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 .
Claims Status
The Amendment filed on 28Dec2023 is acknowledged in which claim(s) 9-11, 14, 22, and 25 were canceled by Applicant.
Applicant’s election without traverse of the invention of Group I and the species of “VHH12” comprising (a) HCDR1-3 of (i) SEQ ID NOs: 57, 85, 86 under Kabat scheme, (ii) SEQ ID NOs: 60, 61, 86 under Chothia scheme; or (iii) SEQ ID NOs: 62, 63, 87 under IMGT scheme; and (b) a VHH of SEQ ID NO: 98, in the reply filed on 23Jul2026 is acknowledged. Claims 16-19, 21 and 24 are withdrawn from further consideration pursuant to 37 CFR 1.142(b) as being drawn to a nonelected invention, there being no allowable generic or linking claim.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 23Jul2026.
Claim(s) 1-8, 12-13, 15, 20, and 23 is/are presented for examination on the merits.
Specification
The disclosure is objected to because it contains an embedded hyperlink and/or other form of browser-executable code [e.g., ¶ 0058, 0137]. Applicant is required to delete the embedded hyperlink and/or other form of browser-executable code; references to websites should be limited to the top-level domain name without any prefix such as http:// or other browser-executable code. See MPEP § 608.01.
Claim Objections
Claim(s) 3 is/are objected to because of the following informalities: in line 3 there should be an “wherein” between “and/or HCDR3;” and “the mutations can be selected..”. Appropriate correction is required.
Claim(s) 15 is/are objected to because of the following informalities: line 6 recites “…CD137, CD258, PD-1, PD-L1, 4-1BB…”, but CD137 and 4-1BB are different names for the same surface marker. Appropriate correction is required.
Claim Rejections - 35 USC § 112(b)
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 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(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.
Claim(s) 1-8, 12-13, 15, 20, 23 is/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.
Regarding instant claim(s) 1, 3-8, 12-13, 15, 20, 23, recites the phrase “…comprises a combination of CDRs; the combination of CDRs comprises CDR1, CDR2, and CDR3; and the CDR1, CDR2, and CDR3 have HCDR1, HCDR2, and HCDR3 selected from a VHH sequence as shown in…SEQ ID NOs: [Applicant elected 98]…” in lines 2-5 of claim 1, rendering the claim indefinite. The instant disclosure provides “…In some specific embodiments, the HDR1, HCDR2, and HCDR3 are determined according to the Kabat, Chothia or IMGT numbering system…” [e.g., ¶ 0010], and “…’CDR’ are used interchangeably herein and generally refer to hypervariable regions (HVRs)…the hypervariable regions under one set of criteria (such as IMGT or KABAT)…” [e.g., ¶ 0057]. As the claim does not recite the CDR numbering scheme, and the instant disclosure teaches that CDRs may comprise any one or more of the non-limiting examples of CDR definitions in the specification, it is unclear if phrase above means CDRs comprise the (1) Kabat scheme; (2) Chothia scheme; (3) IGMT scheme; (4) an unlisted scheme (e.g., AbM, contact, etc.); or (5) something else. For the purposes of compact prosecution, the CDRs are considered to be any combination of 6 CDRs of the elected species. Applicant may overcome this rejection by amending claim(s) 1 to recite (I) the SEQ ID NOs of the 6 CDRs (e.g., HCDR1-3 and LCDR1-3) of the anti-hCD16 antibody or antigen binding fragment thereof, without variability in the CDR sequences thereof; (II) recite the SEQ ID NOs for each of the 6 CDR sets for each scheme (e.g., a) Kabat HCDR1-3 and LCDR1-3; b) Chothia HCDR1-3 and LCDR1-3; etc.), without variability in the CDR sequences thereof; or (III) to otherwise clearly recite the limitations of the instant invention. Dependent claim(s) 3-8, 12-13, 15, 20, 23 can overcome this rejection by amending claim(s) 1 as described above.
Claim(s) 2, is rejected for making reference to tables within the specification and/or figure(s). Where possible, claims are to be complete in themselves. Incorporation by reference to a specific figure or table “is permitted only in exceptional circumstances 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.” See MPEP 2173.05(s). This rejection may be overcome by removing references to tables within the specification and/or figure(s) in claim(s) 2.
Regarding claim(s) 2-3, 6-8, 13, recite(s) the phrase(s) "optionally" and/or “preferably” rendering the claim(s) indefinite because it is unclear whether the limitation(s) following the phrase(s) are part of the claimed invention. See MPEP § 2173.05(h)(II). It is unclear if the limitation(s) following the phrase are limitation(s) or merely provided as an example. For the purposes of compact prosecution, the limitations following the phrase(s) are not considered part of the claimed invention. This rejection may be overcome by amending claim(s) 2 to remove “optional” limitations and/or the phrase “optionally”.
Claim(s) 2, recites the joining word “and” between the listed limitation groups (e.g., “optionally, the…”), rendering the claim(s) indefinite. Specifically, it is unclear how HCDR1-3 can simultaneously comprise multiple different Kabat, Chothia, or IMGT scheme sequences. For the purposes of compact prosecution, the phrase will be considered to be joined by an “or”. This rejection may be overcome by amending claim(s) 2 as recited above or to otherwise clearly recite the limitation(s) of the instant invention.
Claim(s) 3, recite(s) “…comprise(s) an amino acid sequence with 1, 2 or 3 mutations on the HCDR1, HCDR2 and/or HCDR3…” in line(s) 2-3, rendering the claim(s) indefinite. Specifically, it is unclear if the “and” limitation of the phrase means (1) 1, 2, or 3 mutations across HCDR1-3; (2) 1, 2, or 3 mutations for each of HCDR1-3; or (3) something else. For the purposes of compact prosecution, the phrase will be considered to mean “comprising 1, 2, or 3 mutations to the sequence of each of HCDR1-3”. This rejection may be overcome by amending claim(s) 3 as recited above or to otherwise clearly recite the limitation(s) of the instant invention.
Claim(s) 4, recite(s) “…comprise(s) a sequence having at least 80%...or 100% identity to the HCDR1, HCDR2 and/or HCDR3…” in line(s) 2-4, rendering the claim(s) indefinite. Specifically, it is unclear if the “and” limitation of the phrase means that the recited percentage identity (e.g., 80%, 85%, etc.) applies (1) across HCDR1-3 (e.g., less than 80% in a single CDR, but totaling 80% or above across the sequences for all 3 HCDRs); (2) for each individual HCDR sequence; or (3) something else. For the purposes of compact prosecution, the phrase will be considered to mean “comprising [Applicant listed percentages]” to the sequence of each of HCDR1-3”. This rejection may be overcome by amending claim(s) 4 as recited above or to otherwise clearly recite the limitation(s) of the instant invention.
Regarding claim(s) 8, recite(s) “…wherein the antibody or antigen-binding fragment is: (1) a chimeric antibody…(2) a humanized antibody… or (3) a fully human antibody…”. The instant disclosure teaches that VHH12 (e.g., the elected antibody comprising SEQ ID NO: 98) is a humanized antibody [e.g., tbl. 24]. Further, the instant disclosure states that the instant claimed VHH single domain antibody 3 CDRs (e.g., according to the Kabat, Chothia, or IMGT scheme) are llama-derived [e.g., ¶ 0137] and provides evidence of function testing for humanized (e.g., not fully human) antibodies or antigen binding fragments thereof [e.g., tbl. 27]. One of ordinary skill in the art would understand that llama-derived antibodies can be chimeric or humanized, but not fully human. Additionally, Biointron (The Future of Therapeutics: Fully Human Antibodies, Biointron webpage, 21Aug2024) teaches fully human antibodies are entirely derived from human genetic material [e.g., pgs. 1-2, “Understanding Fully Human Antibodies”]. As indicated by the art, a fully human antibody must be derived from human genetic material only, and cannot be created from a llama-derived antibody or antigen binding fragment thereof. Thus, the metes and bounds of the claim are unclear. This rejection may be overcome by amending claim 8 to remove any reference to ‘fully human’ antibodies.
Claim(s) 8, recites no joining word between the listed the limitations, rendering the claim(s) indefinite. Specifically, it is unclear if instant claim 8 means that every limitation is required (e.g., if joined by an “and”) or if only one grouping of limitations (e.g., joined by an “or”) is required. For the purposes of compact prosecution, the phrase will be considered to be joined by an “or”. This rejection may be overcome by amending claim(s) 8 as recited above or to otherwise clearly recite the limitation(s) of the instant invention.
Claim(s) 12, recite(s) “…or binds weakly…” in line(s) 3, rendering the claim(s) indefinite. The instant specification does not define the metes and bounds of the term “weakly”. Specifically, it is unclear if the phrase means (1) binding at or below a specific Kd; (2) binding is weaker relative to some control (e.g., another unspecified antibody); or (3) something else. For the purposes of compact prosecution, the phrase will be considered to mean any amount of binding taught in the prior art for the instant-elected CDRs (see above for details). This rejection may be overcome by amending claim(s) 12 to clearly recite the limitation(s) of the instant invention.
Claim 13 recite(s) “…wherein the antibody…is also linked to other functional molecules…can be selected from one or more of the flowing: a signal peptide, a protein tag, a cytokine, an angiogenesis inhibitor or an immune checkpoint inhibitor…” in lines 2-5. The instant specification does not define functional molecules, but rather restates the instant claim [e.g., ¶ 0021]. The claim and specification provided examples that ‘can be selected’ are considered non-limiting examples. Therefore, it is unclear what other molecules would be considered a “functional molecule” and read on the instant invention. Specifically, it is unclear if ‘functional molecules’ in the phrase above means (1) any enzyme; (2) any protein substrate; (3) any protein; (4) any polynucleotide; (5) any small molecule; (6) any soluble factor; or (7) something else would read on the instant invention because it is unclear what molecule(s) are encompassed by the instant invention. This rejection may be overcome by amending claim(s) 13 to clearly recite the limitation(s) of the instant invention.
Claim(s) 15, recites the joining word “and” between the listed limitation groups, rendering the claim(s) indefinite. Specifically, it is unclear how all of the recited limitations or possible combinations thereof could be simultaneously met, as indicated by the “and” joining word. For the purposes of compact prosecution, the phrase will be considered to be joined by an “or”. This rejection may be overcome by amending claim(s) 15 as recited above or to otherwise clearly recite the limitation(s) of the instant invention.
Claim Rejections - 35 USC § 112(d)
Claim 5 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. Specifically, claim 5, which depends from claim 1, recites “…wherein the antibody or the antigen-binding fragment comprises a single-domain antibody…” in lines 2-3; and claim 1 recites “…have HCDR1, HCDR2 and HCDR3 selected from a VHH sequence…” in line 4, and therefore the antibody of claim 1 is inherently a single-domain type (e.g., VHH) antibody. Therefore reciting that the antibody comprises a single-domain antibody is not considered further limiting. Applicant may cancel the claim(s), amend the claim(s) to place the claim(s) in proper dependent form, rewrite the claim(s) in independent form, or present a sufficient showing that the dependent claim(s) complies with the statutory requirements.
Claim Rejections - 35 USC § 112(a) – written description
Claim(s) 1-8, 12-13, 15, 20, 23 is/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.
Claimed Invention
Claim(s) 1-8, 12-13, 15, 20, 23, are drawn to a VHH single domain antibody that binds CD16 antigen.
Breadth of Claims
Claim(s) 1-2 are drawn to a mix and match of VHH CDRs. Specifically, the invention as disclosed in claim(s) 1 (and claims 2-8, 12-13, 15, 20, 23) recite(s) “…a combination of CDRs…comprises CDR1, CDR2 and CDR3…have HCDR1, HCDR2 and HCDR3 selected from a VHH sequence” in lines 2-5; and claim(s) 2 recite(s) “…optionally the HCDR1 is selected from SEQ ID NO:…57, 60, 62…optionally, the HCDR2 is selected from SEQ ID NO:…61,63…85…optionally, the HCDR3 is selected from SEQ ID NO:…86 or 87…” in lines 4-8. These claims read that one would be able to mix and match the VHH CDRs of different numbering definitions (e.g., Kabat, Chothia, IMGT) and arrive at an antibody that binds to CD16 antigen. However, according to Applicant’s disclosure there are specific SEQ ID pairings for each HCDR1-3 set (e.g., Kabat, Chothia, IMGT; see summary table below). One of ordinary skill in the art would understand that to mix and match HCDRs between different definitions, the HCDR1-3 sequences must be identical (e.g., variability can only occur in non-CDR regions of the VHH). An example alignment of the VHH antibody Kabat, Chothia, and IMGT CDRs claimed show that different HCDR1-3 definitions (e.g., Kabat, Chothia, IMGT) have different sequences:
PNG
media_image1.png
161
722
media_image1.png
Greyscale
Further, the invention as disclosed in claim(s) 3 recite(s) “…the CDR1, CDR2 and/or CDR2 comprise(s) an amino acid sequence with 1, 2, or 3 mutations…” in lines 2-3; and claim(s) 4, recite(s) “…the CDR1, CDR2 and/or CDR2 comprise(s) a sequence having at least 80%...identity…” in lines 2-3. The claim(s) encompass CDRs comprising variability (e.g., 3 mutations, 80% identical) which are claimed as having the function of specifically binding to CD16. This means that the variability in sequence identity specifically occurs in the CDRs, the domains that are critical for the antibody binding to its target, which one of ordinary skill in the art would understand to result in unpredictable binding characteristics with no reasonable expectation of maintaining CD16 antigen binding. Additionally, the instant disclosure does not provide a structure-function correlation that would allow for a person of ordinary skill in the art to envision what variation can occur to the VHH antibody CDR regions, such that the obtained structure would result in the claimed functions.
The invention as disclosed in claim(s) 6 recite(s) “…the single domain antibody comprises a sequence with at most 20…mutation relative to…SEQ ID NO: 98” in lines 4-6, and “…the single domain antibody comprises a sequence having at least 80%...identity to…SEQ ID NO: 98…” in lines 9-11. The claim(s) encompass a genus of VHH variable regions comprising variability (e.g., 20 mutations, 80% identical) in the VHH that is claimed as having the function of specifically binding to CD16. This means that the variability in sequence identity can also occur in the CDRs, the domains that are critical for the antibody binding to its target, which one of ordinary skill in the art would understand to result in unpredictable binding characteristics with no reasonable expectation of maintaining CD16 antigen binding. Additionally, the instant disclosure does not provide a structure-function correlation that would allow for a person of ordinary skill in the art to envision what variation can occur in the VHH, particularly in the CDR regions, such that the obtained structure would result in the claimed functions.
Scope of Disclosed Species
PNG
media_image2.png
200
400
media_image2.png
Greyscale
The elected anti-CD16 VHH single domain antibody in the Applicant disclosure (see summary table above for details) with 100% sequence identity either the Kabat HCDR1-3, Chothia HCDR1-3, or IMGT HCDR1-3 of the VHH variable region represents the anti-CD16 VHH single domain antibodies that the applicant was in possession of at the time of filing.
State of the Prior Art
At the time of filing, VHH single domain antibody antigen binding domain functionality was known to depend on the entire structure, particularly a full complement of three CDRs. It is understood by one of ordinary skill in the art that that uncharacterized CDR binding is unpredictable and that each construct requires function testing.
Bever et al. (Anal Bioanal Chem (2016) 408:5985–6002; hereinafter “Bever”) teaches VHH antibodies, and the production and screening thereof [e.g., title, abstract]. Bever teaches Nanobodies® are VHH domain antibodies that are heavy chain only (e.g. HcAb) that are naturally produced by camelids and sharks [e.g., pg. 5985, “Introduction”]. Bever teaches the overview of process of making VHH antibodies wherein (1) an alpaca is the camelid species, (2) mRNA is collected from the alpaca and a cDNA library is constructed therefrom, (3) VHH genes are isolated, (4) a phage-display VHH library is generated, (5) solid phase panning conducted to select the desired VHH, and (6) desired VHH is obtained [e.g., fig. 2].
Hacisuleyman and Erman (Journal of Biological Physics (2020) 46:189–208; hereinafter “Hacisuleyman”) teaches VHH optimization [e.g., title, abstract]. Hacisuleyman teaches VHH antibodies comprise 3 CDRs which determine target specificity, with CDR3 being the “dominating contributor in antigen recognition” [e.g., pg. 191; fig. 2]. Hacisuleyman further teaches residue numbers for the VHH CDRs may vary, and that in nature CDRs are mutated naturally to increase the binding affinity and specificity towards a target antigen [e.g., pg. 191]. Hacisuleyman teaches that computational screening methods for optimization are a first step that is then followed by experimental strategies [e.g., pg. 191]. Hacisuleyman does not support de novo generation of VHH CDRs to bind a selected antibody, but rather requires the researcher start with a VHH antibody known to bind the target antigen [e.g., 191].
At the time of filing, Zhao et al. (Cancer Biology & Therapy, 2020, Vol 21, No. 1, 72-80; hereinafter “Zhao”) taught the identification of anti-CD16 single domain antibodies and applications thereof [e.g., title, abstract]. Zhao taught six separate species of anti-CD16 VHH single domain antibody antigen binding domains [e.g., tbl. 1; figs. 1-6]. Therefore, the prior art demonstrates that the binding of CD16 is possible by various anti-CD16 VHH single domain antibodies/antigen binding domains thereof. The prior art does not teach a known structure activity relationship for HCDR1-3 in the VHH anti-CD16 antibody that would allow prediction of all of the possible combinations of CDR sequences that specifically bind to CD16 antigen.
Conclusion
As indicated by the art above, a full complement of 3 HCDRs are required for VHH single domain antibody-antigen binding and one cannot predict all of the possible CDR sequence combinations (e.g., mix and matching of CDRs) and/or mutations to existing CDR sequence(s) that will result in a VHH single domain antibody that binds CD16. Written description can be met if the claims recite the minimal structure that is needed to perform the function recited in the claims. Above, the art indicates that the 3 CDRs in a VHH single domain antibody antigen-binding domain are the minimal structure that binds to a target antigen. Specifically, Applicant claim(s) 1, 3-4 would need to recite the HCDR1-3 set for each definition claimed (e.g., HCDR1-3 of Kabat scheme, HCDR1-3 of Chothia scheme, HCDR1-3 of IMGT scheme) in the VHH single domain antibody that bind CD16 antigen, without variability in the sequences thereof. Claims 2, 5-8, 12-13, 15, 20, and 23 can overcome this rejection by amending claim 1 as described above. It is noted for the Applicant that if claims 1 and 3-4 are amended as described above that claims 3-4 will no longer be further limiting.
Free From the Prior Art
During the course of examination, the anti-CD16 “VHH12” antibody antigen binding domain comprising (1) Kabat definition HCDR1-3 of SEQ ID NOs: 57, 85, 86; (2) Chothia definition HCDR1-3 of SEQ ID NOs: 60, 61, 86; or (3) IMGT definition HCDR1-3 of SEQ ID NOs: 62, 83, 87; and/or comprising a VHH of SEQ ID NO: 98, was/were found to nonobvious in view of the closest prior art. Briefly, a sequence search of the prior art returned no 100% matches to any of the instant claimed HCDR1-3 sets and/or VHH (see closest prior art alignments below).
PNG
media_image2.png
200
400
media_image2.png
Greyscale
Alignment of anti-CD16 VHH12 antibody Kabat HCDR1-3 (SEQ ID NO: 57, 85, 86) with WO2021222316-A2 (Anti-SARS-CoV-2 membrane Ab heavy chain variable region, SEQ ID 2655):
PNG
media_image3.png
234
622
media_image3.png
Greyscale
Alignment of anti-CD16 VHH12 antibody Chothia HCDR1-3 (SEQ ID NO: 60, 61, 86) with WO2008143679-A2 (Protein sequence, SEQ ID 62454):
PNG
media_image4.png
234
619
media_image4.png
Greyscale
Alignment of anti-CD16 VHH12 antibody IMGT HCDR1-3 (SEQ ID NO: 62, 83, 87) with WO2020102777-A1 (Anti-ICAM1 antibody heavy chain variable region, SEQ ID 305):
PNG
media_image5.png
235
616
media_image5.png
Greyscale
Alignment of anti-CD16 VHH12 antibody VHH domain (SEQ ID NO: 98) with WO2011039368-A2 (DLL4-binding immunoglobulin single variable domain VHH protein, SEQ:264):
PNG
media_image6.png
317
626
media_image6.png
Greyscale
Conclusion
No claims are currently allowed.
Any inquiry concerning this communication or earlier communications from the examiner should be directed to AMY M CHATTIN whose telephone number is (571)270-0646. The examiner can normally be reached T-F 0600-1600 PST.
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, Julie Wu 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.
Information regarding the status of published or unpublished applications may be obtained from Patent Center. Unpublished application information in Patent Center is available to registered users. To file and manage patent submissions in Patent Center, visit: https://patentcenter.uspto.gov. Visit https://www.uspto.gov/patents/apply/patent-center for more information about Patent Center and https://www.uspto.gov/patents/docx for information about filing in DOCX format. For additional questions, contact the Electronic Business Center (EBC) at 866-217-9197 (toll-free). If you would like assistance from a USPTO Customer Service Representative, call 800-786-9199 (IN USA OR CANADA) or 571-272-1000.
/AMY M. CHATTIN/Examiner, Art Unit 1643
/GARY B NICKOL/Primary Examiner, Art Unit 1643
Prosecution Insights