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 1-31 are the original claims filed 3/8/2023. In the Preliminary Amendment of 6/27/2023, claims 1, 15 and 19-20 are amended and claims 21-31 are canceled. In the second Preliminary Amendment of 7/25/2023, the claims are a resubmission of the claim set filed on 6/27/2023.
Claims 1-20 are all the claims.
Priority
2. USAN 18/119,183, filed 03/08/2023, is a Continuation of PCT/US2021/049724, filed 09/09/2021, PCT/US2021/049724 Claims Priority from Provisional Application 63/076,885, filed 09/10/2020.
Information Disclosure Statement
3. As of 11/17/2025, a total of three (3) IDS are filed for this application: 6/27/2023; 12/11/2024; and 8/20/2025. The initialed and dated 1449 form is considered and of record.
Objections
Drawings
4. The drawing sheets filed on 3/8/2023 for Figure 1 are objected to because they fail to include the sequence identifiers for those sequences > 4 amino acids in length. A SEQ ID NO is required pursuant to 37 CFR 1.821-1.825. Corrected drawing sheets in compliance with 37 CFR 1.121(d) are required in reply to the Office action to avoid abandonment of the application. Any amended replacement drawing sheet should include all of the figures appearing on the immediate prior version of the sheet, even if only one figure is being amended. The figure or figure number of an amended drawing should not be labeled as “amended.” If a drawing figure is to be canceled, the appropriate figure must be removed from the replacement sheet, and where necessary, the remaining figures must be renumbered and appropriate changes made to the brief description of the several views of the drawings for consistency. Additional replacement sheets may be necessary to show the renumbering of the remaining figures. Each drawing sheet submitted after the filing date of an application must be labeled in the top margin as either “Replacement Sheet” or “New Sheet” pursuant to 37 CFR 1.121(d). If the changes are not accepted by the examiner, the applicant will be notified and informed of any required corrective action in the next Office action. The objection to the drawings will not be held in abeyance.
Specification
5. The disclosure is objected to because of the following informalities:
a) The use of the term GloMax, BioFX, PURExpress, BiTE, nanobody, DART, Megalign, DNASTAR, 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 figure legend to Figure 1 is objected to for failing to include the sequence identifiers for those sequences > 4 amino acids in length. A SEQ ID NO is required pursuant to 37 CFR 1.821-1.825. Alternatively, Applicants may submit revised and amended drawing sheets for Figure 1 to rectify the deficiencies.
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.
6. Claims 15 and 19-20 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) A broad range or limitation together with a narrow range or limitation that falls within the broad range or limitation (in the same claim) may be considered indefinite if the resulting claim does not clearly set forth the metes and bounds of the patent protection desired. See MPEP § 2173.05(c).
In the present instance, claim 15 recites the broad recitation “a single domain antibody”, and the claim also recites “a Fd fragment antibody”, “a fragment comprised of only a single monomeric variable domain”, “a VHH antibody” which is the narrower statement of the range/limitation.
In the present instance, claim 15 recites the broad recitation “camelized antibody”, and the claim also recites “VHH antibody” which is the narrower statement of the range/limitation.
The claim(s) are considered indefinite because there is a question or doubt as to whether the feature introduced by such narrower language is (a) merely exemplary of the remainder of the claim, and therefore not required, or (b) a required feature of the claims.
b) Claims 19-20 recite the term “about.” The claims are more confusing by the phrase “less than about.” The specification does not define the meaning of the phrase. The specification defines “about” at
[0178] As used herein, the terms “about” and “approximately,” when used to modify an amount specified in a numeric value or range, indicate that the numeric value as well as reasonable deviations from the value known to the skilled person in the art, for example ±20%, ±10%, or ±5%, are within the intended meaning of the recited value.
The POSA could reasonably conclude that variation for the corresponding claimed EC50 value is highly variable. It is not clear what contributes to the variability. For example, the measured EC50 value may depend heavily on the specific experimental conditions and the biological system used; a lower EC50 value indicates a more potent compound, meaning a smaller concentration is needed to achieve half the maximal effect; or EC50 values can only be reliably compared across experiments if all experimental conditions are kept the same.
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
7. Claims 1-20 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
As regards claims 1-20, the limitations descriptive of the RBD antigen and the antibodies are found to be deficient.
“SARS-CoV-2 receptor binding domain (RBD)”: none of the claims recite the sequence(s) for the SARS-CoV-2 RBD. The specification does not define the protein or nucleic acid encoding the protein sequence for the RBD. The art recognizes protein variation in the RBD region of SARS-CoV-2 where the RBD escape mutations confer resistance of antibody binding and neutralization (Mittal et al (PLoS Pathog 18(2): e1010260; February 17, 2022; See Figure 5 SARS-CoV-2 RBD mutations that escape antibody binding; Safari et al (Archives of Virology (2022) 167:293–305; see Figure 2 Effects of defining genome sequence variations of SARSCoV-2 variants of concern (VOCs) on the domains of the spike protein. A).
The POSA could reasonably conclude that applicants are not in possession of the myriad anti- SARS-CoV-2 RBD binding antibodies without sufficient information defining the epitope or the antigen to which the antibodies “specifically” bind.
“specifically bind”: the specification provides no definition for the meaning of the phrase that corresponds to any particular antigen structure for an RBD more especially where antigenic variation is associated with the RBD protein for the virus.
“Specifically binds” is not art-defined as exclusive binding as evidenced by Bost et al. (Immunol. Invest. (1988) 17:577-586). That an antibody "cross-reacts", i.e., binds to more than one protein sequence, does not mean that the antibody does not "specifically react" or "specifically bind" with both proteins. For example, Bost et al. describe antibodies which "cross-react" with IL-2 and HIV envelope protein, but establish that the binding of each protein is due to the presence of a homologous sequence in each protein in which 4 of 6 residues were identical (see entire document, but especially the Abstract and Discussion). Antibodies that bound either the HIV or IL-2 derived sequence, did not cross react with irrelevant peptides (e.g., "Results, page 579).
Applicants have not demonstrated with sufficient evidence the uniqueness or exclusiveness of any antibody recognizing and binding to any RBD of the virus much less the sequence for the RBD structure correlated with the binding activity.
As regards claims 1 and 15-20, the antibodies comprise amino acid substitutions, insertions or deletions relative to VH-CDR1 of SEQ ID NO: 227 and VH-CDR3 of SEQ ID NO: 45, where they are not defined as being natural, unnatural, synthetic, mimetic, etc. much less by residue position in the sequence by the specific amino acid.
As regards claims 2 and 7, the combination of possible amino acids is within a limited range but the predictability that just any combination within the VH-CDR1 further combined with the VH-CDR2 and the combination of possible amino acids within a limited range for the VH-CDR3 is not provided in the specification as filed.
The POSA could reasonably conclude that the antibodies are single variable domains comprising VH-CDR1-3 domains allegedly binding just any sequence for the RBD with variations to the VH-CDR1 and -3 domains.
The interpretation encompasses a genus of antibody variants beyond those taught in the specification. Because applicant seeks patent protection for all such anti- SARS-CoV-2 RBD 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 variation may encompass any number and kind of amino acids that are natural or non-natural or even mimetics. The variation may encompass the presence of non-naturally occurring thiol groups, e.g., methionine or cysteine, which is potentially disadvantageous because these amino acids can lead to misfolding or mis-conjugation problems. Here, all of the claims encompass anti- SARS-CoV-2 RBD antibodies allegedly binding just any sequence for the RBD with variations to the VH-CDR1 and -3 domains. The genus encompassed by the claims is therefore very large and there is substantial variation within the genus.
State of the Relevant Art
While an 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. Here is the case where the specific antigen is recognized in the art as being hyper variable much less that the antibody comprises a single domain region comprising VH-CDR1-3.
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, 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). 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 for the anti- SARS-CoV-2 RBD antibodies could be modified to create an unlimited change in amino acid(s) for the VHCDR-1 and VHCDR-3 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 anti-SARS-CoV-2 RBD VHH antibody clones selected to bind the SARS-CoV-2 RBD protein (Sino Biological, Cat. No. 40592-V02H) with the VHH domains disclosed in Figure 1 and Sequence Appendix in the specification.
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 amino acid variation for the VHCDR-1 and VHCDR-3 of the claimed antibodies. The genus of all possible anti- SARS-CoV-2 RBD antibodies encompassed by the claimed CDR variation would be structurally distinct but unpredictable whether the structure/function correlation was met for binding to just any RBD from any SARS-CoV-2 virus. The specification does not identify which amino acids are permissive for substitution, insertion or deletion in the respective VH-CDR1 or VH-CDR3, or which subset of residues in the combination of CDRs is essential for the recited function of binding just any SARS-CoV-2 RBD. 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 just any SARS-CoV-2 RBD. 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. One of ordinary skill in the art would have understood that the anti-SARS-CoV-2 RBD clones functioned similarly, but would not have known which residues could have been replaced while still maintaining selectivity and affinity for just any RBD from any SARS-CoV-2, and which residues could be conservatively changed much less which could not be changed at all.
It is unclear what structural features the genus of anti- SARS-CoV-2 RBD antibodies need to share in order to maintain bind binding for just any RBD in what is recognized in the art as being mutation variable. 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, 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.
The sequence of SARS-CoV-2 RBD is predicted as being variable, therefore, this would not have translated into knowledge of the genus of antibodies that could possibly engage just any RBD protein. 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 with specific binding for just any SARS-CoV-2 RBD, which would support the premise that the inventors possessed the full scope of the claimed invention.
Claim Rejections - 35 USC § 102
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 the appropriate paragraphs of 35 U.S.C. 102 that form the basis for the rejections under this section made in this Office action:
A person shall be entitled to a patent unless –
(a)(1) the claimed invention was patented, described in a printed publication, or in public use, on sale, or otherwise available to the public before the effective filing date of the claimed invention.
(a)(2) the claimed invention was described in a patent issued under section 151, or in an application for patent published or deemed published under section 122(b), in which the patent or application, as the case may be, names another inventor and was effectively filed before the effective filing date of the claimed invention.
9. Claim(s) 1-2, 4-5, 7-10, 15-20 is/are rejected under 35 U.S.C. 102(A)/(1) or (2) as being anticipated by US/17760300B (VIB VZW; US 20230227537) or US/18559915 (VIB VZW; US 20240228596).
The sequences of SEQ ID NO: 6 (‘300) and SEQ ID NO: 5 (‘915) teach the corresponding VHH anti- SARS-CoV-2 spike protein antibody comprising CDR1-3 as shown in instant claimed linked SEQ ID NO: 227-38-45:
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Absent a showing to the contrary, the antibodies possess the inherent properties of having an EC50 of about 0.1 ug/ml.
Products of identical or substantially similar chemical composition cannot have mutually exclusive properties. A chemical composition and its properties are inseparable. Therefore, if the prior art teaches the chemical structure, the properties applicant discloses and/or claims are necessarily present. In re Spada 15 USPQ2d 1655, 1658 (Fed. Cir. 1990). See MPEP 2112.01. Thus, where the claimed and prior art products are identical or substantially identical in structure or composition, a prima facie case of anticipation has been established. In re Best, 562 F.2d 1252, 1255, 195 USPQ 430, 433 (CCPA 1977). “When the PTO shows a sound basis for believing that the products of the applicant and the prior art are the same, the applicant has the burden of showing that they are not.” In re Spada, 911 F.2d 705, 709, 15 USPQ2d 1655, 1658 (Fed. Cir. 1990). Therefore, the prima facie case can be rebutted by evidence showing that the prior art products do not necessarily possess the characteristics of the claimed product. In re Best, 562 F.2d at 1255, 195 USPQ at 433. See also Titanium Metals Corp. v. Banner, 778 F.2d 775, 227 USPQ 773 (Fed. Cir. 1985).”
Conclusion
10. No claims are allowed.
11. The following reference is considered pertinent but not effective as art over the instant claims: Flagship Pioneering Innovations VI, LLC (US 11987616; priority 20200826) teaches in Table 1 an anti-SARS-CoV-2 antibody comprising the sequences GRTFSEYA (SEQ ID NO:6) and AAAGLGTVVSEWDYDYDY (SEQ ID NO 9) that correspond with instant claimed SEQ ID NO: 227 and SEQ ID NO: 45, respectively. The reference does not disclose any sequences for instant claimed SEQ ID NOs: 38, 228-230.
12. 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.
Examiner interviews are available via telephone, in-person, and video conferencing using a USPTO supplied web-based collaboration tool. To schedule an interview, applicant is encouraged to use the USPTO Automated Interview Request (AIR) at http://www.uspto.gov/interviewpractice.
If attempts to reach the examiner by telephone are unsuccessful, the examiner’s supervisor, Wu Julie can be reached at 571-272-5205. The fax phone number for the organization where this application or proceeding is assigned is 571-273-8300.
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LYNN ANNE BRISTOL
Primary Examiner
Art Unit 1643
/LYNN A BRISTOL/Primary Examiner, Art Unit 1643