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
Status of the Claims
1. Claims 1-27 are the original claims in the two sets of claims filed 4/28/2023. In the Preliminary Amendment of 4/28/2023, claims 1-27 are canceled and new claims 28-47 are added. No claims are amended in the Reply filed 12/5/2025.
Claims 28-47 are all the claims.
Election/Restriction
2. Applicant’s election without traverse of Group I in the reply filed on 12/5/2025 is acknowledged.
3. Applicant’s election of species without traverse for a therapy (treatment; A61K 39/0011 or A61K 2039/507) in the reply filed on 12/5/2025 is acknowledged. The species for a prophylactic (prevention; A61P 39/00) is withdrawn from further consideration pursuant to 37 CFR 1.142(b) as being drawn to a nonelected invention, there being no allowable generic or linking claim. Election was made without traverse in the reply filed on 12/5/2025.
4. Claims 28-47 are all the claims under examination.
Priority
5. USAN 18/034,499, filed 04/28/2023, is a National Stage entry of PCT/US21/ 57209, International Filing Date: 10/29/2021, PCT/US21/ 57209 Claims Priority from Provisional Application 63/113,920, filed 11/15/2020, PCT/US21/57209 Claims Priority from Provisional Application 63/109,814, filed 11/04/2020. The priority filing date of 11/04/2020 is granted.
Information Disclosure Statement
6. As of 2/18/2026, a total of one (1) IDS is filed: 12/5/2025. The corresponding initialed and dated 1449 form is considered and of record.
Objections
Specification
7. The abstract of the disclosure is objected to because: the abstract exceeds 150 words; and describes the invention as “novel”.
Applicant is reminded of the proper content of an abstract of the disclosure.
A patent abstract is a concise statement of the technical disclosure of the patent and should include that which is new in the art to which the invention pertains. The abstract should not refer to purported merits or speculative applications of the invention and should not compare the invention with the prior art.
If the patent is of a basic nature, the entire technical disclosure may be new in the art, and the abstract should be directed to the entire disclosure. If the patent is in the nature of an improvement in an old apparatus, process, product, or composition, the abstract should include the technical disclosure of the improvement. The abstract should also mention by way of example any preferred modifications or alternatives.
Where applicable, the abstract should include the following: (1) if a machine or apparatus, its organization and operation; (2) if an article, its method of making; (3) if a chemical compound, its identity and use; (4) if a mixture, its ingredients; (5) if a process, the steps.
Extensive mechanical and design details of an apparatus should not be included in the abstract. The abstract should be in narrative form and generally limited to a single paragraph within the range of 50 to 150 words in length.
See MPEP § 608.01(b) for guidelines for the preparation of patent abstracts.
A corrected abstract of the disclosure is required and must be presented on a separate sheet, apart from any other text. See MPEP § 608.01(b).
8. A new title is required that is compliant with MPEP 606. Remove the term “novel” from the title.
9. The disclosure is objected to because of the following informalities:
a) The use of the term Octet, NCBI, GenBank, Tris, Triton, LuminoSkan Ascent, GraphPad, UniProt, BiaCore, BLASTX, PRISM, AKTA, which is a trade name or a mark used in commerce, has been noted in this application. The term should be accompanied by the generic terminology; furthermore the term should be capitalized wherever it appears or, where appropriate, include a proper symbol indicating use in commerce such as ™, SM , or ® following the term.
Although the use of trade names and marks used in commerce (i.e., trademarks, service marks, certification marks, and collective marks) are permissible in patent applications, the proprietary nature of the marks should be respected and every effort made to prevent their use in any manner which might adversely affect their validity as commercial marks.
b) The specification contains peptides that are > 4 amino acids in length that pursuant to 37 CFR 1.821-1.825 are required to be identified by SEQ ID NO. See [095].
c) The specification contains an apparent typographical error at
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Table 5 lists the bifunctional antagonist molecules of the present invention. In the “ID” column, there is no disclosure for “A-119 and A-120.” Moreover, none of Figures 6-8 identify clones corresponding to A-119 and A-120.
Appropriate correction is required.
Claim Objections
10. Claims 28-47 are objected to because of the following informalities:
a) Amend claims 28-47 for consistency to recite “according to claim _” or “of claim _” but not both.
b) Amend claim 29 to reduce verbiage that does not change the scope of the invention:
An isolated multispecific antagonist according to claim 28, wherein the first antigen-binding molecule specifically binds an Activin or Activin-related ligand comprising an amino acid sequence selected from the group consisting of comprising an amino acid sequence selected from the group consisting of
c) Amend claim 31 to reduce verbiage that does not change the scope of the invention:
An isolated multispecific antagonist according to claim 30, wherein the Activin-binding polypeptide is a sequence selected from the group consisting of wherein the TGF-β-binding polypeptide is a sequence selected from the group consisting of
d) Amend claim 34 to reduce verbiage that does not change the scope of the invention:
An isolated multispecific antagonist according to claim 28, wherein the multispecific antagonist comprises an amino acid sequence selected from the group consisting of
e) Amend claim 35 to reduce verbiage that does not change the scope of the invention:
An isolated multispecific antagonist according to claim 28, wherein the multispecific antagonist is a polypeptide comprising a heavy chain sequence selected from the group consisting of , and a light chain sequence selected from the group consisting of
f) Amend claim 40 to reduce verbiage that does not change the scope of the invention:
An isolated bifunctional multispecific antagonist according to claim 36, wherein the bifunctional multispecific antagonist is a heavy chain comprising a sequence selected from the group consisting of, and a light chain sequence selected from the group consisting of
g) Amend claim 41 to reduce verbiage that does not change the scope of the invention:
An isolated bifunctional multispecific antagonist according to claim 40, wherein the bifunctional multispecific antagonist a heavy chain comprising a sequence selected from the group consisting of, and a light chain sequence comprising
g) Amend claim 42 to reduce verbiage that does not change the scope of the invention:
An isolated bifunctional multispecific antagonist according to claim 40, wherein the bifunctional multispecific antagonist a polypeptide comprising a heavy chain sequence selected from the group consisting of, and a light chain sequence comprising .
Appropriate correction is required.
Claim Rejections - 35 USC § 112
The following is a quotation of 35 U.S.C. 112(b):
(b) CONCLUSION.—The specification shall conclude with one or more claims particularly pointing out and distinctly claiming the subject matter which the inventor or a joint inventor regards as the invention.
The following is a quotation of 35 U.S.C. 112 (pre-AIA ), second paragraph:
The specification shall conclude with one or more claims particularly pointing out and distinctly claiming the subject matter which the applicant regards as his invention.
11. Claims 28-47 are rejected under 35 U.S.C. 112(b) or 35 U.S.C. 112 (pre-AIA ), second paragraph, as being indefinite for failing to particularly point out and distinctly claim the subject matter which the inventor or a joint inventor (or for applications subject to pre-AIA 35 U.S.C. 112, the applicant), regards as the invention.
a) Claims 28-35, 43 and 45-46 recite the limitation "the multispecific antagonist molecule" in claim 28. There is insufficient antecedent basis for this limitation in generic claim 28. Claim 28 is drawn to “a multispecific antagonist” that is comprised of a 1st and 2nd antigen-binding molecule.
b) Claims 36-42, 44 and 47 recite the limitation "the bifunctional multispecific antagonist molecule" in claim 36. There is insufficient antecedent basis for this limitation in generic claim 36. Claim 36 is drawn to “a bifunctional multispecific antagonist” that is comprised of a 1st, 2nd and 3rd antigen-binding polypeptide.
c) Claims 45-47 recite the limitation "said subject" and “the subject”, respectively. There is insufficient antecedent basis for this limitation in each of the generic claims. Proper antecedency comprises a limitation such as “a subject” or “a subject in need thereof.” See [0205-0207].
d) Claim 30 is indefinite for reciting parenthetical text: “(including anti-Activin A antibody and anti-Activin B antibody)” and “(including TGFβRIIA and TGFβRIIB).” It is unclear whether the limitation(s) following the phrase are part of the claimed invention. See MPEP § 2173.05(d).
e) Claim 32 is indefinite for reciting the phrase “for example” “(e.g.,)” and for the parenthetical text: “(e.g., Fab, Fab', F(ab')2, Fv, Fc, etc.)”. It is unclear whether the limitation(s) following the phrase are part of the claimed invention. See MPEP § 2173.05(d).
f) Claim 36 is indefinite for reciting the phrase “(“PD-1/PD-L1/CTLA-4-Binding Polypeptide”).” It is unclear whether the limitation(s) following the phrase are part of the claimed invention. See MPEP § 2173.05(d).
g) Claim 36 is indefinite for reciting the phrase “(“PD-1/PD-L1/CTLA-4-Binding Polypeptide”)” where the forward slash in the limitation is not shown to equate with alternative language “or” in the immediately preceding line: “a third antigen-binding polypeptide that specifically binds to either T-cell immune checkpoint PD-1 ligand, PD-L1 ligand or CTLA-4 ligand.”
h) Claim 37 is indefinite in depending from claim 36 for reciting “a third antigen-binding polypeptide that specifically binds to PD-1 ligand…” The bifunctional multispecific antagonist of claim 37 comprises two (2) third antigen binding polypeptides.
i) Claim 38 is indefinite in depending from claim 36 for reciting “a third antigen-binding polypeptide that specifically binds to a CTLA-4 ligand…” The bifunctional multispecific antagonist of claim 38 comprises two (2) third antigen binding polypeptides.
j) Claim 39 is indefinite in depending from claim 36 for reciting “a third antigen-binding polypeptide that specifically binds to a PD-L1 ligand…” The bifunctional multispecific antagonist of claim 39 comprises two (2) third antigen binding polypeptides.
k) Claims 28-35, 43 and 45-46 recite the limitation “wherein the multispecific antagonist molecule simultaneously neutralizes Activin signaling and TGF-β signaling in a potent manner” in claim 28. The term “potent” is not per se defined in the specification. The specification supports measuring neutralizing activin signaling and TGF-beta signaling with the mutilspecific antagonist antibodies in cell-based assays that measure IC50:
[0040] FIG. 7 depicts line graphs showing that multispecific antagonist molecules A115, A116, A117 and A118 potently neutralize Activin A and Activin B in cell-based assays. The IC50 values were calculated and plotted using Prism software (GraphPad Software).
[0041] FIG. 8 depicts line graphs showing that multispecific antagonist molecules A115, A116, A117 and A118 potently neutralize TGF-β1 and TGF-β3 in cell-based assays. The IC50 values were calculated and plotted using Prism software (GraphPad Software).
The correlation between IC50 values and potency are not well explained in the specification. See www.promegaconnections.com/ic50-ec50-and-kd-what-is-the-difference-and-why-do-they-matter.
“While Kd measures the strength of binding, IC50 measures functional inhibition and is the concentration of a drug or molecule that is needed to inhibit a biological process or response by 50% (meaning it is one half the maximal inhibitory concentration). This inhibition is tied to a specific cellular activity— like cell growth or protein activity. Typically, dose response curves are used to determine IC50. A low IC50 value suggests higher potency, meaning less drug is needed to achieve the desired response.”
Amending claim 28 to clarify the meaning of a potent manner could overcome this rejection.
l) Claim 32 recites the limitation "or antigen-binding fragment thereof" as regards the isolated anti-Activin antibody and the isolated anti-TGF-β antibody, respectively. There is insufficient antecedent basis for this limitation in the claim. Claim 30 and from which claim 32 depends is not drawn to an isolated anti-Activin antibody “or antigen-binding fragment thereof” nor to an isolated anti-TGF-β antibody “or antigen-binding fragment thereof.”
m) Each of Claims 45-47 recite the limitations “said subject” and "the subject". There is insufficient antecedent basis for both limitations in the respective claims and in the claims from which they depend.
n) Claims 36-42, 44 and 47 are indefinite for the phrase “bifunctional multispecific antagonist” in that they comprise a 1st, 2nd and 3rd antigen binding polypeptide that binds activin, TGF-β, and a T cell immune checkpoint, respectively. “Immunoglobulins, or antibodies, are monospecific, bivalent antigen-binding molecules. Bifunctional antibodies are bispecific, with each arm binding to a different antigen,” (Nolan et al. PTO 892). Accordingly, the multispecific antagonist is seemingly trifunctional with trispecific antigen binding based on the claim construction and BRI standard of claim 36.
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.
Written Description
12. Claims 28-33 and 35-47 are rejected under 35 U.S.C. 112(a) or 35 U.S.C. 112 (pre-AIA ), first paragraph, as failing to comply with the written description requirement. The claim(s) contains subject matter which was not described in the specification in such a way as to reasonably convey to one skilled in the relevant art that the inventor or a joint inventor, or for applications subject to pre-AIA 35 U.S.C. 112, the inventor(s), at the time the application was filed, had possession of the claimed invention.
Claim interpretation
Claims 28-33, 35, 43 and 45-46 drawn to isolated multispecific antagonist comprising a first antigen-binding molecule that specifically binds to Activin or Activin-related ligand and a second antigen-binding molecule that specifically binds to TGF-β ligand, wherein the multispecific antagonist molecule simultaneously neutralizes Activin signaling and TGF-β signaling in a potent manner.
“potent manner”: the specification does not define the meaning of the phrase. The specification refers to specific antagonists having strongly neutralizing effects on signaling for some target antigens:
[0230] As depicted in FIGS. 6-8, bifunctional multi-specific antagonists A115, A116, A117 and A118 A-119 and A-120 strongly neutralize Activin A and Activin B (FIG. 6), TGF-β1 and TGF-β3 (FIG. 7), and GDF-8 and GDF-11 (FIG. 8) in cell-based assays.
The specification supports measuring neutralizing activin signaling and TGF-beta signaling with the mutilspecific antagonist antibodies in cell-based assays that measure IC50:
[0040] FIG. 7 depicts line graphs showing that multispecific antagonist molecules A115, A116, A117 and A118 potently neutralize Activin A and Activin B in cell-based assays. The IC50 values were calculated and plotted using Prism software (GraphPad Software).
[0041] FIG. 8 depicts line graphs showing that multispecific antagonist molecules A115, A116, A117 and A118 potently neutralize TGF-β1 and TGF-β3 in cell-based assays. The IC50 values were calculated and plotted using Prism software (GraphPad Software).
The correlation between IC50 values and potency are not well explained in the specification. See www.promegaconnections.com/ic50-ec50-and-kd-what-is-the-difference-and-why-do-they-matter.
“While Kd measures the strength of binding, IC50 measures functional inhibition and is the concentration of a drug or molecule that is needed to inhibit a biological process or response by 50% (meaning it is one half the maximal inhibitory concentration). This inhibition is tied to a specific cellular activity— like cell growth or protein activity. Typically, dose response curves are used to determine IC50. A low IC50 value suggests higher potency, meaning less drug is needed to achieve the desired response.”
Claims 36-42, 44 and 47 drawn to isolated bifunctional multispecific antagonist comprising a first antigen-binding polypeptide that specifically binds to Activin ligand or Activin-related ligand (“Activin-Binding Polypeptide”) and a second antigen-binding polypeptide that specifically binds to TGF-β ligand (“TGF-β-Binding Polypeptide”) and a third antigen-binding polypeptide that specifically binds to either T-cell immune checkpoint PD-1 ligand, PD-L1 ligand or CTLA-4 ligand (“PD-1/PD-L1/CTLA-4-Binding Polypeptide”), wherein the bifunctional multispecific antagonist molecule simultaneously inhibits TGF-β, Activin, and the T-cell immune checkpoint.
“inhibit”: is defined in the specification in the context of a blocking or antagonist antibody
[0093] A “blocking” antibody or an “antagonist” antibody is one that inhibits or reduces a biological activity of the antigen it binds. In some embodiments, blocking antibodies or antagonist antibodies substantially or completely inhibit the biological activity of the antigen. For example, the bispecific antibodies of the invention block the signaling through TGF-β and Activin so as to inhibit TGF-β/Activin-Smad2/3 signaling pathway.
The antigen binding molecules are infinite in scope and not defined by a composite structure comprising the combination of elements as a whole that meet the structure function requirement of the claims much less under MPEP 2163 II(A) (3)(a):
An applicant may also show that an invention is complete by disclosure of sufficiently detailed, relevant identifying characteristics which provide evidence that inventor was in possession of the claimed invention, i.e., complete or partial structure, other physical and/or chemical properties, functional characteristics when coupled with a known or disclosed correlation between function and structure, or some combination of such characteristics. Enzo Biochem, 323 F.3d at 964, 63 USPQ2d at 1613 (quoting the Written Description Guidelines, 66 Fed. Reg. at 1106, n. 49, stating that “if the art has established a strong correlation between structure and function, one skilled in the art would be able to predict with a reasonable degree of confidence the structure of the claimed invention from a recitation of its function”.). “Thus, the written description requirement may be satisfied through disclosure of function and minimal structure when there is a well-established correlation between structure and function.” Id.
Disclosure in the Specification
The specification and claim 30 defines 1st and 2nd antigen binding molecules comprising the multispecific antagonist:
The first antigen-binding molecule that specifically binds to Activin or Activin-related ligand (“Activin-binding polypeptide”) is selected from the group consisting of an anti-Activin antibody (including anti-Activin A antibody and anti-Activin B antibody), a fragment of anti-Activin antibody, wild-type Activin Type 2A Receptor (ActRIIA) or Activin Type 2B Receptor (ActRIIB) extracellular domains (ECDs), modified ActRIIA and ActRIIB extracellular domains, wild-type and modified native Activin-binding proteins such as follistatin, follistatin-like protein and pro-peptide, and a phage display-derived polypeptide targeting Activin or Activin-related ligand; and wherein the second antigen-binding molecule that specifically binds to TGF-β ligand (“TGF-β-binding polypeptide”) is selected from the group consisting of an anti-TGF-β antibody, a fragment of anti-TGF-β antibody, wild-type TGF-β type-2 receptors (including TGFβRIIA and TGFβRIIB) extracellular domains (ECDs), modified TGFβRIIA and TGFβRIIB extracellular domains, and a phage display-derived antagonistic polypeptide targeting TGF-β ligand.
The multispecific antagonists of the invention are disclosed in Tables 5 and 6
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None of the antagonists are small molecule drugs, antisense and non-peptides or non-proteins. On close inspection, that testing of inventive molecules is set forth herein above: enabling for neutralizing Smad2/3 signaling (clones A115, A116, A117, A118; Example 3), cancer cell migration (clone A116; Example 4), cancer cell colony formation (clone A116; Example 5), and neutralizing lung fibrosis (clone A116; Example 6).
A115 (SEQ ID NO: 1/19): hActRIIA-ECD/ hTGF-B RII-ECD isoform 1
A116 (SEQ ID NO: 1/21): hActRIIA-ECD/ hTGF-B RII-ECD isoform 2
A117 (SEQ ID NO: 4/19): hfollistatinΔHBS/ hTGF-B RII-ECD isoform 1
A118 (SEQ ID NO: 4/21): hfollistatinΔHBS/ hTGF-B RII-ECD isoform 2.
Accordingly, there is no other intrinsic or extrinsic evidence showing that just any combination of the claimed multispecific or bifunctional multispecific antagonists would achieve the intended method outcomes.
Applicants have not shown by a preponderance of the evidence that just any combination of any antagonistic binding molecule for Activin/Activin-related ligand plus any antagonistic binding molecule for TGF-B possess simultaneous neutralization in a potent manner.
Applicants have not shown by a preponderance of the evidence that just any combination of any antagonistic binding molecule for Activin/Activin-related ligand, any antagonistic binding molecule for TGF-B, and any antagonistic binding molecule for T-cell immune checkpoint possess simultaneous inhibition.
Status of the Art for therapeutic antibodies
Assuming, arguendo, the 1st, 2nd and 3rd antigen binding molecules are based on antibody VH/VL CDR1-3 and/or VH/VL domains, Applicant has not provided a common structure sufficient to visualize the genus of all possible multispecific antagonists for either claim 28 or claim 36. While the disclosure provides the amino acid sequences of some constructs (Tables 5 and 6), one of ordinary skill in the art would not have known which class of antigen binding molecules could be used much less paired in order to possess the functional attributes.
Therapeutic antibodies are still not understood well enough to allow researchers to predict with certainty what modifications can be made to a primary antibody sequence such that binding is maintained. “[T]he major test of understanding is whether the changes associated with antibody maturation can be predicted with any reasonable accuracy, and whether there is sufficient information for developing therapeutic antibodies,” Vajda et al., “Progress toward improved understanding of antibody maturation,” Current Opinion in Structural Biology, 67 pp. 226-231 (2021 (PTO 892)) at p. 226, col. 2, lines 20-24.
As recently as 2020, researches were still speculating as to how to reliably identify further putative binders from antibody sequence data, see, e.g., Marks et al., “How repertoire data are changing antibody science,” J. Biol. Chem. 295(29) 9823-9837 (2020 (PTO 892)), acknowledging that “there is a vast amount of the antibody sequence space that remains unknown,” p. 9831, col. 2, para. 2.
Computational and machine learning approaches for sequence-based prediction of paratope-epitope interactions are accumulating, but “it remains unclear whether antibody-antigen binding is predictable” (Akbar et al., Cell Reports 34, 108856, Mar. 16, 2021 at p. 2, col. 2, para. 2 (PTO 892)). The current state of the art continues to work toward finding an effective and efficient prediction tool for reliably assigning antibody structure based on known target epitopes. See e.g., Lo et al., “Conformational epitope matching and prediction based on protein surface spiral features,” BMC Genomics volume 22, Article number: 116 (2021 (PTO 892)) (disclosing new algorithms that calculate physicochemical properties, such as polarity, charge or the secondary structure of residues within the targeted protein sequences, and then applying quantitative matrix analyses or machine-learning algorithms to predict linear and conformational epitopes).
It is asserted that neither the specification nor the state of art at the time of filing disclosed structural features common to the members of the genus of multispecific antagonists, which would support the premise that the inventors possessed the full scope of the claimed invention.
Scope of Enablement
13. Claims 45-47 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 neutralizing Smad2/3 signaling (clones A115, A116, A117, A118; Example 3), cancer cell migration (clone A116; Example 4 (A549 lung cancer)), cancer cell colony formation (clone A116; Example 5 (A549 lung cancer)), and neutralizing lung fibrosis (clone A116; Example 6), does not reasonably provide enablement for treating (therapeutic) any NF-κB/Smad2/3 signaling-associated disease and any cancer. 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 and use the invention commensurate in scope with these claims.
Factors to be considered in determining whether undue experimentation is required, are summarized in In re Wands, 8 USPQ2d 1400 (Fed. Cir. 1988). They include the nature of the invention, the state of the prior art, the relative skill of those in the art, the amount of direction or guidance disclosed in the specification, the presence or absence of working examples, the predictability of the art, the breadth of the claims, the quantity of experimentation which would be required in order to practice the invention as claimed.
Claim interpretation
The non-elected species for prevention is withdrawn from the examination.
45. A method of treating or preventing a disease condition whose pathogenesis involves the activation of both TNF-α-mediated NF-κB signaling pathway and Activin-mediated Smad2/3 signaling pathway, comprising administering to said subject a therapeutically effective amount of the composition of claim 43 to the subject. The method depends from generic Claim 28.
46. A method of treating or preventing cancer, comprising administering to said subject a therapeutically effective amount of the composition of claim 43 to the subject, wherein the cancer is selected from the group consisting of melanoma, multiple myeloma, lung cancer, pancreatic cancer, colorectal cancer, liver cancer, gastric cancer, kidney cancer, bladder cancer, head and neck cancer, thyroid cancer, breast cancer, ovarian cancer, endometrial cancer, testicular cancer, prostate cancer and brain cancer. The method depends from generic Claim 28.
47. A method of treating or preventing cancer, comprising administering to said subject a therapeutically effective amount of the composition of claim 44 to the subject, wherein the cancer is selected from the group consisting of melanoma, multiple myeloma, lung cancer, pancreatic cancer, colorectal cancer, liver cancer, gastric cancer, kidney cancer, bladder cancer, head and neck cancer, thyroid cancer, breast cancer, ovarian cancer, endometrial cancer, testicular cancer, prostate cancer and brain cancer. The method depends from generic Claim 36.
No specific or preferred species are defined by a structure that correlates with a function binding the corresponding antigens, simultaneously neutralizes activin/TGB-β signaling in a “potent manner”, and is therapeutically effective in treating the genus of diseases and or cancers as claimed.
Disclosure in the Specification
The multispecific antagonists of the invention are disclosed in Tables 5 and 6
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None of the antagonists are small molecule drugs, antisense and non-peptides or non-proteins. Accordingly, the method claims are not enabled for the use of just any class of drugs. On close inspection, that testing of inventive molecules is set forth herein above:
enabling for neutralizing Smad2/3 signaling (clones A115, A116, A117, A118; Example 3), cancer cell migration (clone A116; Example 4), cancer cell colony formation (clone A116; Example 5), and neutralizing lung fibrosis (clone A116; Example 6).
A115 (SEQ ID NO: 1/19): hActRIIA-ECD/ hTGF-B RII-ECD isoform 1
A116 (SEQ ID NO: 1/21): hActRIIA-ECD/ hTGF-B RII-ECD isoform 2
A117 (SEQ ID NO: 4/19): hfollistatinΔHBS/ hTGF-B RII-ECD isoform 1
A118 (SEQ ID NO: 4/21): hfollistatinΔHBS/ hTGF-B RII-ECD isoform 2.
Accordingly, there is no other intrinsic or extrinsic evidence showing that just any combination of the claimed multispecific or bifunctional multispecific antagonists would achieve the intended method outcomes. Applicants have not shown by a preponderance of the evidence that just any combination of any antagonistic binding molecule for Activin/Activin-related ligand plus any antagonistic binding molecule for TGF-B possess simultaneous neutralization in a potent manner.
The claims are not commensurate in scope with the enablement provided in the specification. The specification does not support the broad scope of the claims which encompass any combination of any antagonistic binding molecule for Activin/Activin-related ligand plus any antagonistic binding molecule for TGF-B possess simultaneous neutralization in a potent manner to the extent of being sufficient to treat a disease or disorder in a subject. The scope of the claims must bear a reasonable correlation with the scope of enablement. See In re Fisher, 166 USPQ 19 24 (CCPA 1970). Without such guidance, the number of all possible combinations of antagonistic binding molecule for Activin/Activin-related ligand plus any antagonistic binding molecule for TGF-B that maintain biological activity, e.g., potent neutralization of the corresponding signaling pathways, is unpredictable and the experimentation left to those skilled in the art is unnecessarily and improperly extensive and undue. See Amgen, Inc. v. Chugai Pharmaceutical Co. Ltd., 927 F,2d 1200, 18 USPQ 1016 (Fed. Cir. 1991) at 18 USPQ 1026 1027 and Ex parte Forman, 230 USPQ 546 (BPAI 1986).
The specification provides no direction or guidance regarding how to produce the myriad combinations as broadly defined by the claims much less a sufficient amount of testing in art-recognized assays correlated with disease/cancer treatment outcomes. Undue experimentation would be required to produce the invention commensurate with the scope of the claims from the written disclosure alone.
Furthermore, the artisan of ordinary skill in the art would have been required to generate the multispecific antagonists, identify and characterize each antigen binding domain, produce and express the multispecific antagonists, measure binding characteristics (e.g., binding specificity, equilibrium dissociation constant (KD), dissociation and association rates (K off and Kon respectively), and binding affinity and/or avidity compared with the parent antibody), and then finally perform bioassays to identify any one or more of the characteristics in bioassays that correlate with method testing. The technology to perform these experiments was available at the time of application filing, but the amount of experimentation required to generate even a single multispecific antagonist and testing the functional properties would not be routine experimentation (MPEP 2164.06, “The test is not merely quantitative, since a considerable amount of experimentation is permissible, if it is merely routine, or if the specification in question provides a reasonable amount of guidance with respect to the direction in which the experimentation should proceed.” (In re Wands, 858 F.2d 731, 737, 8 USQP2d 1400, 1404 (Fed. Cir. 1988) (citing In re Angstadt, 537 F.2d 489, 502-04, 190 USPQ 214, 217-19 (CCPA 1976)).
MPEP 2138.05 Birmingham v. Randall, 171 F.2d 957, 80 USPQ 371, 372 (CCPA 1948) “To establish an actual reduction to practice of an invention directed to a method of making a product, it is not enough to show that the method was performed. “[S]uch an invention is not reduced to practice until it is established that the product made by the process is satisfactory, and [ ] this may require successful testing of the product.”
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.
The factual inquiries for establishing a background for determining obviousness under 35 U.S.C. 103 are summarized as follows:
1. Determining the scope and contents of the prior art.
2. Ascertaining the differences between the prior art and the claims at issue.
3. Resolving the level of ordinary skill in the pertinent art.
4. Considering objective evidence present in the application indicating obviousness or nonobviousness.
14. Claim(s) 28, 30, 32, 36, 43-45 is/are rejected under 35 U.S.C. 103 as being unpatentable over Pearsall (US 20200306340; priority to KR 20190115037 (2018-01-31).
Claim(s) 28, 30, 32, 36, 43-45 are prima facie obvious over Pearsall.
As regards claim 28 and 45, Pearsall teaches a multispecific antagonist comprising a first antigen-binding molecule that specifically binds to Activin or Activin-related ligand and a second antigen-binding molecule that specifically binds to TGF-β ligand at [0006]
ActRII antagonists (inhibitors) and TGFβ antagonists (particularly inhibitors of TGFβ2) can be used alone or in combination to treat cancer. In particular, it was shown that treatment with an ActRIIA polypeptide, an ActRIIB polypeptide, or a pan-specific TGFβ antibody, separately, decreased tumor burden and increased survival time a cancer model. Moreover, it was shown that an ActRII antagonist in combination with a TGFβ antagonist can be used to synergistically increase antitumor activity compared to the effects observed with either agent alone.
Pearsall teaches the generic multispecific antagonist molecule simultaneously neutralizes Activin signaling and TGF-β signaling in a potent manner at [0039]
In some embodiments, an agent to be used in accordance with the methods and uses described herein is both an ActRII and TGFβ antagonist (ActRII:TGFβ). An ActRII:TGFβ antagonist is an agent that can inhibit one or more of ActRIIA, ActRIIB, ALK4, ActRII- and ALK4-binding ligands [e.g., GDF11, GDF8, activin (activin A, activin B, activin AB, activin C, activin E) BMP6, GDF3, BMP10, and/or BMP9], and downstream signaling mediators (e.g., Smads) as well as inhibit one or more of TGFβRII; ALK5; betaglycan; ALK5-, and betaglycan-binding ligands [e.g., TGFβ1, TGFβ2 and/or TGFβ3], and downstream signaling mediators (e.g., Smads). For example, an ActRII:TGFβ antagonist may be a bi-specific antibody that binds to and inhibits both activin A and TGFβ2. As another example, an ActRII:TGFβ antagonist may be a polynucleotide or small molecule that inhibits one or more Smads, particularly Smads 2 and 3.
As regards claim 30, Pearsall teaches the TGF-B binding polypeptide at [0050]
In certain aspects, a TGFβ antagonist of the disclosure is an antibody or combination of antibodies. In some embodiments, the TGFβ antagonist antibody binds to TGFβ1. In some embodiments, the TGFβ antagonist antibody binds to TGFβ2. In some embodiments, the TGFβ antagonist antibody binds to TGFβ3. In some embodiments, the TGFβ antagonist is a multi-specific antibody. In some embodiments, the TGFβ antagonist is a bi-specific antibody. In some embodiments, the TGFβ antagonist antibody binds to TGFβ1 and TGFβ2. In some embodiments, the TGFβ antagonist antibody binds to TGFβ1 and TGFβ3. In some embodiments, the TGFβ antagonist antibody binds to TGFβ1 and TGFβ2. In some embodiments, the TGFβ antagonist antibody binds to TGFβ2 and TGFβ3. In some embodiments, the TGFβ antagonist antibody binds to TGFβ1, TGFβ2, and TGFβ3. In some embodiments, the TGFβ antagonist antibody is fresolimumab. In some embodiments, the TGFβ antagonist antibody binds to TGFβRII. In some embodiments, at TGFβ antagonist antibody that binds to TGFβRII further binds to one or more of TGFβ1, TGFβ2, TGFβ3, ALK5, and betaglycan. In some embodiments, the TGFβ antagonist antibody binds to ALK5. In some embodiments, at TGFβ antagonist antibody that binds to ALK5 further binds to one or more of TGFβ1, TGFβ2, TGFβ3, TGFβRII, and betaglycan. In some embodiments, the TGFβ antagonist antibody binds to betaglycan. In some embodiments, at TGFβ antagonist antibody that binds to betaglycan further binds to one or more of TGFβ1, TGFβ2, TGFβ3, TGFβRII, and ALK5. In some embodiments, a TGFβ antagonist antibody of the disclosure is also an ActRII antagonist antibody, particularly in the case of multi-specific antibodies, for example, bi-specific antibodies. Therefore, in some embodiments, an antibody that binds to one or more of TGFβ1, TGFβ2, TGFβ3, TGFβRII, ALK5, and betaglycan and further binds to one or more of ActRIIA, ActRIIB, ALK4, activin A, activin B, GDF11, GDF8, GDF3, BMP6, BMP10, and BMP9. In some embodiments, a multispecific antibody of the disclosure binds to one or more of TGFβ1, TGFβ2, TGFβ3 and activin. In some embodiments, a multispecific antibody of the disclosure binds to TGFβ2 and activin A.
Pearsall teaches the Activin or ActRII antagonist at [0051]
In certain aspects, an ActRII antagonist of the disclosure is an antibody or combination of antibodies. In some embodiments, the ActRII antagonist is a multi-specific antibody. In some embodiments, the ActRII antagonist is a bi-specific antibody. In some embodiments, the ActRII antagonist antibody binds to one or more ligands selected from the group consisting of: activin A, activin B, GDF11, GDF8, GDF3, BMP6, BMP10, and BMP9. In some embodiments, the ActRII antagonist antibody binds activin A. In some embodiments, the ActRII antagonist antibody binds to ActRIIA. In some embodiments, the ActRII antagonist antibody binds to ActRIIB. In some embodiments, the ActRII antagonist antibody binds to ActRIIA and ActRIIB. In some embodiments, the ActRII antagonist antibody binds to ALK4. In some embodiments, an ActRII antagonist antibody that binds to one or more of activin A, activin B, GDF11, GDF8, GDF3, BMP6, BMP10, and BMP9 further binds to one or more of ActRIIA, ActRIIB, and ALK4. In some embodiments, a ActRII antagonist antibody of the disclosure is also an TGFβ antagonist antibody, particularly in the case of multi-specific antibodies, for example, bi-specific antibodies. Therefore, in some embodiments, an antibody that binds to one or more of ActRIIA, ActRIIB, ALK4, activin A, activin B, GDF11, GDF8, GDF3, BMP6, BMP10, and BMP9 further binds to one or more of TGFβ1, TGFβ2, TGFβ3, TGFβRII, ALK5, and betaglycan.
Pearsall teaches the Activin or ActRII ECD domain antagonist at [0061]
FIG. 9 shows an alternative nucleotide sequence encoding ActRIIB(25-131)-hFc (the coding strand is shown at top, SEQ ID NO: 126, and the complement shown at bottom 3′-5′, SEQ ID NO: 127). This sequence confers a greater level of protein expression in initial transformants, making cell line development a more rapid process. Sequences encoding the TPA leader (nucleotides 1-66) and ActRIIB extracellular domain (nucleotides 73-396) are underlined, and substitutions in the wild type nucleotide sequence of the ECD (see FIG. 8) are highlighted. The corresponding amino acid sequence for ActRIIB(25-131) is also shown.
Pearsall teaches the TGFβ ECD domain antagonist at [0062]
FIG. 10 shows the amino acid sequence of native precursor for the B (short) isoform of human TGFβ receptor type II (hTβRII) (NP_003233.4; SEQ ID NO: 34). Solid underline indicates the mature extracellular domain (ECD) (residues 23-159), and double underline indicates valine that is replaced in the A (long) isoform. Dotted underline denotes leader (residues 1-22).
AS regards claim 32, Pearsall teaches antibody fragments at [0228]
The term antibody is used herein in the broadest sense and encompasses various antibody structures, including but not limited to monoclonal antibodies, polyclonal antibodies, multispecific antibodies (e.g., bispecific antibodies), and antibody fragments so long as they exhibit the desired antigen-binding activity. An antibody fragment refers to a molecule other than an intact antibody that comprises a portion of an intact antibody that binds the antigen to which the intact antibody binds. Examples of antibody fragments include but are not limited to Fv, Fab, Fab′, Fab′-SH, F(ab′).sub.2; diabodies; linear antibodies; single-chain antibody molecules (e.g., scFv); and multispecific antibodies formed from antibody fragments. See, e.g., Hudson et al. (2003) Nat. Med. 9:129-134; Plückthun, in The Pharmacology of Monoclonal Antibodies, vol. 113, Rosenburg and Moore eds., (Springer-Verlag, New York), pp. 269-315 (1994); WO 93/16185; and U.S. Pat. Nos. 5,571,894, 5,587,458, and 5,869,046. Antibodies disclosed herein may be polyclonal antibodies or monoclonal antibodies. In certain embodiments, the antibodies of the present disclosure comprise a label attached thereto and able to be detected (e.g., the label can be a radioisotope, fluorescent compound, enzyme, or enzyme co-factor). In preferred embodiments, the antibodies of the present disclosure are isolated antibodies.
AS regards claim 36, Pearsall teaches multispecific antagonists comprising activin:TGF-B:T-cell immune checkpoint at [0337]
Although checkpoint inhibitor against CTLA4, PD1 and PD-L1 are the most clinically advanced, other potential checkpoint antigens are known and may be used as the target of therapeutic inhibitors in combination with the subject ActRII antagonists, such as LAG3, B7-H3, B7-H4 and TIM3 (Pardoll, 2012, Nature Reviews Cancer 12:252-264).
AS regards claims 43-47, Pearsall teaches the multispecific antagonists comprised in pharmaceutical compositions and methods of treatment for disease associated with disease or cancers associated with TGF-B/Activin signaling at [0048]
In certain aspects, the disclosure provides pharmaceutical preparations comprising one or more ActRII antagonist and/or TGFβ antagonist and a pharmaceutically acceptable carrier. A pharmaceutical preparation may also comprise one or more additional active agents such as a compound that is used to treat or prevent a disorder or condition as described herein [e.g., leukemia, melanoma (e.g., metastatic melanoma), lung cancer (e.g., squamous non-small cell lung cancer, renal cell carcinoma, bladder cancer, mesothelioma (e.g., metastatic mesothelioma), head and neck cancer (e.g., head and neck squamous cell cancer), esophageal cancer, gastric cancer, colorectal cancer (e.g., colorectal carcinoma), liver cancer (e.g., hepatocellular carcinoma), lymphoma, multiple myeloma, myelodysplastic syndrome, breast cancer, ovarian cancer, cervical cancer, glioblastoma multiforme, and sarcoma (e.g., metastatic sarcoma)].
[0364] In certain aspects, ActRII and/or TGFβ antagonists, or combinations of such antagonists, of the present disclosure can be administered alone or as a component of a pharmaceutical formulation (also referred to as a therapeutic composition or pharmaceutical composition). A pharmaceutical formation refers to a preparation which is in such form as to permit the biological activity of an active ingredient (e.g., an agent of the present disclosure) contained therein to be effective and which contains no additional components which are unacceptably toxic to a subject to which the formulation would be administered.
The motivation to use immune enhancement mechanisms in disease/ cancer is recognized is recognized in Pearsall. Pearsall teaches in cancer treatment, it has long been recognized that chemotherapy is associated with high toxicity and can lead to emergence of resistant cancer cell variants. Even with targeted therapy against overexpressed or activated oncoproteins important for tumor survival and growth, cancer cells frequently mutate and adapt to reduce dependency on the targeted pathway, such as by utilizing a redundant pathway. Cancer immunotherapy is a new paradigm in cancer treatment that, instead of targeting cancer cells, focuses on activation of the immune system. Its principle is to rearm the host's immune response, especially the adaptive T cell response, to identify and kill the cancer cells and to achieve long-lasting, protective immunity. As these therapies are directed at increasing activity of the immune system, cancer immunotherapy agents are also being investigated for the ability to improve immune responses in other disorders, particularly in infectious diseases wherein the pathogen is immune-evasive and/or compromises the host immune system.
Pearsall provides not only the motivation but reasonable and predictable success teaching the ActRII and TGFβ (and T-cell immune checkpoint) antagonists are used as immunotherapeutics, particularly to treat a wide variety of cancers (e.g., cancers associated with immunosuppression and/or immune exhaustion).
Conclusion
15. No claims are allowed.
16. An activin binding polypeptide of the sequence of SEQ ID NO: 10-17 (claim 31); and a TGF-beta binding polypeptide of the sequence of SEQ ID NO: 22-25 (claim 31) is free from the art. The mutlispecific antagonist comprising a sequence of SEQ ID NO: 54-71 (claim 34) is free from the art. A heavy chain for a mutlispecific antagonist comprising the sequence of SEQ ID NO: 72-84 (claim 35) is free from the art.
17. Any inquiry concerning this communication or earlier communications from the examiner should be directed to LYNN A. BRISTOL whose telephone number is (571)272-6883. The examiner can normally be reached Mon-Fri 9 AM-5 PM.
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/LYNN A BRISTOL/Primary Examiner, Art Unit 1643