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 .
Preliminary Amendment
The preliminary amendment dated 01/12/2026 has been entered. Claims 1-2, 4-13, 15-20 are pending.
Information Disclosure Statement
The Information Disclosure Statement(s) (IDSs) submitted on 12/11/2024, 06/13/2023 and 02/21/2023 have been considered by the examiner.
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. The earliest possible effective filing date for the instant claims is August 21, 2020 based on the filing date of the provisional application 63/068,720.
Election/Restriction
Applicant’s species election with traverse of Group I in the reply filed on 01/12/2026 is acknowledged.
Applicant elects S1-RBD-22 antibody with CDR 1, 2 and 3 represented by SEQ ID Nos 309, 310 and 311, respectively. The complete variable region of S1-RBD-22 is SEQ ID NO: 65
Applicant elects IgG1 Fc region as the species of Fc region. The IgG1 Fc region corresponds to SEQ ID NO: 465.
Claims 9, 12, 16 and 17 are withdrawn from further consideration pursuant to 37 CFR 1.142(b), as being drawn to a nonelected species.
Claims 1-2, 4-8, 10-11, 13, 15, 18-20 are under examination.
Applicant requested that antibodies S1-RBD-22 and S1-36 to be examined. The traversal filed by the Applicant is on the grounds that searching two species of he single domain antibodies does not substantially increase the search burden.
Applicant’s arguments have been fully considered but are not found persuasive as such arguments do not apply when restriction is required under 35 USC 121 and 372, as in the instantly filed application. Thus, when the Office considers international applications as an International Searching Authority, as an International Preliminary Examining Authority, and during the national stage as a Designated or Elected Office under 35 U.S.C. 371, only PCT Rule 13.1 and 13.2 will be followed when considering unity of invention of claims of different categories without regard to the practice in national applications filed under 35 U.S.C. 111. In addition, antibodies S1-RBD-22 and S1-36 are structurally unrelated (see Claim Rejections - 35 USC § 112 – Improper Markush Grouping) and therefore, the request for examining antibody S1-36 is not granted..
The requirement is still deemed proper and is therefore made FINAL.
Drawings Objections
The drawings are objected to because of poor resolution in the following figures:
Figs. 2A (page 3), 2B,7A, 7D, 7G, 8A, 8D, 10A are not legible.
Figs. 8 and 18: there are color references (red, blue etc.) but the figures are black and white therefore, no such colors can be discerned
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.
Claim Rejections - 35 USC § 112 – Improper Markush Grouping
Claims 1-2, 4-8, 10-11, 13, 15, 18-20 are rejected on the judicially-created 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 claims 1-2, 4-13, 15-20 are improper because the alternatives defined by the Markush grouping do not share both a single structural similarity and a common use that flows from the substantial structural feature for the following reasons::
As disclosed in the sequence comparison below, the amino acids from the different CDRs of the distinct single-domain antibodies are clearly distinct.
The antibodies have distinct amino acid sequences and different epitopes even in different proteins (S1 v. S2).
The claims recite discrete antibody binding domains do not all share significant structural similarity. Even minor changes in the amino acid sequences of the heavy and light variable regions, particularly in the CDRs, may dramatically affect antigen-binding function as evidenced by Rudikoff (Proc Natl Acad Sci USA 1982 Vol 79 page 1979). Rudikoff teaches that the alteration of a single amino acid in a single CDR of a phosphocholine-binding myeloma protein resulted in the loss of antigen-binding function (entire article).
It is well established in the art that the formation of an intact antigen-binding site of antibodies generally requires the association of the complete heavy and light chain variable regions of a given antibody, each of which consists of three CDRs or hypervariable regions, which provide the majority of the contact residues for the binding of the antibody to its target epitope (Paul, Fundamental Immunology, 3rd Edition, 1993, pp. 292-295, under the heading “Fv Structure and Diversity in Three Dimensions”). The amino acid sequences and conformations of each of the heavy and light chain CDRs are critical in maintaining the antigen binding specificity and affinity, which is characteristic of the immunoglobulin. It is expected that all of the heavy and light chain CDRs in their proper order and in the context of framework sequences. which maintain their required conformation, are required in order to produce a protein having antigen-binding function and that proper association of heavy and light chain variable regions is required in order to form functional antigen binding sites (Paul, page 293, first column, lines 3-8 and line 31 to column 2, line 9 and lines 27-30). Therefore, it is the full set of CDRs that determines antigen binding function and so it is this set of CDRs that must match among members of a proper antibody genus. Said another way, it is the CDR set as a whole that is the substantial structural feature essential to the utility (antigen binding) of antibodies.
These teachings also apply to the CDR 1, CDR2 and CDR 3 of single-domain antibodies because the three CDRs constitute an intact antigen-binding site.
The following sequences constitute some examples of the CDR3 regions of the single-domain antibodies of claim 1 (which includes about 116 antibodies) and where they bind. (specification Table 1 pages 11- 38) which share no significant structural similarity:
SEQ ID NO:119 CDR3 of S1-1 binding to RBDAsp Ser Lys Gly Trp Ser Glu Trp Gly Met Asp Tyr
SEQ ID NO: 128 CDR3 of S1-4 binding to RBDAsp Arg Gly Tyr Ser Leu Tyr Tyr Tyr Gln Ala Arg Glu Tyr Glu Tyr
SEQ ID NO: 197 CDR3 of S1-36 binding to RBDSer Pro Arg Thr Met Tyr Leu Ala Ser Tyr Tyr Tyr His Arg Thr Ser Tyr Asp Tyr
SEQ ID NO: 311 CDR3 of S1-RBD-22 binding to RBDAsp Arg Ala Tyr Ser Leu Met Tyr Tyr Asp Thr Arg Glu Tyr Glu Tyr
SEQ ID NO: 125 CDR3 of S1-3 NOT binding to RBDLeu Pro Arg Ser Gly Ser
SEQ ID NO: 143 CDR3 of S1-10 NOT binding to RBDHis Leu Gln Lys Tyr Gly Gly Asp Tyr Tyr Ala Arg Ile
SEQ ID NO: 170 CDR3 of S1-24 NOT binding to RBDGly Gly Gly Trp Asp Tyr Arg Asn Ser Tyr Tyr Ile Pro Arg Val Asp Ser
SEQ ID NO: 257 CDR3 of S1-64 NOT binding to RBDGlu Asp Thr Gly Leu Trp Asn Ser Lys Asp Thr Tyr
SEQ ID NO: 398 CDR3 of S2-4 binding to S2Ser Lys Thr Trp Ser Pro Ser Thr Gly Val Ala Thr Glu Tyr Glu Phe
SEQ ID NO:410 CDR3 of S2-9 binding to S2Gln Asn Ser Arg Gly Asp Asn Tyr
SEQ ID NO: 425 CDR3 of S2-15 binding to S2Asp Asp Arg Arg Met Pro Ala Ala Ile Met Thr Ser Val Arg Asp Tyr Val Tyr
SEQ ID NO: 461 CDR3 of S2-59 binding to S2Ala Gly Gly Tyr Tyr Ser Asp Asn Ile Arg Gln Thr Asp Tyr Asn Tyr
Although only CDR3 is used as an example, an artisan would understand that the sequence differences in the CDRs overall would amount to structural differences in the antibody binding region as a whole, and therefore there would be no structural similarity between the antibodies leading to be functionally equivalent and to their common use.
Lastly, while the claims do not recite any function associated with all these diverse CDR structures, the specification discloses “large number of high affinity nanobodies to exploit the available epitope and vulnerability landscape of the SARS-CoV-2 Spike protein” [0032]. This is not an art-recognized class of molecules as defined in MPEP 2117 as: that it was known within the art that each member could be substituted one for the other, with the expectation that the same intended result (be functionally equivalent) would be achieved. This is not the case for these 116 antibodies as their CDRs vary widely and they bind different areas within the spike protein (see Table 1 pages 11- 38) and even when they bind the same general area (RBD, non-RBD and S2), it is unclear they would bind the exact same epitope and therefore they cannot substitute one for the other with the expectation of having the same intended results. In fact. Fig. 5, Fig. 6 Fig 7A, Fig 7D show the differences between these antibodies including Kd Kon and Koff data. Therefore, in the instant case, the structurally different antibodies are not art-recognized substitutions for each other.
Dependent claims are rejected for failing to resolve 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 claims are allowed.
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/IMMA BARRERA/
Examiner, Art Unit 1671
/RACHEL B GILL/Primary Examiner, Art Unit 1671