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 1-58 are the original claims filed 11/17/2022. In the Preliminary Amendment of 5/10/2023, Claims 3-5, 7, 9, 11, 13, 16-17, 19, 21, 23, 25, 28-29, 31, 33, 35, 37, 39-48, and 50-58 are canceled. Claims 1-2, 6, 8, 10, 12, 14-15, 18, 20, 22, 24, 26-27, 30, 32, 34, 36, 38, and 49 are all the claims.
Election/Restriction
2. Applicant’s election without traverse of Group B (Anti-IL1RL1 VH: SEQ ID NO: 302-790) and Group F (Anti-IL1RL1 VL: SEQ ID NO:1812-2112), both drawn to Anti-IL1RL1, in the reply filed on 9/22/2025 is acknowledged.
3. Claims 6, 10, 12, 18, 22, 24, 30, 34, 36 are withdrawn from further consideration pursuant to 37 CFR 1.142(b) as being drawn to a nonelected invention: A. Anti-TSLP VH: SEQ ID NO:1-301; C. Anti-IL1RL2 VH: SEQ ID NO: 791-1187; and D. Anti-CD40L VH: SEQ ID NO: 1188-1628, there being no allowable generic or linking claim. Election was made without traverse in the reply filed on 9/22/2025.
4. Claims 1-2, 8, 14-15, 20, 26-27, 38 and 49 are the claims under examination.
Priority
5. USAN 18/056,648, filed 11/17/2022, Claims Priority from Provisional Application 60/280,834, filed 11/18/2021.
Information Disclosure Statement
6. As of 10/30/2025, a total of three (3) IDS are filed: 5/12/2023; 6/14/2024; and 6/14/2024. The corresponding initialed and dated 1449 form is considered and of record.
Objections
Specification
7. The disclosure is objected to because of the following informalities:
a) The use of the term, i.e., UniProt, NCBI, Alexa, Expi293, GraphPad, DNASTAR, Carterra, FlowCell, 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.
Appropriate correction is required.
Claim Objections
8. Claims 1-2, 8, 14-15, 20, 26-27, 38 and 49 are objected to because of the following informalities:
a) Claims 1-2, 8, 14-15, 20, 26-27, 38 and 49 recite “or antibody fragment” that does no reference the antibody of the claimed invention. Amend the claims to recite “antibody fragment thereof.”
b) Claims 1-2, 8, 14-15, 20, 26-27, 38 and 49 recite “comprising a variable domain,…” This appears to be a typographical error with omission of transitional language, for example, comprising or consisting of. It is permissible to describe the antibody having a variable domain so long as it comprises or consists of the narrower species of claimed variable domain (VH and/or VL). For example, “…comprising a variable domain [,] comprising a heavy chain region (VH).”
c) Claim 38 is objected to under 37 CFR 1.75 as being a substantial duplicate of claim 49. 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).
d) Claims 2, 15 and 27 are unclear for the meaning of the phrase “ab antigen-binding fragments thereof” and how it relates to the antibody or antibody fragment thereof.
e) Claim 2 is inconsistent in depending from claim 1 that requires the presence of both a VH and VL domain. Claim 2 recites examples of single variable domain structures, i.e., a single chain antibody, a Fd fragment, an isolated complementarity determining region (CDR), a fragment comprised of only a single monomeric variable domain.
f) Claim 15 is inconsistent in depending from claim 14 that requires the presence of a VH domain. Claim 15 recites examples of variable domain structures that are smaller in size than a VH, i.e., isolated complementarity determining region (CDR).
g) Claim 27 is inconsistent in depending from claim 26 that requires the presence of a VL domain. Claim 27 recites a Fd fragment (VH-Fc), an isolated complementarity determining region (CDR).
Appropriate correction is required.
Claim Rejections - 35 USC § 112
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
9. Claims 1-2, 8, 14-15, 20, 26-27, 38 and 49 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
Here, the language in the claims referring to “a sequence identity not less than about 90%” is for the VH (SEQ ID NOs: 302-790) and/or the VL (SEQ ID NOs: 1812-2112) of the anti-IL1RL1 antibody fragment thereof.
“at least about 90% identical”: the specification provides methods for determining identity and to a limited extent what changes comprises a sequence variation for example, substitutes at an amino acid level.
[0080] In situations where ALIGN-2 is employed for amino acid sequence comparisons, the % amino acid sequence identity of a given amino acid sequence A to, with, or against a given amino acid sequence B (which can alternatively be phrased as a given amino acid sequence A that has or comprises a certain % amino acid sequence identity to, with, or against a given amino acid sequence B) is calculated as follows: 100 times the fraction X/Y, where X is the number of amino acid residues scored as identical matches by the sequence alignment program ALIGN-2 in that program's alignment of A and B, and where Y is the total number of amino acid residues in B. It will be appreciated that where the length of amino acid sequence A is not equal to the length of amino acid sequence B, the % amino acid sequence identity of A to B will not equal the % amino acid sequence identity of B to A. Unless specifically stated otherwise, all % amino acid sequence identity values used herein are obtained as described in the immediately preceding paragraph using the ALIGN-2 computer program.
[0081] The term “homology” or “similarity” between two proteins is determined by comparing the amino acid sequence and its conserved amino acid substitutes of one protein sequence to the second protein sequence. Similarity may be determined by procedures which are well-known in the art, for example, a BLAST program (Basic Local Alignment Search Tool at the National Center for Biological Information).
The specification does not limit the percent variation to any particular location int eh VH or VL domain to the extent that both CDRs and FRs are potentially mutated by substitution, insertion, and/or deletion.
“about”: the specification is unequivocal in disclosing a percent variation is +/- 10% of the cited value.
[0045] Unless specifically stated or obvious from context, as used herein, the term “about” in reference to a number or range of numbers is understood to mean the stated number and numbers +/−10% thereof, or 10% below the lower listed limit and 10% above the higher listed limit for the values listed for a range.
The interpretation encompasses a genus of antibody variants beyond those taught in the specification. Because applicant seeks patent protection for all such anti- IL1RL1 antibodies, 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
The specification disclosure does not define the meaning of “identity not less than 90%”, per se. Here, all of the claims encompass anti- IL1RL1 antibodies, and variations to the VH and VL domains, in which the variable domains, including the complementarity determining regions (CDRs) could vary relative to the VLC and VHC and CDRs found in the parental antibody in addition to the VL frameworks and VH frameworks. The encompassed antibodies are allowed to vary relative to the parental antibody at any position. The genus encompassed by the claims is therefore very large and there is substantial variation within the genus for the instant claimed anti- IL1RL1 antibodies.
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 was 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 anti- IL1RL1 antibodies, without increasing, eliminating, or in some way altering antigen binding.
Summary of species disclosed in the specification
Applicant’s specification fully discloses in Table 9 VH domains referred to as IL1RL1-1 thru IL1RL1-790; in Table 13 VL domains referred to as IL1RL1-189 thru IL1RL1-489. The specification does not teach an example of a variant from any one of the parental VH or VL domain sequences that are taught in the Tables.
Are the disclosed species representative of the claimed genus?
It is asserted that the disclosed species are not representative of the claimed genus because the claims encompass any amino acid variation so long as the sequence identity it is not less than 90% of the parent VH or VL domain. The genus of all possible anti- IL1RL1 antibodies encompassed by the claimed variation would be structurally distinct but unpredictable whether the structure/function correlation was met for binding to IL1RL1. The specification does not identify which CDRs and/or frameworks, 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 IL1RL1. 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 that binds IL1RL1. The disclosed species therefore do not represent the claimed genus.
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 variants. While the disclosure provides the amino acid sequences of the anti- IL1RL1 VH/VL sequences in Table 9 and 13. One of ordinary skill in the art would have understood that clones depicted in Table 9 and 13 functioned similarly in binding to IL1RL1, but would not have known which residues could have been modified or mutated while still maintaining IL1RL1 selectivity and affinity, which could be conservatively changed much less which could not be changed at all.
While the prior art contains disclosure as to the structural features of several anti- IL1RL1 antibodies, it is unclear what structural features these antibodies need to share in order to maintain binding affinity and stability. Even in 2021, 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, researchers 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 IL1RL1 was known in the art, this would not have translated into knowledge of the genus of antibodies that could possibly engage it. 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 and unlimited antibody structures based on sequence data from parental anti-IL1RL1 VH/VL clones, which would support the premise that the inventors possessed the full scope of the claimed invention.
Conclusion
10. No claims are allowed.
11. 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 ANNE BRISTOL
Primary Examiner
Art Unit 1643
/LYNN A BRISTOL/Primary Examiner, Art Unit 1643