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 .
Election/Restrictions
Applicant’s election of a llama VHH produced by clone 70009-1 having a variable region and full set of three CDRs defined by SEQ ID NOs. 1 and 3–5, drawn to an antigen binding molecule that specifically binds the SARS-CoV-2 spike S1 protein in the reply filed on 06/11/2026 is acknowledged. Because applicant did not distinctly and specifically point out the supposed errors in the restriction requirement, the election has been treated as an election without traverse (MPEP § 818.01(a)).
Claims withdrawn from further consideration pursuant to 37 CFR 1.142(b) as being drawn to a nonelected invention, there being no allowable generic or linking claim.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 06/11/2026.
Claim Status
Claims 3, 8–12, 15, 21, 26–27, 32, 35–37, and 39–43 are cancelled.
Claims 33–34 and 38 are withdrawn.
Claims 1–2, 4–7, 13–14, 16–20, 22–25, 28–31, and 44 are under examination on the merits.
Priority
The U.S. effective filing date of the claims under examination above is set at 04/16/2021.
Information Disclosure Statement
The information disclosure statement (IDS) submitted on 06/11/2023 is being considered by the examiner.
The listing of references in the specification is not a proper information disclosure statement. 37 CFR 1.98(b) requires a list of all patents, publications, or other information submitted for consideration by the Office, and MPEP § 609.04(a) states, "the list may not be incorporated into the specification but must be submitted in a separate paper." Therefore, unless the references have been cited by the examiner on form PTO-892, they have not been considered.
Nucleotide and/or Amino Acid Sequence Disclosures
Summary of Requirements for Patent Applications Filed on Or After July 1, 2022, That Have Sequence Disclosures
37 CFR 1.831(a) requires that patent applications which contain disclosures of nucleotide and/or amino acid sequences that fall within the definitions of 37 CFR 1.831(b) must contain a “Sequence Listing XML”, as a separate part of the disclosure, which presents the nucleotide and/or amino acid sequences and associated information using the symbols and format in accordance with the requirements of 37 CFR 1.831-1.835. This “Sequence Listing XML” part of the disclosure may be submitted:
In accordance with 37 CFR 1.831(a) using the symbols and format requirements of 37 CFR 1.832 through 1.834 via the USPTO patent electronic filing system (see Section I.1 of the Legal Framework for Patent Electronic System (https://www.uspto.gov/PatentLegalFramework), hereinafter “Legal Framework”) in XML format, together with an incorporation by reference statement of the material in the XML file in a separate paragraph of the specification (an incorporation by reference paragraph) as required by 37 CFR 1.835(a)(2) or 1.835(b)(2) identifying:
the name of the XML file
the date of creation; and
the size of the XML file in bytes; or
In accordance with 37 CFR 1.831(a) using the symbols and format requirements of 37 CFR 1.832 through 1.834 on read-only optical disc(s) as permitted by 37 CFR 1.52(e)(1)(ii), labeled according to 37 CFR 1.52(e)(5), with an incorporation by reference statement of the material in the XML format according to 37 CFR 1.52(e)(8) and 37 CFR 1.835(a)(2) or 1.835(b)(2) in a separate paragraph of the specification identifying:
the name of the XML file;
the date of creation; and
the size of the XML file in bytes.
SPECIFIC DEFICIENCIES AND THE REQUIRED RESPONSE TO THIS NOTICE ARE AS FOLLOWS:
This application contains sequence disclosures in accordance with the definitions for nucleotide and/or amino acid sequences set forth in 37 CFR 1.831(a) and 1.831(b). However, this application fails to comply with the requirements of 37 CFR 1.831-1.834. The examiner has noted that Figure 9B contains a “VHH-72” sequence which lack a sequence identifier despite containing four or more specifically defined amino acid residues. Applicant must provide:
A replacement “Sequence Listing XML” part of the disclosure, as described above in item 1. or 2., as well as
A statement that identifies the location of all additions, deletions, or replacements of sequence information in the “Sequence Listing XML” as required by 1.835(b)(3);
A statement that indicates support for the amendment in the application, as filed, as required by 37 CFR 1.835(b)(4);
A statement that the “Sequence Listing XML” includes no new matter in accordance with 1.835(b)(5); and
A substitute specification in compliance with 37 CFR 1.52, 1.121(b)(3), and 1.125 inserting the required incorporation by reference paragraph as required by 37 CFR 1.835(b)(2), consisting of:
A copy of the previously-submitted specification, with deletions shown with strikethrough or brackets and insertions shown with underlining (marked-up version);
A copy of the amended specification without markings (clean version); and
A statement that the substitute specification contains no new matter.
Specific deficiency - Sequences appearing in the drawings are not identified by sequence identifiers in accordance with 37 CFR 1.831(c). Sequence identifiers for sequences (i.e., “SEQ ID NO:X” or the like) must appear either in the drawings or in the Brief Description of the Drawings. Figure 9B should include sequence identifiers for all defined polypeptide sequences containing four or more specifically defined amino acid residues.
Required response – Applicant must provide:
Amended drawings in accordance with 37 CFR 1.121(d) inserting the required sequence identifiers;
AND/OR
A substitute specification in compliance with 37 CFR 1.52, 1.121(b)(3), and 1.125 inserting the required sequence identifiers (i.e., “SEQ ID NO:X” or the like) into the Brief Description of the Drawings, consisting of:
A copy of the previously-submitted specification, with deletions shown with strikethrough or brackets and insertions shown with underlining (marked-up version);
A copy of the amended specification without markings (clean version); and
A statement that the substitute specification contains no new matter.
Specific deficiency - The incorporation by reference paragraph required by 37 CFR 1.834(c)(1), 1.835(a)(2), or 1.835(b)(2) is missing, defective or incomplete. The instant application uses kilobytes (pg. 1, line 14) instead of bytes.
Required response - Applicant must:
Provide a substitute specification in compliance with 37 CFR 1.52, 1.121(b)(3), and 1.125 inserting the required incorporation by reference paragraph, consisting of:
A copy of the previously-submitted specification, with deletions shown with strikethrough or brackets and insertions shown with underlining (marked-up version);
A copy of the amended specification without markings (clean version); and
A statement that the substitute specification contains no new matter.
Specification
The disclosure is objected to because of the following informalities:
Throughout the specification, as it refers to CDR, “complementary” should read “complementarity.”
Appropriate correction is required.
The use of the terms BIACORE (pg. 22, lines 8–9), LLAMABODY (pg. 14, lines 17 and 27; pg. 15, lines 2, 9, 16, and 22), NANOBODY (pg. 19, line 6), SEPHAROSE (pg. 23, line 31), TWEEN (pg. 32, line 3), and PLURONICS (pg. 30, line 4), which are trade names or marks used in commerce, has been noted in this application. The terms should be accompanied by the generic terminology; furthermore, the terms 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.
Claim Objections
Claims 4, 6, 16, and 22–25 are objected to because of the following informalities:
In claims 4 and 16, “complementary” should read “complementarity.”
In claims 6 and 17, for ease of reading, the Applicant is asked to use a lowercase lettered list to identify the two recited antibodies as a) or b).
In claims 22–25, “antibody binding molecule” should read “antigen binding molecule” for claim set consistency.
Appropriate correction is required.
Claims 1–2, 13–14, and 7 are objected to because of the following informalities: These claims depend on claims that follow them in the claim set. Claims should be presented in ascending numerical order consistent with their dependency. See MPEP 608.01(n)III. A dependent claim shall depend on a claim previously set forth.
Appropriate correction is required.
Applicant is advised that should claim 6 be found allowable, claim 44 will be objected to under 37 CFR 1.75 as being a substantial duplicate thereof. 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). The only difference between the two claims is semantics.
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.
Claims 1–2, 4–6, 13–14, 16–20, 22–25, and 28–31 are rejected under 35 U.S.C. 112(a) or 35 U.S.C. 112 (pre-AIA ), first paragraph, because the specification, while being enabling for camelid antibodies comprising three parental CDRs, does not reasonably provide enablement for similar antibodies comprising fewer than all parental CDRs or even one mutated CDR wherein the resulting variants have not been tested and shown to bind antigen. The specification does not enable any person skilled in the art to which it pertains, or with which it is most nearly connected, to make or use the invention commensurate in scope with these claims.
The breadth of the claims is found in claim 4, drawn to an antigen binding molecule that specifically binds the SARS-COV-2 spike S1 protein comprising a set of three recited CDRs, wherein said CDRs can be selected from two clones.
The nature of the invention is an anti-SARS-CoV-2 spike S1 protein antigen binding molecule with embodiments that include embodiments such as antibodies, camelid VHHs, and hcIgGs.
The level of skill of one skilled in this art is high.
The specification teaches camelid VHHs 70009-1 and 70009-2 (pg. 48, line 26), which each comprise three of the six CDRs of claim 5 in one molecule (pg. 55, lines 11–20). The VHHs are camelid (pg. 48, line 5). It appears only two CDR sets were made by Applicant, those of 70009-1 and 70009-2 (pg. 48, line 26). It seems that only the VHHs derived from clone 70009-1 were taught to block binding of target antigen to human ACE-2 (e.g., pg. 51, lines 3–5). It is not clear if the VHH derived from clone 70009-2 likewise blocks said binding.
Importantly, the embodiment of claims that recite sequences allows VHHs to be defined by fewer than a full set of three strictly defined parental CDRs. Claims recite antigen binding molecules which include CDRs which differ from parental CDRs by up to five mutations, variable regions with only 90% variable region sequence identity, or CDR sets that have been mixed-and-matched between clones 70009-1 and 70009-2. Such would not be expected to bind antigen as discussed infra.
The state of the prior art is such that 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 region 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 VHH to its target epitope (Paul, Fundamentals of 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 maintain their required conformation are required in order to produce a protein having antigen-binding function.
VHHs also require proper framework, but instead of six CDRs can bind antigen with only three CDRs. Yau et al. (J Immunol Methods 297: 213–224, 2005) teaches this on page 214, Column 1, paragraph, first. All three are important for antigen binding as demonstrated by the randomization of all three CDRs in the work of Yau (Figure 1). Importantly, the work of Yau also demonstrates the unpredictability of VHH CDR mutation and the ability of identifying a functional nanobody with only one CDR defined. Table 1 shows that CDR mutation leads to unpredictable results, unknown until binding is actually tested. Mutation of CDRs led to loss of substantial antigen binding in several cases, as in Gp3. In addition, one can compare D7 with D8 and see that even when fewer than all three parental CDRs are kept constant, the results are unpredictable. D8 and D7 share a CDR3 but have very different affinities. Thus, all three parental CDRs in a VHH participate and are important for antigen binding. Their mutation leads to unpredictable results. Defining such a VHH by a single parental CDR also leads to unpredictable results, including loss of antigen binding, since the two other CDRs must be identified by screening with no expectation of success, owed to the unpredictability of this art in changing them. This loss of antigen binding via parental CDR mutation is known for conventional antibodies and applies equally to VHH. Even minor changes in the amino acid sequences of the heavy and (in conventional antibodies) light variable regions, particularly in the CDRs, may dramatically affect antigen-binding function as evidenced by Rudikoff et al. (Proc Natl Acad Sci USA 79: 1979–1983, 1982). Rudikoff teaches that the alteration of a single amino acid in the CDR of a phosphocholine-binding myeloma protein resulted in the loss of antigen-binding function (Abstract). Tiller et al. (Front Immunol 8: 986) further teach that point mutations in CDR2 and CDR3 of the N2 VHH yielded unpredictable results. Gains in affinity, when achieved, were only modest, and in fact mutating the parental CDRs often instead imparted large negative impacts on antigen binding (Table 2). Tiller further teaches that the challenges inherent to CDR affinity maturation, as intractably large sub-libraries are required to identify the combinations of mutations necessary for significant increases in VHH binding affinity (pg.2, column 1).
Claims 5 and 17 recite VHHs encompassing those with mixed-and-matched CDRs from multiple parental antibody molecules. This methodology of creating a VHH does mutate parental CDRs and so fails the enablement requirement for the reasons supra. Even if the antibodies contributing to the mix and match are related, this does not cure the concerns of the prior art. As antibodies undergo somatic hypermutation, they receive some mutations that decreases their binding affinity to with antigen as well as those that increase said binding affinity. Destabilizing mutations are compensated by compensatory mutations, yielding an antibody with equal or greater binding affinity for antigen. Panka teaches that a compensatory mutation in the framework of an antibody restored lost binding affinity to an antibody variant (pg. 3083, entire page). This illustrates that any given CDR might contain deleterious mutations which are corrected by the framework regions. CDRs, when mixed and matched, go to their new antibodies without any framework compensatory mutations. Indeed, claims 5 and 17 do not require any specific frameworks be used at all. Therefore, just because a CDR contributes to antigen binding in one antibody, does not mean that it will be able to contribute in a second antibody of different framework. Said another way, the recited VHHs of claims 5 and 17 encompass VHHs that, while they have a full set of three strictly defined CDRs, do not have a full set of strictly defined and functional CDRs. Furthermore, Bonsignori (Cell 165: 449–463, 2016) teaches that compensatory mutations can occur in CDR regions (pg. 459, entire page). This again illustrates that one CDR that functions in one parental antibody, may not be able to play the same role in a second antibody with two other CDRs with which it was not evolved. Thus, clearly, barring evidence to the contrary, no one of ordinary skill in this art would assume that mixed and matched CDRs, even from functional VHHs, would necessarily work in concert to bind antigen. There was no selection for them to work together to function.
Not knowing, absent further experimentation, which modifications function and which do not, when, as set forth above, even a single change of an encoded amino acid can unpredictably affect structure and function, leads to one having no predictability or expectation of success for the function of any given antibody/VHH modification. Such random experimentation to identify at a later time what structure or fragment or modification is or is not functional and is embraced by applicant’s claims is undue experimentation.
Note that an enabling disclosure for the preparation and use of only a few analogs of a product does not enable all possible analogs where the characteristics of the analogs are unpredictable. See Amgen Inc. v. Chugai Pharmaceutical Co. Ltd. (18 USPQ 2d 1027 (CAFC 1991)).
Thus, the state of the art recognized that it would be highly unpredictable that a specific VHH comprising less than all three parental CDRs known to bind antigen would have antigen binding function. The minimal structure which the skilled artisan would consider predictive of the function of binding the antigen of a VHH includes three parental CDRs in the context of framework sequences which maintain their correct spatial orientation and have the requisite binding function. One of skill in the art would neither expect nor predict the appropriate functioning of the VHHs recited in the claims as broadly as currently claimed.
It is recommended that Applicant amend the claims to recite monoclonal VHHs comprising a full set of three strictly defined parental CDRs that have been experimentally demonstrated to bind target antigen.
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 22 and 24 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.
The recitation of “amino acids 319 to 541” in claim 22 lends to multiple claim interpretations which renders it indefinite. There is no sequence identifier reference to anchor SARS-CoV-2 spike protein S1 positions 319–541. The amino acid identity of position 391 could be one of many various residues depending upon the strain of SARS-CoV-2 and its specific spike S1 variant, i.e., whether or not it comprises insertions or deletions. The presence of multiple structural interpretations renders the claim indefinite.
It is also noted that “amino acids 319 to 541” is a parenthetical phrase that could be interpreted as required to define the spike S1 RBD. They could also be interpreted to be just a suggestion of an RBD used, with further truncates of the RBD also being useful to fulfill the claim limitations. The presence of multiple interpretations renders the claim indefinite.
See Ex parte Miyazaki, 89 USPQ2d 1207 (BPAI 2008) (“[R]ather than requiring that the claims are insolubly ambiguous, we hold that if a claim is amenable to two or more plausible claim constructions, the USPTO is justified in requiring the applicant to more precisely define the metes and bounds of the claimed invention by holding the claim unpatentable under 35 U.S.C. § 112, second paragraph, as indefinite.”).
The term “binding … is decreased” in claim 24 renders the claim indefinite. It is not clear from the text of the claim what the decrease in binding of SARS-CoV-1, SARS-CoV-2, and/or both to ACE-2 is a decrease relative to. For example, this could be a percent decrease compared to conditions in which a control antibody is present, or in the absence of antibody altogether. It is recommended a control be added to the claim.
The following is a quotation of 35 U.S.C. 112(d):
(d) REFERENCE IN DEPENDENT FORMS.—Subject to subsection (e), a claim in dependent form shall contain a reference to a claim previously set forth and then specify a further limitation of the subject matter claimed. A claim in dependent form shall be construed to incorporate by reference all the limitations of the claim to which it refers.
The following is a quotation of pre-AIA 35 U.S.C. 112, fourth paragraph:
Subject to the following paragraph [i.e., the fifth paragraph of pre-AIA 35 U.S.C. 112], a claim in dependent form shall contain a reference to a claim previously set forth and then specify a further limitation of the subject matter claimed. A claim in dependent form shall be construed to incorporate by reference all the limitations of the claim to which it refers.
Claim 30 is rejected under 35 U.S.C. 112(d) or pre-AIA 35 U.S.C. 112, 4th paragraph, as being of improper dependent form for failing to further limit the subject matter of the claim upon which it depends, or for failing to include all the limitations of the claim upon which it depends.
The antigen binding molecule of claim 1 is already considered a composition of matter and so, in the absence of a special definition of "composition," in the specification, dependent claim 30 does not further limit claim 1.
Applicant may cancel the claim or present a sufficient showing that the dependent claim complies with the statutory requirements.
Claims 1–2, 4–7, 13–14, 16–18, and 44 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).
The improper Markush grouping includes species of the claimed invention that do not share both a substantial structural feature and a common use that flows from the substantial structural feature. The members of the improper Markush grouping do not share a substantial structural feature and a common use that flows from the substantial structural feature for the following reasons:
MPEP 803.02 provides guidance on the analysis of a proper Markush group. Members of a proper Markush group are disclosed in the specification to possess at least one property in common which is mainly responsible for their function in the claimed relationship, and it is clear from their very nature or from the prior art that all of them possess this property. The MPEP further provides that in the members of a proper Markush group there should be (1) a common utility, and (2) a substantial structural feature essential to that utility.
In the instant case, the group of VHHs of the claims contain species with different CDR sets. As discussed supra, it is well established in the art through the teachings of Paul, Rudikoff, Yau, and Tiller that the formation of an intact antigen-binding site of a VHH requires the association of its complete framework region and full set of three strictly defined CDRs. All three of the VHH CDRs, in their proper order and in the context of the framework sequences which maintain their required conformation, are required in order to produce a protein with the structure necessary for antigen-binding function. 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 VHH Markush group. Said another way, it is the CDR set as a whole that is the substantial structural feature essential to the utility (antigen binding) of both conventional antibodies and VHHs. Since the instant claims contain Markush groups with members of VHHs with differing CDR sets, the claims contain an improper Markush group and are rejected here.
In response to this rejection, Applicant should either amend the claims to recite only individual species or grouping of species that share a substantial structural feature as well as a common use that flows from the substantial structural feature, or present a sufficient showing that the species recited in the alternative of the claims in fact share a substantial structural feature as well as a common use that flows from the substantial structural feature. This is a rejection on the merits and may be appealed to the Board of Patent Appeals and Interferences in accordance with 35 U.S.C. § 134 and 37 CFR 41.31(a)(1).
Art-free Subject Matter
Claims 19, 20, 23, 25, and 28–29, and 31 are 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
All claims are rejected.
Any inquiry concerning this communication or earlier communications from the examiner should be directed to Michael J.A. Bellecourt whose telephone number is (571)270-5356. The examiner can normally be reached M–F, 7:30 a.m.–5:00 p.m.
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, Michael Allen can be reached at (571)270-3497. The fax phone number for the organization where this application or proceeding is assigned is (571)273-8300.
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/MICHAEL J.A. BELLECOURT/Examiner, Art Unit 1671
/Michael Allen/Supervisory Patent Examiner, Art Unit 1671
Prosecution Insights