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 .
Claims 1, 2, 28, 30, 31, 57, 59, 60, 86, 88-91, 98, 102, and 103 are pending and being examined on the merit.
Objections/Rejections Withdrawn
Previous objections to the specification for sequence noncompliance and hyperlink are withdrawn in in view of amendments to the specification.
All previous objections and rejections of claims 99-101 are moot in view of claim cancellation.
Previous rejection of claims 1, 28, 30, 57, 59, 86, 88-91, and 98-103 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or a joint inventor (or for applications subject to pre-AIA 35 U.S.C. 112, the applicant), regards as the invention is withdrawn in view of claim amendments.
Rejections Maintained/New Rejections necessitated by Claim Amendments
Claim Objection
Claims 1, 30, 59, 88, 98, 102 and 103 are objected to for referencing “Figure 17A”. Although only SEQ ID NO:609 is shown in figure 17A, claims are only permitted to incorporate reference to a figure where there is no practical way to define the invention in words and where it is more concise to incorporate by reference than duplicating a drawing or table into the claim.
Applicant is advised to amend “the sequence described in Figure 17A” to “SEQ ID NO:609”.
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.
Claims 1, 28, 30, 57, 59, 86, 88-91, 98, 102 and 103 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 claims are directed to a Markush group of distinct single domain antigen binding domains (scABDs) comprising distinct CDR1, CDR2, and CDR3 sequences that are isolated independently (example 1), and have different binding properties (table 1). Even the sdABD of dependent claims 2 and 31 only include a subset of the CDR sequences of the claims recited in claims 1 and 30.
MPEP 2117 states that a “Markush grouping is proper if the members of a group share a single structural similarity and a common use.” An improper Markush group contains:
(1) the members of the Markush group do not share a "single structural similarity" or
(2) the members do not share a common use.
The instant claims are directed to different scABDs that do not share a single structural similarity. Although all the sdABDs (figures 13) were identified with the same yeast surface displayed nanobody assay, they are distinct different sdABDs, each comprising 3 distinct CDR sequences, (Example 1) and have different binding properties (table 1). A proper Markush group comprising different sdABD should share the same binding properties, including binding to the same epitopes, and are derived from the same parental sdABD.
For instance, pNVBCOV006A and the affinity matured variants, mNBCOV6 sdABD comprising the amino acid sequences of SEQ ID NOs:77-79 are a proper Markush group.
Thus, the claim sdABD are distinct and are part of an improper Markush group.
For the purpose of expedited prosecution, affinity matured pNBCOV006A sdABDs comprising SEQ ID NOs:77, 78 and 79 9 (example 2) are part of a proper Markush group that will be examined.
Response to Arguments
Applicant argued:
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Applicants noted that the instant claimed sdABD share a common structural framework and functional internation with the same antigen, SARS-CoV-2 Spike protein as shown in figures 13-16. And the fact that the claimed sdABD do not contain the same CDR sequences does not render the Markush grouping improper. The claimed sdABD shared the same antigen binding architecture and target-binding function.
Applicant further argued that differences in unclaimed epitope specificity or binding affinity do not defeat the claimed common use because the claimed use is not limited to any particular epitope or affinity threshold.
Applicant also argued that the same parent antibody clone is not required for the claimed sdABD to be part of the same Markush group. Applicant noted that the claimed sdABD belongs to the same function class of Spike-binding sdABD that are engineered to neutralize SARS-CoV-2.
Applicant cited In Re Harnish, 631 F.2d 716 (CCPA 1980) that the claims encompasses a broad and chemically diverse set of coumarin derivatives, which the courts found the Markush group to be proper because the compound shared a common coumarin structure feature and common functional property as dyes. Applicant noted that the instant claimed sdABD shared the same single domain antibody architecture and common functional interaction with the same viral spike protein.
Applicant's arguments filed on June 12, 2026 have been fully considered but they are not persuasive. Examiner agreed that the instant claimed sdABD does bind to the spike protein comprising SEQ ID NO:300 or 609 comprising a mix of the recited CDR1, CDR2, and CDR3 sequences.
The instant claims do not require framework sequences as noted by the applicant as a common feature for the claimed sdABD. Even if the framework sequences was required by the claims, which is not, the claimed sdABD are comprised of distinct CDR sequences, which are the residues that mediate antigen binding (Zebetakis et al., PLOS One, 2013, 8:e77678 pages 1-7, of record; see “introduction”). Thus, the framework sequence in light of the claimed sdABD would not dictate epitope binding or functional properties of the claimed sdABD.
It is well accepted that a typical size of a VHH epitope is around 8-25 amino acids long. The epitope on antigens that is bound by VHH dictates whether the VHH functions as an antagonist or agonist, neutralizing, stimulate internalization, competitive inhibitor, etc. Instant SEQ ID NOs:300 and 609 correspond to 634 amino acid sequences that have a 92.8% sequence similarity. Thus, simply stating that all the claimed antibodies bind to anywhere on the spike protein comprising SEQ ID NO:300 or 609 will show that the claimed sdABD have the same function is not proper.
The instant specification also noted that “21 unique nanobodies” were identified and these fall into two classes. Class I, named Nb6, binds to RBD and competes directly with ACE2-Fc, and is able to bind to RBD alone (paragraph 00251). Class II, Nb3, binds to the Spike protein and displays no binding to RBD alone (00251).
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As noted in Table 1 of instant specification, different groups of sdABD binds to RBD region, SPIKE ECD, SPIKE ECD in the presence of ACE2-Fc.
The instant specification went on to show that the different sdABD binds to different epitopes on the SPIKE protein to mediate distinct functional properties (paragraphs 0253 and 0254).
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These findings demonstrated that the claimed sdABD have different CDR sequences that results in distinct functional properties. The instant specification even described them as 21 unique sdABD. Thus, the instant claimed sdABD is distinct from In Re Harnish, 631 F.2d 716 (CCPA 1980), because the sdABD are not related by structure or function.
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, 28, 30, 57, 59, 60, 86, 88-91, 98, 102, and 103 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.
The claimed invention. The instant claims are directed to a subgenus of single domain antigen binding domains (sdABD) that bind to the trimeric Spike protein comprising SEQ ID NO:300 or SEQ ID NO:609, where the sdABD comprises mixing of the recited 47 CDR1 sequences, 47 CDR2 sequences, and 444 CDR3 sequences. Based on the recited sequences, over 980k different possible combination of different sdABD are encompassed by the claims, and only a subset of these sdABD binds to SEQ ID NO:300 or 609 as required by the instant claims.
State of the prior art.
Single domain antibody, variable heavy chain antibody (VHH), heavy chain antibody or nanobody is an antibody that is comprised of a variable heavy (VH) chain comprising three distinct CDR sequences, CDR1, CDR2, and CDR3 domains that form the antigen binding domain that mediates binding to a cognate epitope on an antigen (Bannas et al., Frontiers in Immunology, 2017, 8: 1603, pages 1-13, of record; abstract; figure 2; page 2, right column, paragraphs 1 and 2). VHH CDR3 region is generally longer than a conventional VH CDR3 domain (Bannas et al, page 3, left column) and provides major contribution to antibody diversity and specificity (Bannas et al.; figure 2; page 2, right column, paragraph 2). Vishwakarma et al. (Internation Journal of Molecular Science, 2022, 23:3721, pages 1-32, of record) teaches that the paratope region of VHH directly interacts with antigens in the nanomolar to micromolar range (page 2).
Zebetakis et al. (PLOS One, 2013, 8:e77678 pages 1-7, of record) performed CDR swapping of different VHH to study the contributions of the VHH CDRs of VHH for thermal stability and antigen binding. Zebetakis et al. showed that altering the CDRs of VHHs dramatically reduce the thermal stability and antigen binding of the VHHs (abstract; table 1). Zebetakis et al. found that the CDR2 is a major contributor to VHH stability and that all three CDRs in the proper orders are required for antigen binding (page 4 and table 1). Asaadi et al. (Biomarker Research, 2021, 9:87, pages 1-20, of record) teaches that all 3 CDR sequences of VHH contribute to antigen binding (page 3, left column, paragraph 2).
Screening phage display libraries comprising llama VHH monovalent antibodies have been used to isolate VHH antibodies that bind to a specific antigen. Groot et al. (Laboratory Investigation, 2006, 86:345-356, of record) teaches screening a phage display library with 6X109 clones of VHH monovalent binding fragments to identify the VHH that bind to a specific antigen (entire document, specifically page 347, See “Selection of VHH”). Groot et al. identified five VHHs that bind to different regions of HIF-1α, the antigen of interest. This highlights one cannot simply predict which of the VHH out of the 6X109 VHH monovalent antibodies would bind to the specific antigen. Also, the phage library that is used for the screen can generate different antibodies.
Even post-filing review article, Vishwakarma et al. (Internation Journal of Molecular Science, 2022, 23:3721, pages 1-32), teaches that there are numerous modeling programs, but none can accurately predict the 3D structure of all the VHH antibodies (abstract). Vishwakarma et al. teaches that VHH CDRs are variable and flexible, which makes predicting the structure difficult (page 21, paragraph 1).
Bert (WO2021156490A2, of record) further teaches specific VHH antibodies that binds to the RBD region of the Spike protein to neutralize SARS-CoV-2 (abstract; page 5) are comprised of 3 distinct CDR sequences (page 43). The antibodies of Bert are distinct from the instant disclosed ABD on Figures 13 and 15.
Scope of species disclosed in original specification.
Using yeast surface displayed nanobody assay, 24 different single domain (sdABD), each comprising 3 distinct CDR sequences, were isolated (Example 1a and figure 3). Even though the same screening assay was performed, only 13 of these sdABD antibodies bind to the trimeric spike protein comprising residues 446, 447, 449, 453, 455, 456, 483-486, 489-490, 493-496, 498, 501, and 505 within the ACE2 binding region of the SC2 spike RBD, and residues 342, 343, 367, 371-375, 404, and 436-441 (figure 13; Table1). This highlights the unpredictability in the arts to isolate scABDs that can bind to a specific epitope.
The instant specification also disclosed different variants of pNbCOV0016A comprising SEQ ID NO:87 that are identified through affinity maturation (Example 2). All of these antibodies are also comprised of distinct 3 CDR sequences (figures 15).
MPEP § 2163 states that 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. While the disclosure appears to describe numerous heavy chain antibodies that binds the SPIKE protein, these antibodies are comprised of distinct combinations of CDR1, CDR2, CDR3 sequences. The disclosed sdABD on figure 13 is not representative of a genus of VHH, because they are distinct VHH.
In the absence of a representative number of species, the written description requirement for a claimed genus may be satisfied 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 subgenus of sdABD comprising different combination of the recited CDR1, CDR2, and CDR3 sequences.
Accordingly, the disclosure only provides adequate written description for VHH antibodies that are described in figure 15 of the instant specification that can bind to the spike protein comprising SEQ ID NOs:300 or 609.
Conclusion. For all of the reasons presented above, one of skill in the art cannot visualize a subgenus of antibodies that can bind to a spike protein comprising either SEQ ID NO:300 or 690. Given the lack of shared structural properties that provide the claimed binding activity, the limited number of species described, and the fact that the species that were described cannot be considered representative of the broad genus, the Applicant did not possess the full genus of antibodies as broadly claimed at the time the application was filed.
Claim 102 and 103 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 a method of treating or neutralizing SARS-CoV2 comprised of administering an sdABD comprising the amino acid sequences of SEQ ID NOs:77-79, does not reasonably provide enablement for treating, neutralizing, nor preventing SARS-CoV2 comprised of administering the vast number of claimed sdABD comprising:
vhCDR1 is selected from the group consisting of SEQ ID NOs:5, 8, 11, 14, 17, 20, 23, 26, 29, 32, 35, 38, 41, 44, 47, 50, 53, 56, 59, 62, 65, 68, 71, 74, 88, 92, 94- 113, and 400-401,
vhCDR2 is selected from the group consisting of SEQ ID NOs:6, 9, 12, 15, 18,21,24,27,30,33,36,39,42,45,48,51,54,57,60,63,66,69,72,75, 89, 114-133, and 397-399, and
vhCDR3 is selected from the group consisting of SEQ ID NOs:7, 10, 13, 16, 19,22,25,28,31,34,37,40,43,46,49,52,55,58,61,64,67,70,73,76, 134-153, 179-299, and 301-582.
The specification does not enable any person skilled in the art to which it pertains, or with which it is most nearly connected, to the invention commensurate in scope with these claims.
Enablement is considered in view of the Wands factors (MPEP 2164.01 (a)). The court in Wands states: "Enablement is not precluded by the necessity for some experimentation such as routine screening. However, experimentation needed to practice the invention must not be undue or reasonable experimentation. (Wands, 8 USPQ2d 1404). Clearly, enablement of a claimed invention cannot be predicated on the basis of quantity of experimentation required to make or use the invention. "Whether undue experimentation is needed is not a single, simple factual determination, but rather is a conclusion reached by weighing many factual considerations." (Wands, 8 USPQ2d 1404). The factors to be considered in determining whether undue experimentation is required include:
(A) The nature of the invention;
(B) The breadth of the claims;
(C) The amount of direction provided by the inventor;
(D) The existence of working examples;
(E) The state of the prior art;
(F) The level of predictability in the art;
(G) The quantity of experimentation needed to make or use the invention based on the content of the disclosure and
(H) The level of one of ordinary skill. While all of these factors are considered, a sufficient amount for amount for a prima facie case are discussed below.
The nature of the invention
The instant claims are directed to a method of treating, neutralizing, or preventing SARS-CoV2 viral infection comprised of administering a vast possible combination of sdABD comprising:
vhCDR1 is selected from the group consisting of SEQ ID NOs:5, 8, 11, 14, 17, 20, 23, 26, 29, 32, 35, 38, 41, 44, 47, 50, 53, 56, 59, 62, 65, 68, 71, 74, 88, 92, 94- 113, and 400-401,
vhCDR2 is selected from the group consisting of SEQ ID NOs:6, 9, 12, 15, 18,21,24,27,30,33,36,39,42,45,48,51,54,57,60,63,66,69,72,75, 89, 114-133, and 397-399, and
vhCDR3 is selected from the group consisting of SEQ ID NOs:7, 10, 13, 16, 19,22,25,28,31,34,37,40,43,46,49,52,55,58,61,64,67,70,73,76, 134-153, 179-299, and 301-582.
The possible number of different sdABD that is encompassed by the instant claim is over 980k. The instant specification has tested binding properties of 24 distinct sdABD that binds to instant SEQ ID NO:300 or 609 (Table 1).
The amount of direction provided by the inventor/the existence of working examples
Using yeast surface displayed nanobody assay, 24 different single domain (sdABD), each comprising 3 distinct CDR sequences, were isolated (Example 1a and figure 3). Even though the same screening assay was performed, only 13 of these sdABD antibodies bind to the trimeric spike protein comprising residues 446, 447, 449, 453, 455, 456, 483-486, 489-490, 493-496, 498, 501, and 505 within the ACE2 binding region of the SC2 spike RBD, and residues 342, 343, 367, 371-375, 404, and 436-441 (figure 13; Table1). This highlights the unpredictability in the arts to isolate scABDs that can bind to a specific epitope.
The instant specification disclosed that NbCOV6 and mNbCOV6 binds to the receptor binding domain (RBD) and the ectodomain of the SPIKE protein of SARS-CoV2 (Example 2) and neutralizes the SARS-CoV2 infection (Example 4). Not all of the claimed sdABD can neutralize SARS-CoV2 infection (Example 4). Further, the instant specification have not tested all the possible subspecies of sdABD for binding to a Spike protein comprising SEQ ID NO:300 or 609, nor their ability to treat, neutralize or prevent SARS-CoV2 infection as required by the claims.
The state of the art/the level of predictability in the art
Single domain antibody, variable heavy chain antibody (VHH), heavy chain antibody or nanobody is an antibody that is comprised of a variable heavy (VH) chain comprising three distinct CDR sequences, CDR1, CDR2, and CDR3 domains that form the antigen binding domain that mediates binding to a cognate epitope on an antigen (Bannas et al., Frontiers in Immunology, 2017, 8: 1603, pages 1-13, of record; abstract; figure 2; page 2, right column, paragraphs 1 and 2). VHH CDR3 region is generally longer than a conventional VH CDR3 domain (Bannas et al, page 3, left column) and provides major contribution to antibody diversity and specificity (Bannas et al.; figure 2; page 2, right column, paragraph 2). Vishwakarma et al. (Internation Journal of Molecular Science, 2022, 23:3721, pages 1-32, of record) teaches that the paratope region of VHH directly interacts with antigens in the nanomolar to micromolar range (page 2).
Zebetakis et al. (PLOS One, 2013, 8:e77678 pages 1-7, of record) performed CDR swapping of different VHH to study the contributions of the VHH CDRs of VHH for thermal stability and antigen binding. Zebetakis et al. showed that altering the CDRs of VHHs dramatically reduce the thermal stability and antigen binding of the VHHs (abstract; table 1). Zebetakis et al. found that the CDR2 is a major contributor to VHH stability and that all three CDRs in the proper orders are required for antigen binding (page 4 and table 1). Asaadi et al. (Biomarker Research, 2021, 9:87, pages 1-20, of record) teaches that all 3 CDR sequences of VHH contribute to antigen binding (page 3, left column, paragraph 2).
Screening phage display libraries comprising llama VHH monovalent antibodies have been used to isolate VHH antibodies that bind to a specific antigen. Groot et al. (Laboratory Investigation, 2006, 86:345-356, of record) teaches screening a phage display library with 6X109 clones of VHH monovalent binding fragments to identify the VHH that bind to a specific antigen (entire document, specifically page 347, See “Selection of VHH”). Groot et al. identified five VHHs that bind to different regions of HIF-1α, the antigen of interest. This highlights one cannot simply predict which of the VHH out of the 6X109 VHH monovalent antibodies would bind to the specific antigen. Also, the phage library that is used for the screen can generate different antibodies.
Even post-filing review article, Vishwakarma et al. (Internation Journal of Molecular Science, 2022, 23:3721, pages 1-32), teaches that there are numerous modeling programs, but none can accurately predict the 3D structure of all the VHH antibodies (abstract). Vishwakarma et al. teaches that VHH CDRs are variable and flexible, which makes predicting the structure difficult (page 21, paragraph 1).
Bert (WO2021156490A2, of record) further teaches specific VHH antibodies that binds to the RBD region of the Spike protein to neutralize SARS-CoV-2 (abstract; page 5) are comprised of 3 distinct CDR sequences (page 43). The antibodies of Bert are distinct from the instant disclosed sdABD on Figures 13 and 15.
The quantity of experimentation needed to make or use the invention based on the 5 and 4
content of the disclosure
The prior art demonstrated that 3 distinct CDR sequences are required to form a function antigen binding domain on VHH, and epitope mapping and functional studies are required to identify the VHH with specific properties.
The instant specification showed that only a subset of the sdABD that is encompassed by the claims, specifically sdABD comprising amino acid sequences of SEQ ID NOs:77-79, can bind to the Spike protein comprising SEQ ID NO:300 or 609 and can neutralize SARS-CoV-2 (Examples 2 and 4).
Conclusion
Applicant is enabled for a method of treating or neutralizing SARS-CoV2 comprised of administering an sdABD comprising the amino acid sequences of SEQ ID NOs:77-79. However, in view of the Wands factors as discussed above, one of ordinary skill in the art would have to engage in undue experimentation to practice the full scope of the instant claimed invention.
Allowable Subject Matter
Claims 2, 31, and 60 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
Claims 1, 28, 30, 57, 59, 86, 88-91, 98, 102 and 103 are rejected.
Claims 2, 31, and 60 are objected.
Applicant's amendment necessitated the new ground(s) of rejection presented in this Office action. Accordingly, THIS ACTION IS MADE FINAL. See MPEP § 706.07(a). Applicant is reminded of the extension of time policy as set forth in 37 CFR 1.136(a).
A shortened statutory period for reply to this final action is set to expire THREE MONTHS from the mailing date of this action. In the event a first reply is filed within TWO MONTHS of the mailing date of this final action and the advisory action is not mailed until after the end of the THREE-MONTH shortened statutory period, then the shortened statutory period will expire on the date the advisory action is mailed, and any nonprovisional extension fee (37 CFR 1.17(a)) pursuant to 37 CFR 1.136(a) will be calculated from the mailing date of the advisory action. In no event, however, will the statutory period for reply expire later than SIX MONTHS from the mailing date of this final action.
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/JULIE WU/Supervisory Patent Examiner, Art Unit 1643
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