CTNF 17/996,743 CTNF 90090 Notice of Pre-AIA or AIA Status 07-03-aia AIA 15-10-aia 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 Applicant’s election without traverse of Group I, claims 1-4, 6-9, 25, and 27, in the reply filed on 11/24/2025 is acknowledged. With respect to the species election requirement, Applicant elected VHH molecules comprising CDRs 1-3 of 1) SEQ ID NO(s): 4-6, 2) SEQ ID NO(s): 190-192, and 3) SEQ ID NO(s): 199-201, which are comprised within the VHH molecules of SEQ ID NO(s): 263, 325, and 328, respectively. Claims 1-4, 6-10, 12, 15-22, 25, and 27 are pending. 08-06 AIA Claim s 10, 12, and 15-22 are withdrawn from further consideration pursuant to 37 CFR 1.142(b) as being drawn to a nonelected invention , there being no allowable generic or linking claim. Election was made without traverse in the reply filed on 11/24/2025 . 08-06 AIA Claim s 2 and 4 are withdrawn from further consideration pursuant to 37 CFR 1.142(b) as being drawn to a nonelected species , there being no allowable generic or linking claim. Election was made without traverse in the reply filed on 11/24/2025 . Claims 1, 3, 6-9, 25, and 27 are under examination on the merits . Priority Applicant’s claim for the benefit of a prior-filed application under 35 U.S.C. 119(e) or under 35 U.S.C. 120, 121, 365(c), or 386(c) is acknowledged. Claims 1, 3, 6-9, 25, and 27 have an effective filing date of 04/20/2020, corresponding to PRO 63/012,751. Information Disclosure Statement The information disclosure statements (IDS) submitted on 12/14/2023 and 11/24/2025 are in compliance with the provisions of 37 CFR 1.97. Accordingly, the information disclosure statements are being considered by the examiner. Objection to the Drawings 06-22 AIA The drawings are objected to, because some of the drawings are blurry and difficult to read, see drawings 2 and 10 . 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. Notes on the Prior Art The prior art does not teach or suggest the claimed anti-coronavirus VHH molecules. At the effective filing date of the invention, anti-coronavirus VHH molecules were known in the art. For example, at p. 2, De Vlieger et al. (Antibodies, 8(1): 1-22, 2019) teach that “[n]umerous virus-neutralizing VHHs have been described and different steps in the viral life cycle can be perturbed (Figure 1). For example, VHHs that prevent virus entry by blocking the receptor binding have been described for influenza (targeting the hemagglutinin (HA) protein), HIV (targeting gp120) and Middle East respiratory syndrome coronaviruses (MERS CoV) (targeting the spike proteins…” The prior art does not, however, teach anti-coronavirus VHH molecules comprising CDRs 1-3 of 1) SEQ ID NO(s): 4-6, 2) SEQ ID NO(s): 190-192, or 3) SEQ ID NO(s): 199-201. The instantly claimed anti-coronavirus VHH molecules are also not an obvious variant of any art-known anti-coronavirus VHH molecules, and as such the instantly claimed anti-coronavirus VHH molecules are free of the prior art. Claim Rejections 35 U.S.C. 112(a) 07-30-01 AIA 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. 07-31-01 AIA Claim s 1, 3, 6-9, 25, and 27 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 pre-AIA 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. Diamond 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 elected species in the instant case encompass an antibody or antigen-binding fragment thereof that binds to a coronavirus S protein, comprising: a heavy chain single variable domain (VHH) comprising complementarity determining regions (CDRs) 1, 2, and 3, wherein the VHH CDR1 region comprises an amino acid sequence that is at least 80% identical to a selected VHH CDR1 amino acid sequence, the VHH CDR2 region comprises an amino acid sequence that is at least 80% identical to a selected VHH CDR2 amino acid sequence, and the VHH CDR3 region comprises an amino acid sequence that is at least 80% identical to a selected VHH CDR3 amino acid sequence; wherein the selected VHH CDRs 1, 2, and 3 amino acid sequences are one of the following: (1) the selected VHH CDRs 1, 2, 3 amino acid sequences are set forth in SEQ ID NOs: 4-6, respectively; (2) the selected VHH CDRs 1, 2, 3 amino acid sequences are set forth in SEQ ID NOs: 190-192; respectively and (3) the selected VHH CDRs 1, 2, 3 amino acid sequences are set forth in SEQ ID NOs: 199-201, respectively. In view of the “ at least 80% identical ” language in the claims, the claims encompass a large genus of anti-coronavirus VHH molecules having different CDR sequences. The specification adequately describes three species within the claimed genus, specifically, anti-coronavirus VHH molecules comprising CDRs 1-3 of 1) SEQ ID NO(s): 4-6, 2) SEQ ID NO(s): 190-192, and 3) SEQ ID NO(s): 199-201; however in view of this disclosure, Applicant is claiming a broad genus of molecules that would be expected to encompass multiple anti-coronavirus VHH molecules having diverse heavy chain CDR sequences. Even though Applicant has disclosed three species within said genus, the specification does not provide adequate written description for the entire claimed genus, because 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 heavy chain CDR sequences (and combinations of said CDR sequences) give rise to VHH molecules capable of binding coronavirus. As detailed below Applicant’s disclosure is not sufficient to demonstrate possession of the entire claimed genus, and as such Applicant’s disclosure does not satisfy the written description requirement of 35 U.S.C. 112(a). 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. PNG media_image1.png 18 19 media_image1.png Greyscale 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. In the instant case, Applicant has disclosed three species within the genus claimed; however given the substantial antibody structure variation within the genus, as well as the high level of unpredictability in the art, the disclosure of two species comprised within the claimed genus is not sufficiently representative of the entire genus. Furthermore Applicant has not disclosed relevant, identifying characteristics of CDR region amino acid sequences (or combinations thereof) that confer upon a VHH molecule the ability to bind coronavirus, because the instant specification does not provide structural antibody features that correlate with a functional ability to bind coronavirus. It is known in the art that the antigen-combining site of a VHH molecule is a three-dimensional structure that fully comprises three CDRs, typically heavy chain CDRs. The amino acid sequences of the CDRs are hypervariable, and the amino acid residues contained within the CDRs determine much of the VHH’s antigen-binding specificity. It is apparent that VHH molecules having less than all three CDRs that form the antigen binding site of a conventional VHH do not describe the particularly identifying structural feature of the VHH that correlates with the VHH’s ability to bind antigen. Absent a description of the at least minimal structural features correlating with a functional ability to bind coronavirus which are shared by members of a genus of VHH molecules commonly sharing this function, it is submitted that the skilled artisan could not immediately envision, recognize, or distinguish which CDR amino acid sequences (or combinations thereof) may be combined such that the resultant VHH comprises three CDRs that confer the ability to bind coronavirus. 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 in a series of experiments involving a monoclonal antibody to Legionella pneumophilia serotype 1, McCarthy et al. (J. Immunol. Methods, 251(1-2): 137-149, 2001) demonstrated that a single V H CDR3 substitution of tyrosine to serine at position 95 resulted in the total loss of antigen recognition in an ELISA. Lin et al. (African Journal of Biotechnology, 10(79):18294-18302, 2011) teach that a single amino acid substitution in the VL CDR3 of an anti-avian infectious bronchitis virus (IBV) single-chain antibody (ZL.80) may abrogate binding. For example at Figure 3, Lin et al. demonstrate that replacing either the Cys105 or Asp106 residue in the VL CDR3 of ZL.80 with an alanine residue reduces binding to near negative control levels. Lin et al. also teach that some single amino acid substitutions in the VL CDR3 of ZL.80 may significantly improve binding. For example replacing the Val108 residue in the VL CDR3 of ZL.80 with a tyrosine residue results in a 12.9-fold increase in affinity compared to parental ZL.80. Accordingly absent empirical determination, one skilled in the art would be unable to predict or envision which CDR residues of 1) SEQ ID NO(s): 4-6, 2) SEQ ID NO(s): 190-192, and 3) SEQ ID NO(s): 199-201 could be changed such that the resultant variant CDR residues form a VHH molecule capable of binding coronavirus. 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 heavy chain CDR amino acid sequences, that correlate with the ability of a VHH molecule to bind coronavirus, and because the three disclosed species detailed above are 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. Claim 3 is included in this rejection, because the claim encompasses 80% identity variants of full-length VHH molecules, which allows for variability within the CDRs. As indicated above absent empirical determination, one skilled in the art would be unable to readily envision which 80% identity variants of the recited VHH SEQ ID NO(s) may be altered such that a resultant VHH molecule is capable of binding coronavirus. Although screening techniques can be used to isolate CDR variant VHH molecules that possess the ability to bind coronavirus, 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.” Accordingly given the unpredictability associated with antibody or VHH CDR region changes on antigen binding and given the lack of particularity with which the claimed VHH molecules are described in the specification, it is submitted that the skilled artisan could not immediately envision, recognize, or distinguish at least most of the members of the genus to which the claims are directed, and therefore the specification would not reasonably convey to the skilled artisan that Applicant was in possession of the claimed invention at the time the application was filed. Applicant is informed that this rejection of the claims under 35 U.S.C. 112(a) may be overcome by amending the claims to remove the “80% identity” language . Allowable Subject Matter 12-151-08 AIA 07-43 12-51-08 Claim 7 is objected to as being dependent upon a rejected base claim, but would be allowable if rewritten in independent form including all of the limitations of the base claim and any intervening claims. Conclusion No claims are allowed. Any inquiry concerning this communication or earlier communications from the examiner should be directed to NELSON B MOSELEY II whose telephone number is (571)272-6221. The examiner can normally be reached on M-F, 9:00-6:00 EST. If attempts to reach the examiner by telephone are unsuccessful, the examiner’s supervisor, Samira Jean-Louis, can be reached at 571-270-3503. The fax phone number for the organization where this application or proceeding is assigned is 571-273-8300. Information regarding the status of an application may be obtained from the Patent Application Information Retrieval (PAIR) system. 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If you would like assistance from a USPTO Customer Service Representative or access to the automated information system, call 800-786-9199 (IN USA OR CANADA) or 571-272-1000. /NELSON B MOSELEY II/Primary Examiner, Art Unit 1642 Application/Control Number: 17/996,743 Page 2 Art Unit: 1642 Application/Control Number: 17/996,743 Page 3 Art Unit: 1642 Application/Control Number: 17/996,743 Page 4 Art Unit: 1642 Application/Control Number: 17/996,743 Page 5 Art Unit: 1642 Application/Control Number: 17/996,743 Page 6 Art Unit: 1642 Application/Control Number: 17/996,743 Page 7 Art Unit: 1642 Application/Control Number: 17/996,743 Page 8 Art Unit: 1642 Application/Control Number: 17/996,743 Page 9 Art Unit: 1642 Application/Control Number: 17/996,743 Page 10 Art Unit: 1642