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 1-32 are the original claims filed 8/29/2022. In the Preliminary Amendment of 3/20/2023, claims 4, 11, 15, 21, and 27-32 are amended and claims 2, 5-9, 12-13, 16-20, and 22-26 are canceled. In the Preliminary Amendment of 9/8/2025, claims 1, 3-4, 10-11, 14-15, 21, 27-30 and 32 are amended. In the response of 2/23/2026, claims 1, 11, 14, 15, and 21 are amended, claims 3, 4, and 10 are cancelled, and new claims 33-39 are added.
Claims 1, 11, 14-15, 21, and 27-39 are pending. The amendment of the claims raises new grounds for objection and rejection. The Office Action is final.
Priority
2. USAN 17/907,781, filed 08/29/2022, is a National Stage entry of PCT/US21/ 20291, International Filing Date: 03/01/2021, PCT/US21/20291 Claims Priority from Provisional Application 62/983,374, filed 02/28/2020. Applicants’ submission of a revised version of FIG. 7 that includes all of the SEQ ID NOs in clean and marked-up versions is acknowledged.
Information Disclosure Statement
3. As of 4/14/2026, a total of seven (7) IDS are filed: 3/29/2023; 4/15/ 2024; 7/12/2024; 4/18/2025; 7/10/2025; 10/8/2025; and 2/23/2026. The corresponding initialed and dated 1449 is considered and of record.
Withdrawal of Objections
Drawings
4. The corrected drawing sheet for Figure 7 is in compliance with 37 CFR 1.121(d) and 37 CFR 1.821-1.825.
Specification
5. The objection to the abstract of the disclosure is withdrawn.
6. The objections to the disclosure because of informalities is withdrawn.
a) The figure legend for Figure 7 is amended to recite sequence identifiers (SEQ ID NOs).
b) The specification is amended to rectify the improper use of the term, i.e., Tween, Octet, SpetraMAx, BioFX, NuPage, Carestream, GenBank, which is a trade name or a mark used in commerce. The objection the terms Tris, ATCC, ForteBio, and NCBI is dropped for the reasons set forth in the Response.
Claim Objections
7. The objections to Claims 1, 3-4, 10-11, 14-15, 21, and 27-32 because of informalities is moot for the canceled claims and withdrawn for the pending claims.
a) The amendment of Claims 1, 3-4, 10-11, 14-15, 21, and 27-32 is a bona fide effort to rectify the deficiencies for improper punctuation.
b) Claims 3-4 and 10 are canceled. Claims 11, 14, and 21 are amended to bring the claims into consistency.
c) Claim 31 is amended to recite “the vascular condition[[s]] is…”
Withdrawal of Rejections
Written Description
8. The rejection of Claims 30-32 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 is withdrawn. The amendment of the claims removes the method invention from achieving preventative outcomes.
Claim Rejections - 35 USC § 103
9. The rejection of Claim(s) 1, 3, 10, and 27-31 under 35 U.S.C. 103 as being unpatentable over Weber et al (WO 2019/086331; published 9/5/2019; BAYER; IDS 3/29/2023) is moot for the canceled claims and withdrawn for the pending claims. The amendment of the claims to recite the scfv for each of elements (i) and (ii) of claim 1 and the insertion of the “wherein” clause for the anti-ALK4, anti-ALK6 and anti-ALK7 binding domains overcomes the rejection.
Rejections Withdrawn-in-part/ Maintained-in-Part
Claim Rejections - 35 USC § 112(a)
The following is a quotation of the first paragraph of 35 U.S.C. 112(a):
(a) IN GENERAL.—The specification shall contain a written description of the invention, and of the manner and process of making and using it, in such full, clear, concise, and exact terms as to enable any person skilled in the art to which it pertains, or with which it is most nearly connected, to make and use the same, and shall set forth the best mode contemplated by the inventor or joint inventor of carrying out the invention.
The following is a quotation of the first paragraph of pre-AIA 35 U.S.C. 112:
The specification shall contain a written description of the invention, and of the manner and process of making and using it, in such full, clear, concise, and exact terms as to enable any person skilled in the art to which it pertains, or with which it is most nearly connected, to make and use the same, and shall set forth the best mode contemplated by the inventor of carrying out his invention.
Written Description
10. The rejection of Claims 130-32 and 39 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 is:
Moot for the canceled claims (Claims 3 and 10);
Withdrawn-in-part for claims 1, 14, and 27-29 (claim 1 amended to replace the optional phrase with scfv for the antigen-binding fragment; identify the VH/VL CDR1-3, VH/VL, and full scfv sequence for the anti-ALK4, anti-ALK6 and ALK7 antigen binding domains from canceled claim 4); and
Maintained-in-part for claims 30-32 that depend from amended claim 1. Claim 39 is joined under the rejection because it depends from claim 1 and recites identical subject matter as rejected claim 32
Applicants allege ample number of species have been described to support the breadth of claim 1 citing table on pp. 34-35 and Tables B and C; and claim 1 is amended to incorporate the subject matter of canceled claim 4.
Response to Arguments
The rejected claims are drawn to therapeutic antibodies, where the tetravalent construct of claim 1(i) is defined for the scfv feature for the 1st antigen binding domain but not in claim 1(ii) for the scfv feature for the 2nd antigen binding domain. The VH/VL CDR1-3 structures that impart both binding to BMPRII protein much less the functionalized structure for its therapeutic attribute in treating any vascular condition (claim 30) or any liver fibrosis (claims 32 and 39) for the construct, are not defined in the claims.
The tetravalent antibody constructs examined by experimentation in Example 3 and made from scFv clones binding to ACVRL1 (ACVRL1.8) and BMPR2 (BMPR2.12) are expressed as a single molecule, with spacers of varying lengths as specified. Alternatively, they were designed as tetravalent IgG-Fc proteins generated by two 10 bispecific scFvs expressed as an IgG Fc fusion protein, then associated as two disulfide-linked homodimeric Fc complexes.
Data in Figures 8 and 9 reveal the constructs were able to generate potent BMP signaling in cells (see FIG. 8) Tetravalent complexes of anti-ACVRL1 and anti-BMPR2 elicited BMP transcriptional activity in endothelial cells. TIME cells (human telomerase immortalized microvascular 15 endothelial cells) were cultured and transiently transfected with plasmid expressing the BMP response element (BRE-luciferase) reporter. BMP9 (1 ng/mL) elicited BMP transcriptional activity in these cells, based on the detection of luciferase activity, divided by the relative number of cells, based on an MTS colorimetric viability assay (RLU/viability). A bispecific construct consisting of a single anti-ACVRL1 scFv and a 20 single anti-BMPR2 scFv joined by a spacer, and with a C-terminal His tag domain (“ACVRL1.8-L-BMPR2. 12-His”) did not elicit signaling activity by itself, but was active when combined with monoclonal anti-His antibodies to complex these bispecific molecules into a tetravalent complex. To demonstrate the signaling of a tetravalent complex when expressed as a disulfide linked heterotetramer, a tetravalent complex 25 consisting of the same bispecific molecule expressed as an IgG Fe domain fusion protein and assembled into disulfide linked homodimers (“ACVRL1.8-L-BMPR2. 12-Short-Fc”) elicited potent signaling. Consistent with in vitro signaling activity, in vivo signaling BMP signaling activity was demonstrated (Fig. 9) based on Id1 gene transcriptional activity assayed in 30 whole lung tissues from 8-week old mice 24 hours after tail vein injection of saline.
Accordingly, the specification describes a limited number of species of antibody having the structure and functions with BMP signaling effects on lung tissues. The working examples are not shown to have a preventative effect on either lung or liver-related disorders.
The Office Action of 10/23/2025 (excerpted below) surveys the art-recognized unpredictability in the screening of antibodies for therapeutic use, in vivo, to which Applicants have not responded. Accordingly, as regards claims 30-32 and 39, the response is incomplete.
“The claims encompass a genus of binding molecules and antibody fragments with binding activity for BMPRI and BRMPII beyond those taught in the specification. Because applicant seeks patent protection for all such BMPRI and BRMPII binding domains, this genus must be adequately described. A description adequate to satisfy 35 U.S.C. § 112(a) must clearly allow persons of ordinary skill in the art to recognize that the inventor invented what is claimed (Ariad Pharms., Inc. v. Eli Lilly & Co., 598 F.3d 1336, 1351 (Fed. Cir. 2010) (en banc) (citation omitted, alteration in original). The purpose of the written description requirement is to “ensure that the scope of the right to exclude, as set forth in the claims, does not overreach the scope of the inventor’s contribution to the field of art as described in the patent’s specification” (In re Katz Interactive Call Processing Patent Litig. 639 F.3d 1303, 1319 (Fed. Cir 2011).
Scope of the claimed genus
Here is the case where all of the claims encompass a vast repertoire BMPRI and BRMPII binding domains. With respect to antibody formats, variations to the VH and VL domains include the complementarity determining regions (CDRs) that could vary relative to the VLC and VHC and CDRs found in a parental antibody in addition to the VL frameworks and VH frameworks as one example. Antibody fragments comprising a de minimus CDR domain are envisioned in the teachings of the specification. The genus of molecules and fragments thereof encompassed by the claims is therefore very large and there is substantial variation within the genus.
State of the Relevant Art
By the time the invention was made, it was also well-established in the art that the formation of an intact antigen-binding surface on an antibody required the association of the complete heavy and light chain variable regions, each of which consists of three CDRs which provide the majority of the contact residues for the binding of the antibody to its target epitope (Almagro & Franssen, Frontiers in Bioscience, 13:1619-33 (2008) (PTO-892) (see Section 3 “Antibody Structure and the Antigen Binding Site” and Figure 1). While this overall architecture is shared among antibodies from a wide variety of sources (human, rat, mouse, rabbit), the structure each antibody uses to bind its particular epitope on an antigen is structurally distinct and is formed by a recombination event that results in high variability at the amino acid sequence level, even when the same antigen is bound (Edwards et al., J Mol Biol 334:103-118 (2003) (PTO-892); see also Marchalonis et al., Dev & Comp Immunol. 30:223-247 (2006) (PTO-892), summarized in Abstract and Conclusion.
Methods of preparing antibodies from a variety of species to a protein or peptide of interest were well-established in the art at the time the invention was made. But application of those methods to any given antibody is still a matter of trial-and-error testing, and the skilled person could not automatically predict which residues in the CDRs would be tolerant of mutations, or which amino acid substitutions would maintain antigen binding. Overall, at the time the invention was made, the level of skill for preparing antibodies and then selecting those antibodies with desired functional properties was high. For example, it is generally the case that absent the fundamental structure provided for by all six CDRs of a parental antibody in the context of appropriate VH and VL framework sequences, a person of ordinary skill cannot visualize or otherwise predict, what an antibody with a particular set of functional properties would look like structurally.
Moreover, persons of ordinary skill in the art have long since acknowledged that even minor changes in the amino acid sequences of the VH and VL, particularly in the CDRs, may dramatically affect antigen-binding function. Lippow, for example, teaches that a single point mutation in the CDR of a parent antibody led to as much as an eightfold improvement in binding affinity in the resulting mutant (p. 1172, left col., lines 7-8 from end of first full paragraph and Table 1a) (Lippow et al., “Computational design of antibody-affinity improvement beyond in vivo maturation,” Nature Biotechnology, 25(10):1171-1176 (2007) (PTO-892).
Sulea teaches that individual point mutations gave an improvement of one order of magnitude in binding affinity, which in turn, generated a 6-fold enhancement of efficacy at the cellular level (Abstract) (Sulea et al., “Application of Assisted Design of Antibody and Protein Therapeutics (ADAPT) improves efficacy of a Clostridium difficile toxin A single-domain antibody," Scientific Reports, 8(260):1-11 (2018) (PTO-892). Hasegawa et al. reports that a single amino acid substitution in the variable region was sufficient to alter the efficiency of biosynthesis and the variant antibody acquired stronger binding affinity to its antigen than the parent (Hasegawa et al., “Single amino acid substitution in LC-CDR1 induces Russell body phenotype that attenuates cellular protein synthesis through elF2a phosphorylation and thereby downregulates IgG secretion despite operational secretory pathway traffic,” MABS, VOL. 9, NO. 5, pp. 854-873 (2017) (PTO-892)). Altshuler teaches that generally, “CDR mutations should not involve residues that can play structural functions (form parts of the domain ‘internal core’, internal salt bridges, hydrogen bonds, etc.).” “Usually these are conservative residues, and any substitution of these residues causes decrease[s] in affinity” (Altshuler et al., “Generation of Recombinant Antibodies and Means for Increasing Their Affinity,” Biochemistry (Moscow), 75(13):1584-1605 (2010) at p. 1600, col. 1, para. 2, lines 1-5 (PTO-892). Accordingly, a person of ordinary skill in the art would have recognized that it was highly unpredictable that any of the CDRs or FRs could be modified to create an unlimited change in amino acids for both the CDRs and FRs of the claimed antibodies, without increasing, eliminating, or in some way altering antigen binding.
Summary of species disclosed in the specification
Applicant’s specification fully discloses bispecific constructs in Example 2 and tetravalent constructs in Example 3. Most notably, Applicants specification does not provide a sequence for the claimed ALK5 antigen binding domain.
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Are the disclosed species representative of the claimed genus?
The genus of all possible binding molecules much less antibodies encompassed by the claims would be structurally distinct but unpredictable whether the structure/ function correlation was met for binding to BMPRI and BRMPII, respectively. The disclosed species include VH/VL domain pairs with corresponding binding activity to BMPRI and BRMPII, respectively. The specification does not identify which CDRs, which combination of fewer than all six CDRs, or which subset of residues in the combination of CDRs is essential for the recited function of binding BMPRI and BRMPII, respectively. Neither the specification nor the prior art provides guidance as to what structural changes can be made to the parent sequences and still predictably arrive at an antibody much less fragments thereof that bind to BMPRI and BRMPII, respectively. The disclosed species therefore do not represent the claimed genus of tetravalent antigen binding domains.
Has Applicant provided a common structure sufficient to visualize the genus?
Applicant has not provided a common structure sufficient to visualize the genus of all possible functional antigen binding domains for BMPRI and BRMPII, respectively. One of ordinary skill in the art would not know which residues could be eliminated, replaced or added while still maintaining BMPRI or BRMPII selectivity and affinity.
While the prior art contains disclosure as to the structural features of several anti- BMPRI and BRMPII antibodies, it is unclear what structural features these antibodies need to share in order to maintain binding affinity and stability. Even in 2021, therapeutic antibodies (see claims 30-31) 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.
Even though the protein sequence of BMPRI and BRMPII was known in the art, this would not have translated into knowledge of the genus of antibodies that could possibly engage either one. 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 for reliably assigning different antibody structures based on sequence data for two antibody clones, which would support the premise that the inventors possessed the full scope of the claimed invention.”
The rejection is maintained.
New Grounds for Objection
Claim Objections
11. Claims 1, 11, 14-15, 21, and 27-39 are objected to because of the following informalities:
a) Claims 1, 11, 14, 27-32 are objected to for improper numbering of the romanettes. Amend the final “wherein” clause of claim 1 to replace “(iv)”, “(vi)” and “(vi)” with “[(iv)] (a)”, “[(vi”)] (b)”and “[(vi)] (c)”.
b) Amend claim 1 to delete “or” between elements (iv) and the first instance of (vi) in the final “wherein” clause.
c) Amend claim 15 to delete “or” between elements (i)-(iv).
d) Amend claim 21 to delete “or” between elements (i)-(ii).
e) Claims 33-38 are objected to for improper numbering of the romanettes. Amend the final “wherein” clause of claim 33 to replace “(i)” and “(ii)” with “[(i)] (a)” and “[(ii)] (b).”
f) Amend claim 33 to delete “or” between elements (i) and (ii) of the final “wherein” clause.
g) Amend claims 37 and 39 to recite “to [a] the subject in need thereof.”
h) Amend claim 38 to recite “wherein the vascular condition [bis] is a pulmonary vascular leak syndrome.”
i) Applicant is advised that should claim 32 be found allowable, claim 39 will be objected to under 37 CFR 1.75 as being a substantial duplicate thereof. When two claims in an application are duplicates or else are so close in content that they both cover the same thing, despite a slight difference in wording, it is proper after allowing one claim to object to the other as being a substantial duplicate of the allowed claim. See MPEP § 608.01(m).
Appropriate correction is required.
New Grounds for Rejection
Claim Rejections - 35 USC § 112
The following is a quotation of 35 U.S.C. 112(d):
(d) REFERENCE IN DEPENDENT FORMS.—Subject to subsection (e), a claim in dependent form shall contain a reference to a claim previously set forth and then specify a further limitation of the subject matter claimed. A claim in dependent form shall be construed to incorporate by reference all the limitations of the claim to which it refers.
The following is a quotation of pre-AIA 35 U.S.C. 112, fourth paragraph:
Subject to the following paragraph [i.e., the fifth paragraph of pre-AIA 35 U.S.C. 112], a claim in dependent form shall contain a reference to a claim previously set forth and then specify a further limitation of the subject matter claimed. A claim in dependent form shall be construed to incorporate by reference all the limitations of the claim to which it refers.
12. Claim 14 is rejected under 35 U.S.C. 112(d) or pre-AIA 35 U.S.C. 112, 4th paragraph, as being of improper dependent form for failing to further limit the subject matter of the claim upon which it depends, or for failing to include all the limitations of the claim upon which it depends.
Claim 14 recites “the first antigen binding domain binds to ALK1, ALK2, ALK3, ALK4, ALK5, ALK6, or ALK7” in each of elements (i)-(iii). Claim 14 depends from claim 1 that is amended to the first antigen binding domain that binds to ALK4, ALK6, or ALK7. Claim 14 is broadening for the antigen binding domains to ALK1, ALK2, ALK3, and ALK5.
Applicant may cancel the claim(s), amend the claim(s) to place the claim(s) in proper dependent form, rewrite the claim(s) in independent form, or present a sufficient showing that the dependent claim(s) complies with the statutory requirements.
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
13. Claims 33-38 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 33-38 are drawn to the tetravalent construct of claim 133 where claim 33(i) is not defined for the scfv feature for the 1st antigen binding domain but claim 33(ii) for the scfv feature for the 2nd antigen binding domain is. The VH/VL CDR1-3 structures that impart both binding to BMPRI protein much less the functionalized structure for its therapeutic attribute in treating any vascular condition (claim 37) for the construct, are not defined in the claims.
Claims 33-38 are drawn to claim 33(ii) for the scfv feature for the 2nd antigen binding domain having at least 95% identity to the claimed VH/VL CDR1-3 for element (i)-(iii) of the final “wherein” clause.
The VH/VL CDR1-3 structures that impart both binding to BMPRI protein much less the functionalized structure for its therapeutic attribute in treating any vascular condition (claim 37) for the construct, are not defined in the claims.
The VH/VL CDR1-3 structures that impart both binding to BMPRII protein much less the functionalized structure for its therapeutic attribute in treating any vascular condition (claim 37) for the construct, are not defined in the claims with respect to having at least 95% identity to any one or the combination of VHCDR1-3 and VLCDR1-3.
The claims encompass a genus of binding molecules and antibody fragments with binding activity for BMPRI and BRMPII beyond those taught in the specification. Because applicant seeks patent protection for all such BMPRI and BRMPII binding domains, this genus must be adequately described. A description adequate to satisfy 35 U.S.C. § 112(a) must clearly allow persons of ordinary skill in the art to recognize that the inventor invented what is claimed (Ariad Pharms., Inc. v. Eli Lilly & Co., 598 F.3d 1336, 1351 (Fed. Cir. 2010) (en banc) (citation omitted, alteration in original). The purpose of the written description requirement is to “ensure that the scope of the right to exclude, as set forth in the claims, does not overreach the scope of the inventor’s contribution to the field of art as described in the patent’s specification” (In re Katz Interactive Call Processing Patent Litig. 639 F.3d 1303, 1319 (Fed. Cir 2011).
Disclosure in the Specification
The tetravalent antibody constructs examined by experimentation in Example 3 and made from scFv clones binding to ACVRL1 (ACVRL1.8) and BMPR2 (BMPR2.12) are expressed as a single molecule, with spacers of varying lengths as specified. Alternatively, they were designed as tetravalent IgG-Fc proteins generated by two 10 bispecific scFvs expressed as an IgG Fc fusion protein, then associated as two disulfide-linked homodimeric Fc complexes.
Data in Figures 8 and 9 reveal the constructs were able to generate potent BMP signaling in cells (see FIG. 8) Tetravalent complexes of anti-ACVRL1 and anti-BMPR2 elicited BMP transcriptional activity in endothelial cells. TIME cells (human telomerase immortalized microvascular 15 endothelial cells) were cultured and transiently transfected with plasmid expressing the BMP response element (BRE-luciferase) reporter. BMP9 (1 ng/mL) elicited BMP transcriptional activity in these cells, based on the detection of luciferase activity, divided by the relative number of cells, based on an MTS colorimetric viability assay (RLU/viability). A bispecific construct consisting of a single anti-ACVRL1 scFv and a 20 single anti-BMPR2 scFv joined by a spacer, and with a C-terminal His tag domain (“ACVRL1.8-L-BMPR2. 12-His”) did not elicit signaling activity by itself, but was active when combined with monoclonal anti-His antibodies to complex these bispecific molecules into a tetravalent complex. To demonstrate the signaling of a tetravalent complex when expressed as a disulfide linked heterotetramer, a tetravalent complex 25 consisting of the same bispecific molecule expressed as an IgG Fe domain fusion protein and assembled into disulfide linked homodimers (“ACVRL1.8-L-BMPR2. 12-Short-Fc”) elicited potent signaling. Consistent with in vitro signaling activity, in vivo signaling BMP signaling activity was demonstrated (Fig. 9) based on Id1 gene transcriptional activity assayed in 30 whole lung tissues from 8-week old mice 24 hours after tail vein injection of saline.
Accordingly, the specification describes a limited number of species of antibody having the structure and functions with BMP signaling effects on lung tissues. The working examples are not shown to have a preventative effect on either lung or liver-related disorders.
Scope of the claimed genus
Here is the case where all of the claims encompass a vast repertoire BMPRI and BRMPII binding domains. With respect to antibody formats, variations to the VH and VL domains include the complementarity determining regions (CDRs) that could vary relative to the VLC and VHC and CDRs found in a parental antibody in addition to the VL frameworks and VH frameworks as one example. Antibody fragments comprising a de minimus CDR domain are envisioned in the teachings of the specification. The genus of molecules and fragments thereof encompassed by the claims is therefore very large and there is substantial variation within the genus.
State of the Relevant Art
By the time the invention was made, it was also well-established in the art that the formation of an intact antigen-binding surface on an antibody required the association of the complete heavy and light chain variable regions, each of which consists of three CDRs which provide the majority of the contact residues for the binding of the antibody to its target epitope (Almagro & Franssen, Frontiers in Bioscience, 13:1619-33 (2008) (PTO-892; 10/23/2025) (see Section 3 “Antibody Structure and the Antigen Binding Site” and Figure 1). While this overall architecture is shared among antibodies from a wide variety of sources (human, rat, mouse, rabbit), the structure each antibody uses to bind its particular epitope on an antigen is structurally distinct and is formed by a recombination event that results in high variability at the amino acid sequence level, even when the same antigen is bound (Edwards et al., J Mol Biol 334:103-118 (2003) (PTO-892; 10/23/2025); see also Marchalonis et al., Dev & Comp Immunol. 30:223-247 (2006) (PTO-892; 10/23/2025), summarized in Abstract and Conclusion.
Methods of preparing antibodies from a variety of species to a protein or peptide of interest were well-established in the art at the time the invention was made. But application of those methods to any given antibody is still a matter of trial-and-error testing, and the skilled person could not automatically predict which residues in the CDRs would be tolerant of mutations, or which amino acid substitutions would maintain antigen binding. Overall, at the time the invention was made, the level of skill for preparing antibodies and then selecting those antibodies with desired functional properties was high. For example, it is generally the case that absent the fundamental structure provided for by all six CDRs of a parental antibody in the context of appropriate VH and VL framework sequences, a person of ordinary skill cannot visualize or otherwise predict, what an antibody with a particular set of functional properties would look like structurally.
Moreover, persons of ordinary skill in the art have long since acknowledged that even minor changes in the amino acid sequences of the VH and VL, particularly in the CDRs, may dramatically affect antigen-binding function. Lippow, for example, teaches that a single point mutation in the CDR of a parent antibody led to as much as an eightfold improvement in binding affinity in the resulting mutant (p. 1172, left col., lines 7-8 from end of first full paragraph and Table 1a) (Lippow et al., “Computational design of antibody-affinity improvement beyond in vivo maturation,” Nature Biotechnology, 25(10):1171-1176 (2007) (PTO-892; 10/23/2025).
Sulea teaches that individual point mutations gave an improvement of one order of magnitude in binding affinity, which in turn, generated a 6-fold enhancement of efficacy at the cellular level (Abstract) (Sulea et al., “Application of Assisted Design of Antibody and Protein Therapeutics (ADAPT) improves efficacy of a Clostridium difficile toxin A single-domain antibody," Scientific Reports, 8(260):1-11 (2018) (PTO-892; 10/23/2025). Hasegawa et al. reports that a single amino acid substitution in the variable region was sufficient to alter the efficiency of biosynthesis and the variant antibody acquired stronger binding affinity to its antigen than the parent (Hasegawa et al., “Single amino acid substitution in LC-CDR1 induces Russell body phenotype that attenuates cellular protein synthesis through elF2a phosphorylation and thereby downregulates IgG secretion despite operational secretory pathway traffic,” MABS, VOL. 9, NO. 5, pp. 854-873 (2017) (PTO-892; 10/23/2025)). Altshuler teaches that generally, “CDR mutations should not involve residues that can play structural functions (form parts of the domain ‘internal core’, internal salt bridges, hydrogen bonds, etc.).” “Usually these are conservative residues, and any substitution of these residues causes decrease[s] in affinity” (Altshuler et al., “Generation of Recombinant Antibodies and Means for Increasing Their Affinity,” Biochemistry (Moscow), 75(13):1584-1605 (2010) at p. 1600, col. 1, para. 2, lines 1-5 (PTO-892; 10/23/2025). Accordingly, a person of ordinary skill in the art would have recognized that it was highly unpredictable that any of the CDRs or FRs could be modified to create an unlimited change in amino acids for both the CDRs and FRs of the claimed antibodies, without increasing, eliminating, or in some way altering antigen binding.
Summary of species disclosed in the specification
Applicant’s specification fully discloses bispecific constructs in Example 2 and tetravalent constructs in Example 3. Most notably, Applicants specification does not provide a sequence for the claimed ALK5 antigen binding domain.
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Are the disclosed species representative of the claimed genus?
The genus of all possible binding molecules much less antibodies encompassed by the claims would be structurally distinct but unpredictable whether the structure/ function correlation was met for binding to BMPRI and BRMPII, respectively. The disclosed species include VH/VL domain pairs with corresponding binding activity to BMPRI and BRMPII, respectively. The specification does not identify which CDRs, which combination of fewer than all six CDRs, or which subset of residues in the combination of CDRs is essential for the recited function of binding BMPRI and BRMPII, respectively. Neither the specification nor the prior art provides guidance as to what structural changes can be made to the parent sequences and still predictably arrive at an antibody much less fragments thereof that bind to BMPRI and BRMPII, respectively. The disclosed species therefore do not represent the claimed genus of tetravalent antigen binding domains.
Has Applicant provided a common structure sufficient to visualize the genus?
Applicant has not provided a common structure sufficient to visualize the genus of all possible functional antigen binding domains for BMPRI and BRMPII, respectively. One of ordinary skill in the art would not know which residues could be eliminated, replaced or added while still maintaining BMPRI or BRMPII selectivity and affinity.
While the prior art contains disclosure as to the structural features of several anti- BMPRI and BRMPII antibodies, it is unclear what structural features these antibodies need to share in order to maintain binding affinity and stability. Even in 2021, therapeutic antibodies (see claims 37-38) 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; 10/23/2025)) 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; 10/23/2025)), acknowledging that “there is a vast amount of the antibody sequence space that remains unknown,” p. 9831, col. 2, para. 2.
Even though the protein sequence of BMPRI and BRMPII was known in the art, this would not have translated into knowledge of the genus of antibodies that could possibly engage either one. 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; 10/23/2025)). 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; 10/23/2025)) (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 for reliably assigning different antibody structures based on sequence data for two antibody clones, which would support the premise that the inventors possessed the full scope of the claimed invention.”
Conclusion
14. No claims are allowed.
15. 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.
16. 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
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