are no in vivo working examples. A method of preventing and/or treating disease in the absence of in vivo working examples is unpredictable.
For example, Strop et al (of record, Chemistry and Biology 20: 161-167, 2013; PTO 892) teach drug position can have a significant effect on linker stability and antibody pharmacokinetics. The site of conjugation on the drug and antibody can influence ADC properties differently in mice and rats, highlighting potential pitfalls of examining efficacy in mouse xenograft models and toxicity in rats or nonhuman primates, see abstract, p 166, p. 168 right col, in particular.
Nejadmoghaddam (of record, Avicenna Journal of Medical Biotechnology 2(1): 3-23, 2019; PTO 892) discusses major obstacles of antibody-drug conjugates include off-target toxicity, tumor marker selection, antibody specificity, adequately affinity and receptor-mediated internalization are major aspects of choice, cytotoxic payload (e.g., up to 7 drugs per antibody), cytotoxic payload linkage strategy, aqueous solubility, non-immunogenic and stability in storage and bloodstream, see entire document, abstract, p. 15, in particular.
Regarding the therapeutic moiety is a Rho-kinase inhibitor, a JAK-2 inhibitor, a neprilysin inhibitor or a angiotensin II receptor antagonist (claims 49, 65), the specification does not teach any and all possible Rho-kinase inhibitors, a JAK-2 inhibitors, a neprilysin inhibitors or a angiotensin II receptor antagonists. The specification does not teach the chemical structure-identifying information about all possible Rho-kinase inhibitors, a JAK-2 inhibitors, a neprilysin inhibitors or a angiotensin II receptor antagonists. The specification does not teach a representative number of species falling within the scope of the genus or structural common to the members of the genus of Rho-kinase inhibitors, a JAK-2 inhibitors, a neprilysin inhibitors or a angiotensin II receptor antagonists conjugated to the claimed binding molecule so that one of skill in the art can make and use without undue experimentation.
Clayton (Front. Cell and Dev. Biol 8(222): 1-12, 2020; PTO 892) teaches although significant effort has been made to develop ROCK (Rho-kinase) inhibitors for cancer intervention, the vast majority of compounds have not progressed to clinical trials. The ATP competitive ROCK inhibitorsY-27632 and fasudil have been used extensively as tool compounds and have been shown to inhibit cancer cell migration in various in vitro cancer models (Wei et al., 2016). Todate, only one ROCK inhibitor has progressed into clinical trials for cancer treatment. AT13148 is an orally available multi-AGC kinase inhibitor that was identified through a fragment-based screen and was found to potently inhibit ROCK1 and ROCK2 (Yap et al., 2012). AT13148 was shown to have anti-tumor effects in pre-clinical models of pancreatic (Rath et al., 2018), breast, prostate and uterine cancer (Yap et al., 2012) and was well tolerated in a phase I clinical trial in patients with advanced solid tumors (NCT01585701) (Kumar et al., 2014), see p. 7-8, in particular. Clayton concludes that the role of Rho GTPases as key regulators of cell migration and invasion has been recognized for decades, yet few compounds targeting Rho GTPase signaling networks have been developed beyond an early preclinical stage. Due to the challenges of inhibiting Rho GTPase activation directly, targeting Rho GTPase effectors remains the most promising approach. Whilst PAK and ROCK inhibitors have progressed to phase I clinical trials, further work is needed to elucidate the context-dependent roles of Rho GTPase effectors and to identify compensatory feedback networks which may limit the success of these targeted therapies. Genome sequencing of human tumors has identified several mutations in Rho GTPases, yet the functional and clinical significance of many of these mutants remain poorly understood, see p. 9, in particular.
One of skilled in the art cannot predict which inhibitor of Rho-kinase, JAK-2, or neprilysin, or angiotensin II antagonist is effective for preventing or treating which disease associated with or characterized by the upregulation of PDGFRB expression such as such as liver fibrosis, cirrhosis, lung fibrosis, renal fibrosis, systemic sclerosis/scleroderma, inflammatory bowel disease and any cancer relating to a (sclerosing) malignant tumor, any secondary clinical manifestation that is attributable to liver fibrosis, cirrhosis, lung fibrosis, renal fibrosis, systemic sclerosis/scleroderma, inflammatory bowel disease or a cancer relating to a (sclerosing) malignant tumor, pulmonary hypertension in pulmonary fibrosis, oesophageal bleeding in portal hypertension and/or cardiovascular failure, and/or pulmonary failure in pulmonary hypertension, any breast cancer, lung cancer, colon cancer or prostate cancer.
Thus, in view of the breadth of the claims and the minimal showing of the specification, it would take undue trials and errors to practice the claimed invention.
Given the lack of any rebuttal, the rejection is maintained for these reasons and reasons of record.
Claim objection
Claim 67, 69 and 70 are objected to because of the following informality: the parenthesis in (secondary) should be removed.
Claim 71 is objected to because of the following informality: duplicate “preventing and/or treating” should be deleted. It is suggested that claim 71 be amended to recite “The method of treating a disease or disorder associated with or characterized by the upregulation of PEDGFR expression of claim 65, wherein the disease is breast cancer, …or prostate cancer.” Please do similar amendment to claims 66, 67, 68, 69, 70.
Conclusion
No claim is allowed.
Applicant's amendment necessitated the new ground(s) of rejection presented in this Office action. Accordingly, THIS ACTION IS MADE FINAL. See MPEP § 706.07(a). Applicant is reminded of the extension of time policy as set forth in 37 CFR 1.136(a).
A shortened statutory period for reply to this final action is set to expire THREE MONTHS from the mailing date of this action. In the event a first reply is filed within TWO MONTHS of the mailing date of this final action and the advisory action is not mailed until after the end of the THREE-MONTH shortened statutory period, then the shortened statutory period will expire on the date the advisory action is mailed, and any nonprovisional extension fee (37 CFR 1.17(a)) pursuant to 37 CFR 1.136(a) will be calculated from the mailing date of the advisory action. In no event, however, will the statutory period for reply expire later than SIX MONTHS from the mailing date of this final action.
Any inquiry concerning this communication or earlier communications from the examiner should be directed to PHUONG HUYNH whose telephone number is (571)272-0846. The examiner can normally be reached on 9:00 a.m. to 6:30 p.m. The examiner can also be reached on alternate alternative Friday from 9:00 a.m. to 5:30 p.m.
If attempts to reach the examiner by telephone are unsuccessful, the examiner's supervisor, Misook Yu, can be reached at 571-270-3497. The fax phone number for the organization where this application or proceeding is assigned is 571-272-0839.
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/PHUONG HUYNH/ Primary Examiner, Art Unit 1641
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