Detailed Action
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 .
Claim 11 is cancelled.
Applicant’s election without traverse of Group II (claims 12-14) and the species of SEQ ID NOs: 37, 55, 73 and 28, 46, 64 for LCDRs1-3 and HCDRs1-3, respectively, with their corresponding HCVR and LCVR sequences, SEQ ID NOs: 10 and 19, respectively, and the mAb 13G6 in the reply filed on 03/09/2026 is acknowledged. The elected species of SEQ ID NOs: 37, 55, 73 and 28, 46, 64 for LCDRs1-3 and HCDRs1-3, respectively, with their corresponding HCVR and LCVR sequences, SEQ ID NOs: 10 and 19 has been searched and is deemed to be free from the prior art such that the species election is withdrawn in its entirety.
Claims 1-2, 4-10, and 15-21 are withdrawn from further consideration pursuant to 37 CFR 1.142(b) as being drawn to a nonelected Groups/Inventions, there being no allowable generic or linking claim. Election was made without traverse in the reply filed on 03/09/2026.
Claim 3 is rejoined in light of Applicant’s claim amendments dated 03/09/2026 that alter the scope of claim 3 to now reflect a product dependent from instant claim 12.
Claims 1-10 and 12-21 are pending.
Claims 3 and 12-14 are under examination on the merits.
Priority
This application is a 371 of PCT/EP2021/054139, filed 02/19/2021, which claims priority to EUROPEAN PATENT OFFICE (EPO) Application No. 20158636.9, filed 02/20/2020. Receipt is acknowledged of certified copies of papers required by 37 CFR 1.55.
IDS
The information disclosure statements (IDS’s) filed 08/22/2022, 04/14/2023, 01/15/2025, 03/11/2025, 06/25/2025, 09/18/2025, and 12/29/2025 have been considered.
Specification
The disclosure is objected to because of the following informalities: the disclosure makes reference to SEQ ID NO: 66 (see for example, the table at page 71), but SEQ ID NO: 66 is listed as 000 in the sequence listing/CFRE, not as the specified sequence of ‘GNL’ (see for example, the table at page 71). While an amino acid sequence having less than 4 amino acids is not required to be given a SEQ ID NO under ST. 26 rules, the reference to a SEQ ID NO which does not reflect the defined sequence is inconsistent, improper, and requires correction.
Appropriate correction is required.
Claim Interpretation
Where SEQ ID NO: 66 is recited, SEQ ID NO: 66 is being interpreted to mean a sequence consisting of GNL, as is consistent with Table C at page 71 of the instant specification.
Claim Objections
Claim 3 is objected to because of the following informalities: ‘thereof, of claim’ in line 2 should read ‘thereof of claim’. Additionally, claim 3 is presently drafted to depend from claim 12. This is improper as dependent claims should be preceded by the claim from which they depend.
Claim 12 is objected to because of the following informalities: “shown” in part (a2) should read ‘sequence’. The claim is being interpreted as such. Claim 12 is further objected to because of the following informalities: “BMP-10” should be fully spelled out for clarity as this is the first instance of this acronym in the related chain of dependency.
Appropriate correction is required.
Claim Rejections - 35 USC § 112
35 USC § 112(a)
The following is a quotation of the first paragraph of 35 U.S.C. 112(a):
(a) IN GENERAL.—The specification shall contain a written description of the invention, and of the manner and process of making and using it, in such full, clear, concise, and exact terms as to enable any person skilled in the art to which it pertains, or with which it is most nearly connected, to make and use the same, and shall set forth the best mode contemplated by the inventor or joint inventor of carrying out the invention.
The following is a quotation of the first paragraph of pre-AIA 35 U.S.C. 112:
The specification shall contain a written description of the invention, and of the manner and process of making and using it, in such full, clear, concise, and exact terms as to enable any person skilled in the art to which it pertains, or with which it is most nearly connected, to make and use the same, and shall set forth the best mode contemplated by the inventor of carrying out his invention.
Claims 3 and 12-14 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.
The purpose of the written description requirement is to ensure that the inventor had possession, at the time the invention was made, of the specific subject matter claimed. To satisfy the written description requirement, a patent specification must describe the claimed invention in sufficient detail that one skilled in the art can reasonably conclude that the inventor had possession of the claimed invention. See, e.g., Moba, B. V. v. Dianwnd Automation, Inc., 325 F.3d 1306, 1319, 66 USPQ2d 1429, 1438 (Fed. Cir. 2003); Vas-Cath, Inc. v. Mahurkar, 935 F.2d at 1563, 19 USPQ2d at 1116.
The Application claims a broad genus of antibodies and fragments thereof by impermissibly allowing variation within/interchangeability of the CDRs without disclosure of a conserved structure/representative number of species to adequately describe said genus. The Application discloses 9 antibodies against BMP-10 are (see page 71 at Tables C and D) and does not provide evidence that all of the claimed CDR combinations, with the claimed degree of variation/interchangeability would function to bind as claimed. Therefore, in view of this disclosure, Applicant is claiming a broad genus of antibodies without a representative number of species of said genus. The specification does not provide adequate written description for the entire claimed genus of species of antibodies (let alone fragments thereof) or of CDRs binding as claimed, because in the absence of empirical determination, one skilled in the art would be unable to immediately envision, recognize, or distinguish at least most of the members comprised within the genus claimed, specifically, which light and heavy chain CDR sequence combinations (bearing any mutations or not) might be included in the genus. It is further unclear which fragments of the claimed antibodies would function to bind as claimed.
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, reduction to drawings, 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. See Eli Lilly, 119 F.3d at 1568, 43 USPQ2d at 1406. A “representative number of species” means that the species which are adequately described are representative of the entire genus. Thus, when there is substantial variation within the genus, one must describe a sufficient variety of species to reflect the variation within the genus. Applicant has only fully disclosed 9 set of 6 CDRs (9 species) for consideration. These 9 species are heterogenous without a clear structure-function correlation (see for example, the Clustal Omega alignments attached to this Office Action). Thus, given the substantial antibody structure variation within the genus as well as the high level of unpredictability in the art, the disclosure of only 9 species is not sufficiently representative of the entire genus claimed (encompassing multiple combinations of the CDRs).
Furthermore, Applicant has not disclosed relevant, identifying characteristics of CDR region amino acid sequences that confer upon an antibody the ability to function as claimed because the instant specification does not provide structural antibody features that correlate with a functional ability to function.
Absent a clear description of the at least minimal structural features correlating with a functional ability to function as claimed which are shared by members of a genus commonly sharing this function, it is submitted that the skilled artisan could not immediately envision, recognize, or distinguish which heavy and light chain CDR amino acid sequences may be mutated/varied/interchanged such that the resultant heavy and light chain variable regions comprise six CDRs that confer the ability to function as claimed.
Furthermore, while the prior art teaches some understanding of the structural basis of antigen-antibody recognition, it is noted that the art is characterized by a high level of unpredictability, since the skilled artisan still cannot accurately and reliably predict the consequences of amino acid substitutions, insertions, and deletions in the antigen-binding domains. For example, Al Qaraghuli et al (2020, Nature Scientific Reports 10:13969), state that the six CDRs form a continuous surface to form the paratope that binds the epitope of the cognate antigen. This suggests that a change in the CDR sequence may result in a conformationally different paratope which may fail to bind target as claimed. Here, a mutation in the CDRs may result in a paratope unable to bind BMP-10 (or BMP-10-type proteins). Rabia et al (2018, Biochemical Engineering Journal 137:365-374) teach what effects mutations can have on an antibody's stability, solubility, binding affinity and binding specificity. Rabia et al report that an increase in antibody affinity can be associated with a decrease in stability (p. 366, col. 2 last paragraph; Fig. 2). Tiller et al (2017, J. Biol. Chem. (2017) 292(40) 16638–16652) and Tsuji et al (2022, J Virol 96:e00071-22) teach that mutations in the CDRs (especially HCDR3 are unpredictable and accompanied by tradeoffs in performance (for example increased affinity may lead to decreased specificity); see references in their entirety paying particular attention to the abstract of Tiller et al and the abstract and results section of Tsuji et al). The above cited references underscore the unpredictability of even a single mutation in the CDRs. The instant claims allow for mutations in the CDRs whereupon the mutated paratope may fail to bind BMP-10 (or BMP-10-type proteins), as claimed. Thus, the claims need to specify exact CDR1-6 sequences of the anti-BMP-10 (or anti-BMP-10-type proteins) antibody.
Moreover, it is well-known in the art that specificity of an antibody stems from the interaction of six CDRs and CDRs are not generally recognized as interchangeable, such that using one CDR from one antibody would not be reasonably expected to confer the same binding properties or even the same binding target when combined with two to five CDRs from other antibodies (HCDRS may not be arbitrarily paired with LCDRs with a reasonable expectation of binding an envisioned antigen and vice a versa). For example, WO 2008068048 A2 discloses an antibody with a heavy chain comprising three CDRs (SEQ ID NO: 2) that binds secreted aspartyl protease from Candida sp. US 20170355756 A1 describes the same three CDRs in the heavy chain (C10-VH3) combined with a different light chain that binds human TDP-43. There is no disclosed evidence to support or describe which combinations of claimed CDRs would form an antibody capable of binding BMP-10 (or BMP-10-type proteins) as claimed. Likewise, there is no description of which fragments would form an antibody capable of binding BMP-10 (or BMP-10-type proteins) as claimed.
Accordingly, absent empirical determination, one skilled in the art would be unable to predict or envision which CDR sequences comprised within the genus comprising the claimed CDR sequences may be combined/mutated such that the resultant antibody possesses an antigen-binding site capable functioning as claimed. The general knowledge and level of skill in the art does not adequately supplement the omitted description, because specific, not general guidance is needed. Since the disclosure fails to describe relevant, identifying structural characteristics, in the form of fixed heavy and light chain CDR amino acid sequence combinations, that correlate with the ability to function as claimed, and because the one disclosed species detailed above is not sufficient to describe the claimed genus, it is submitted that the written description requirement of 35 U.S.C. 112(a) has not been met.
The claims require an antibody binding BMP-10 (or BMP-10-type proteins). The specification does not describe which amino acid residues of the antibody are responsible for the functions claimed. Rather, the specification implies that these potential agents must first be screened in an assay to ascertain if the agents have the functions required by the instant claims. Although the specification provides disclosure of 9 antibodies, it fails to disclose the structures common to all members of the genus of antibodies (or fragments thereof) encompassed by the broad recitation claimed by applicant. The specification does not disclose the structure of all of the claimed variant antibodies/fragments thereof and fails to disclose which sequences are responsible for the functions claimed. In the absence of a known or disclosed correlation between structure and function, claims which encompass variants defined by their function are generally not considered described.
Applicant is directed to MPEP § 2163 for guidelines on compliance with the written description requirement. Here, applicant has not described a reasonable number of members of the genus of antibodies that would function in the method(s) as claimed, but rather has presented the public with an idea of how to perform an assay that might identify some peptides that fall within the scope of the claim. Of course, depending on what agents are used in the screening assay, it may well identify none. The Court of Appeals for the Federal Circuit addressed claims of this sort in great detail in University of Rochester v. G.D. Searle and Co. (69 USPQ 2nd 1886, CAFC 2004). In Rochester, the Federal Circuit upheld the district court's ruling that patent claims which recited administration of compounds not disclosed, but rather to be identified in a screening assay, were invalid on their face.
In Ariad, the court further noted that the written description plays a particularly important role in the biological arts, where patentees might otherwise be tempted to claim a genus of compounds by its function or result:
“The written description requirement also ensures that when a patent claims a genus by its function or result, the specification recites sufficient materials to accomplish that function—a problem that is particularly acute in the biological arts. 5 See Guidelines for Examination of Patent Applications Under the 35 U.S.C. 112, 1, “Written Description” Requirement, 66 Fed. Reg. 1099, 1105-1106 (Jan. 5, 2001). This situation arose not only in Eli Lilly but again in University of Rochester v. G.D. Searle & Co., Inc., 358 F.3d 916 [69 USPQ2d 1886] (Fed. Cir. 2004). In Rochester, we held invalid claims directed to a method of selectively inhibiting the COX-2 enzyme by administering a non-steroidal compound that selectively inhibits the COX-2 enzyme. Id. at 918. We reasoned that because the specification did not describe any specific compound capable of performing the claimed method and the skilled artisan would not be able to identify any such compound based on the specification's function description, the specification did not provide an adequate written description of the claimed invention. Id. at 927-28. Such claims merely recite a description of the problem to be solved while claiming all solutions to it and, as in Eli Lilly and Ariad's claims, cover any compound later actually invented and determined to fall within the claim's functional boundaries—leaving it to the pharmaceutical industry to complete an unfinished invention.”
Ariad Pharmaceuticals., Inc. v. Eli Lilly & Co., 94 USPQ2d 1161, 1173 (Fed. Cir. 2010) (en banc). Emphasis added.
The Federal Circuit has clarified Written Description as it applies to antibodies in the recent decision Amgen v. Sanofi, 872 F.3d 1367 (Fed. Cir. 2017). The Federal Circuit explained in Amgen that when an antibody is claimed, 35 U.S.C. 112(a) (or pre-AIA first paragraph) requires adequate written description of the antibody itself. Amgen, 872 F.3d at 1378-79. The Amgen court expressly stated that the so-called “newly characterized antigen” test, which had been based on an example in USPTO-issued training materials and was noted in dicta in several earlier Federal Circuit decisions, should not be used in determining whether there is adequate written description under 35 U.S.C. 112(a) for a claim drawn to an antibody. Citing its decision in Ariad Pharmaceuticals, Inc. v. Eli Lilly & Co., the court also stressed that the “newly characterized antigen” test could not stand because it contradicted the quid pro quo of the patent system whereby one must describe an invention in order to obtain a patent. Amgen, 872 F.3d at 1378-79, quoting Ariad, 598 F.3d 1336, 1345 (Fed. Cir. 2010). In view of the Amgen decision, adequate written description of an antigen alone is not considered adequate written description of a claimed antibody to that antigen, even when preparation of such an antibody is routine and conventional. Id.
While generically the structure of antibodies is known, the structure of the presently recited antibodies can vary substantially within the above given claimed recitations. As noted in Amgen, knowledge that an antibody binds to a particular epitope on an antigen tells one nothing at all about the structure of the antibody, wherein “instead of analogizing the antibody-antigen relationship to a ‘key in a lock,’ it [is] more apt to analogize it to a lock and ‘a ring with a million keys on it.” (Internal citations omitted). The relevant antibody art confirms this quandary, indicating that “knowledge of an epitope or antigen used to generate a monoclonal antibody is insufficient for making the original antibody available, even if suitable in vitro test systems for screening are used.” See p. 8, lines 3-5 of WO 2009/033743 A1. Therefore, those of skill in the art would not accept that the inventor had been in possession of the full genus of antibodies in the present claims.
Applicant is further directed to In re Alonso (545 F.3d 1015 (Fed. Cir. 2008), which involved claims that were directed to methods of using antibodies wherein the court found that the claims lacked adequate written description for the recited genus of antibodies recited in the methods. (C) See p. 8, 3rd paragraph, where Applicant argues that the claims recite all essential features of the invention. Therefore, products used in methods are rightfully subject to the written description requirement.
Although screening techniques can be used to isolate CDR variant antibodies that possess the ability to function as claimed, Applicant is reminded that the written description requirement of 35 U.S.C. 112 is severable from the enablement provision. As stated in Vas-Cath Inc. v. Mahurkar (CA FC) 19 USPQ2d 1111, 935 F2d 1555, “The purpose of the 'written description' requirement is broader than to merely explain how to 'make and use'; the applicant must also 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.”
Regarding the recited BMP-10-type protein(s) the antibody binds, this recitation encompasses and expansive and undefined set of epitopes. The closest description is provided at pages 10-11 of the instant specification. This definition is not closed. The artisan must dispute what is encompassed by the claim language and is not reasonably able to readily envisage the species of the genus claimed which the recited antibodies may bind. The epitopes encompassed by ‘BMP-10-type proteins’ fail to comply with the requirement for written description under 35 USC §112(a).
Regarding the state of the art, Listov et al (Opportunities and challenges in design and optimization of protein function. Nat Rev Mol Cell Biol 25, 639–653 (2024)) teach that the primary amino acid sequence determines downstream structure (protein folding), which then determines function (presenting both the inverse folding problem and the inverse function problem (see for example, Figure 1 and its caption; see also Mishra et al (Inaccurate secondary structure predictions often indicate protein fold switching. Protein Sci. 2019 Aug;28(8):1487-1493. doi: 10.1002/pro.3664. Epub 2019 Jun 17)). Expanding on these problems in proteomics, Reardon (Nature 635, 246-248 (2024)) explains that the goal of designing a protein with known and predictable function, binding partners, size, location, and other traits is, for the moment, a dream. Reardon teaches that further challenges in protein design include predicting how a protein, even if it binds to target, will function upon said binding. Reardon teaches that the primary structure (amino acid sequence) of a protein is critical to function, noting that even proteins of similar shape do not execute the same functions, while those with different shapes may carry out the same tasks. Reardon goes on to teach that it is not always apparent which parts of the primary sequence are important; a seemingly useless amino-acid chain on the side of an enzyme, for instance, might affect how tightly a protein can bind to other molecules or its ability to flip between conformational states. Moreover, Reardon explains that when researchers attempt to solve the structure of a protein experimentally, they often end up seeing only the most stable conformation, which is not necessarily the form the protein takes when it is active (see for example, pages 246-247 of Reardon).
Antibody-antigen binding is highly complex and unpredictable. Machine-learning models and in silico approaches generally remain unable to predict antigen-antibody binding, even when sifting between data sets of known antibodies and antigens to predict compatible binding and often produces incorrect models/pairings (see for example, Lowe, D. (Predicting Antibody Binding: No Champagne Just Yet, Science (2026); obtained from: http://www.science.org/content/blog-post/predicting-antibody-binding-no-champagne-just-yet). Underscoring the unpredictable state of the art, Subedy et al (bioRxiv 2026.01.17.700115; doi: https://doi.org/10.64898/2026.01.17.700115 (2026)) teach that achieving accurate predictions of complete antibody–antigen complexes is still an open challenge. Likewise, Spoendlin et al (Nat Mach Intell 7, 1755–1767 (2025). https://doi.org/10.1038/s42256-025-01131-6) teach that the flexibility of antibody complementarity-determining region (CDR) loops influences binding affinity and specificity, making it a key factor in understanding and designing antigen interactions, but predicting protein flexibility remains challenging, as current structure prediction tools struggle to capture multiple conformational states, particularly for antigen receptor CDRs.
Therefore, the antibodies/fragments and epitopes, as claimed are only disclosed by function/insufficient structure, without a representative number of species or unifying, conserved structure clearly enabling one skilled in the art to readily envisage the members of the genus claimed which would function as claimed in the claimed method(s). Therefore, claims 3 and 12-14 are deemed to fail to meet the written description requirement, as presently drafted.
35 USC § 112(b)
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.
Claims 3 and 12-14 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.
Claim 12 recited SEQ ID NO: 66. SEQ ID NO: 66 is listed as 000 in the sequence listing/CRFE, but is defined as consisting of GNL in the specification at page 71, Table C. The recitation of SEQ ID NO: 66 in the claim leads to unnecessary confusion regarding what is encompassed by the claim and would infringe the claim. One artisan may refer to Table C and interpret SEQ ID NO: 66 to consist only of GNL, where as another artisan may feel that SEQ ID NO: 66 encompasses a different sequence to be determined. Therefore, the metes and bounds of the claim are indefinite as drafted.
Claims 3 and 13-14 depend from claim 12 and, via dependency, incorporate and fail to remedy the above noted ambiguity.
Improper Markush
Claim 3 and 12-14 are further rejected on the basis that they contain an improper Markush grouping of alternatives. See In re Harnisch, 631 F.2d 716, 721-22 (CCPA 1980) and Ex parte Hozumi, 3 USPQ2d 1059, 1060 (Bd. Pat. App. & Int. 1984). A Markush grouping is proper if the alternatives defined by the Markush group (i.e., alternatives from which a selection is to be made in the context of a combination or process, or alternative chemical compounds as a whole) share a “single structural similarity” and a common use. A Markush grouping meets these requirements in two situations. First, a Markush grouping is proper if the alternatives are all members of the same recognized physical or chemical class or the same art-recognized class, and are disclosed in the specification or known in the art to be functionally equivalent and have a common use. Second, where a Markush grouping describes alternative chemical compounds, whether by words or chemical formulas, and the alternatives do not belong to a recognized class as set forth above, the members of the Markush grouping may be considered to share a “single structural similarity” and common use where the alternatives share both a substantial structural feature and a common use that flows from the substantial structural feature. See MPEP § 2117.
The Markush grouping of an antibody/fragment thereof comprising:
(a) a light chain variable domain comprising:
(al) a light chain CDR1 sequence selected from SEQ ID NOs: 34-42;
(a2) a light chain CDR2 shown selected from SEQ ID NOs: 52-60; and
(a3) a light chain CDR3 selected from SEQ ID NOs: 70-78; and
(b) a heavy chain variable domain comprising:
(bl) a heavy chain CDR1 selected from SEQ ID NOs: 25-33;
(b2) a heavy chain CDR2 selected from SEQ ID NOs: 43-51; and
(b3) a heavy chain CDR3 selected from SEQ ID NOs: 61-69,
is improper because the alternatives defined by the Markush grouping do not share both a single structural similarity and a common use for the following reasons: the antibodies/fragments thereof which are recited in the claims do not share a single structural similarity (see for example, the Clustal Omega alignments attached to this Office Action). The CDRs of the encompassed antibodies/portions are not structurally related as shown by the lack of amino acid percent identity/consensus between the sequences and the structural similarity which may be possessed in common (antibody structure) is not sufficient to provide for the common use (binding BMP-10 (or BMP-10-type proteins)). The different collections of heavy chain/light chain and CDRs relate to specific antibodies which bind a specific target. The structures of these heavy/light chains and CDRs is not shared by the different alternatives and therefore, the recited species do not share a common structure which provides for a common function and therefore, are not proper species of one another.
Claims 3 and 13-14, via dependency, incorporate and fail to remedy the improper Markush grouping.
To overcome this rejection, Applicant may set forth each alternative (or grouping of patentably indistinct alternatives) within an improper Markush grouping in a series of independent or dependent claims and/or present convincing arguments that the group members recited in the alternative within a single claim in fact share a single structural similarity as well as a common use.
Conclusion
No claim is allowed.
Notice:
The 9 antibodies requiring the CDR1-6 combinations shown in in tables C and D at page 71 of the instant specification have been searched and are deemed to be free from the prior art.
The closest prior art is Wyeth et al (WO2008151078; citation 1 under Foreign Patent Documents on the IDS dated 08/22/2022) teaches BMP-10 binding agents, e.g., antibody molecules, binding domain fusion variants, antisense nucleic molecules which interact with, or more preferably specifically bind to BMP-10 polypeptides or fragments thereof, (see for example, page 14 bridging page 15 and Fig. 2 at page 2/81 depicting SEQ ID NO: 2; noting teachings of the epitope bound and that SEQ ID NO: 2 of Wyeth is identical to instant SEQ ID NO: 1 [see the alignment via ABSS appended to the Restriction Requirement dated 12/09/2025]).
Wyeth et al do not teach antibodies having the instantly claimed CDR1-6 sequences shown in tables C and D at page 71 of the instant specification, which are deemed to be free from the prior art.
While the prior art teaches some understanding of the structural basis of antigen-antibody recognition, it is noted that the art is characterized by a high level of unpredictability, since the skilled artisan still cannot accurately and reliably predict the consequences of amino acid substitutions, insertions, and deletions in the antigen-binding domains. For example, Al Qaraghuli et al (2020, Nature Scientific Reports 10:13969), state that the six CDRs form a continuous surface to form the paratope that binds the epitope of the cognate antigen. This suggests that a change in the CDR sequence may result in a conformationally different paratope which may fail to bind target as claimed. Here, a mutation in the CDRs may result in a paratope unable to bind BMP-10. Rabia et al (2018, Biochemical Engineering Journal 137:365-374) teach what effects mutations can have on an antibody's stability, solubility, binding affinity and binding specificity. Rabia et al report that an increase in antibody affinity can be associated with a decrease in stability (p. 366, col. 2 last paragraph; Fig. 2). Tiller et al (2017, J. Biol. Chem. (2017) 292(40) 16638–16652) and Tsuji et al (2022, J Virol 96:e00071-22) teach that mutations in the CDRs (especially HCDR3 are unpredictable and accompanied by tradeoffs in performance (for example increased affinity may lead to decreased specificity); see references in their entirety paying particular attention to the abstract of Tiller et al and the abstract and results section of Tsuji et al). The above cited references underscore the unpredictability of even a single mutation in the CDRs.
Therefore, a difference of a single amino acid in the VH or VL domain is enough to render an antibody free of the art. In the instant Application, the recitation of novel CDR sequences is sufficient to render the antibody and the methods requiring said antibody free of the art.
Accordingly, absent empirical determination, one skilled in the art would be unable to predict or envision the CDR1-6 sequences of the 9 antibodies described in Tables C and D at page 71 of the instant specification falling within the scope of antibodies recited in instant claim 12. These 9 antibodies are deemed to be described and free from the prior art.
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/Ashley Gao/
Examiner, Art Unit 1678
/GREGORY S EMCH/Supervisory Patent Examiner, Art Unit 1678
Prosecution Insights