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 20Feb2024 is acknowledged in which claim(s) 11-12 were canceled, and claim(s) 16-18 are new.
Claim(s) 1-10 and 13-18 is/are presented for examination on the merits.
Claim Objections
Claim(s) 2 is/are objected to because of the following informalities: the period is inside of the table but should be after table. Appropriate correction is requested.
Claim(s) 15, 17 is/are objected to because of the following informalities: “the step of:” in line 1 of claim(s) 15 and 17 is not needed. Appropriate correction is requested.
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.
Claim(s) 1, 3, 5, 10, 14, 17-18 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.
Claim(s) 1, 3, 5, 10, 17-18, recite(s) the phrase “A complementary determining region (CDR)…wherein the complementary determining region (CDR) of the VHH chain comprises: CDR1…CDR2…and CDR3…” in claim(s) 1, rendering the claim(s) indefinite. Specifically, the claims are indefinite because the preamble claims “a” CDR (e.g., singular), but then recites that said CDR comprises CDR1-3 (e.g., 3 CDRs is plural), and a skilled artisan would understand each of CDR1-3 to be a distinct region within the VHH antibody and not something that could be comprised within a single CDR. Therefore, it is unclear if Applicant is attempting to claim a single CDR, or CDR1-3 of the VHH antibody. For the purposes of compact prosecution, claim(s) 1 will be considered to recite “A VHH antibody comprising a CDR1, a CDR2, and a CDR3; where CDR1 comprises…CDR2 comprises…; and CDR3 comprises..”. Claim(s) 1 can overcome this rejection by clearly amending claim(s) 1 as described above or to otherwise clearly claim the invention. Claim(s) 3, 5, 10, 17-18 may overcome this rejection by amending claim(s) 1 as discussed above.
Regarding claims 14, the phrase “(diagnostic and non-diagnostic)” is not defined in the terms preceding it. Thus, the phrase “(diagnostic and non-diagnostic)” renders the claim indefinite because it is unclear whether the limitation(s) in the parentheses are a part of the claimed invention. See MPEP 2173.05(d). To promote compact prosecution, the phrase “(diagnostic and non-diagnostic)” is not considered a limitation of the claim(s). This rejection may be overcome by amending claim(s) 14 to delete the phrase “(diagnostic and non-diagnostic)”.
Claim Rejections - 35 USC § 112(a) – written description
Claim(s) 1, 3, 5, 10, 17-18 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, 3, 5, 10, 17-18, are drawn to a VHH antibody that binds PTK7 antigen.
Breadth of Claims
Further, claim(s) 1 (and claim(s) 3, 5, 10, 17-18) is/are drawn to a mix and match of CDRs. Specifically, the inventions as disclosed in claim(s) 1 recite(s) “…VHH chain comprises: CDR1 as shown in any one of SEQ ID Nos: 9-11; CDR2 as shown in any one of SEQ ID Nos: 12-14; and CDR3 as shown in any one of SEQ ID Nos: 15-18…”. These claims read that one would be able to mix and match CDR1-3 and arrive at a VHH antibody that binds to PTK7 antigen. However, according to Applicant’s disclosure there are specific SEQ ID pairings for each VHH antibody, and CDR1-3 thereof (see summary table below). One of ordinary skill in the art would understand that to mix and match CDRs between VHH antibodies, the HCDR1-3 sequences must be identical (e.g., variability can only occur in non-CDR regions). An example alignment of the VHH antibody CDR sequences claimed show that the variable domains where HCDR1-3 exist have different sequences:
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Scope of Disclosed Species
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The anti-PTK7 VHH antibodies in the Applicant disclosure (see summary table above for details) with 100% sequence identity in the CDR regions represents the anti-PTK7 VHH antibodies that the applicant was in possession of at the time of filing.
State of the Prior Art
At the time of filing, VHH 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 mixing and matching of CDRs results in binding that 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].
While anti-PTK7 VHH antibodies were not common in the art before or at the time of filing, the instant specification teaches various separate species of anti-PTK7 VHH antibodies (see summary table above). Therefore, the applicant’s own disclosure teaches that the binding of PTK7 is possible by multiple anti-PTK7 VHH antibodies. The prior art and the instant specification do not teach a known structure activity relationship for CDR1-3 in anti-PTK7 VHH antibody that would allow prediction of which CDR residues specifically bind to PTK7 antigen.
Thus, making changes to the CDR sequence of a VHH antibody is a highly unpredictable process and one skilled in the art could not a priori make any predications with any reasonable expectation of success nor envisage the breadth of structurally unrelated CDR combinations that would still possess the required function(s).
Conclusion
As indicated by the art, a full complement of 3 CDRs are required for antigen binding and one cannot predict which CDR sequences may be mixed and matched and still result in a VHH antibody that binds PTK7 antigen. 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 CDR1-3 in a VHH antibody antigen-binding domain are the minimal structure that binds to a target antigen. Specifically, Applicant claim(s) 1 would need to recite the each of the CDR sets (e.g., as recited in instant claim 2) in each VHH antibody that binds PTK7 antigen, without variability in the sequences thereof. Claim(s) 3, 5, 10, 17-18 can overcome this rejection by amending claim(s) 1 as recited above.
Allowable Subject Matter – Objected Claim(s)
Claim(s) 2, 6-9 is/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. Briefly, claim(s) 2 is/are drawn to an anti-PTK7 antibody comprising any one of 4 recited 3 CDR pairs and claim(s) 6-9 are drawn to a polynucleotide (e.g., DNA sequence) encoding an anti-PTK7 VHH antibody. See ‘reasons for allowance’ below for details regarding why the anti-PTK7 antibodies are considered non-obvious in view of the closest prior art.
Allowable Subject Matter- Allowed Claim(s)
The following is an examiner’s statement of reasons for allowance:
Scope of Invention
The instant invention (claim(s) 4, 13, 15-16) is/are drawn to an anti-PTK7 VHH antibody comprising one of four HCDR1-3 sets (summary table provided below for ease of review).
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Closest Prior Art
A sequence search returned no 100% sequence identity matches of the instant claimed HCDR1-3 set (see table above for sequence details; see closest prior art alignments below).
Alignment of anti-PTK7 HCDR1-3 (SEQ ID NOs: 9, 12, 15) with WO2001075067-A2 (Novel human diagnostic protein #5678):
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Alignment of anti-PTK7 HCDR1-3 (SEQ ID NOs: 10, 13, 16) with CN114106167-A (Anti-L. monocytogenes nano antibody protein D10):
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Alignment of anti-PTK7 HCDR1-3 (SEQ ID NOs: 10, 13, 17) with CN114106167-A (Anti-L. monocytogenes nano antibody protein D10):
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Alignment of anti-PTK7 HCDR1-3 (SEQ ID NOs: 11, 14, 18) with WO2011051327-A2 (Antibody-like single chain protein (ASCP)-body protein SEQ:796):
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In summary, the closest prior art does not teach any 100% matches to any of the instant claimed HCDR1-3 sets of the VHH antibodies, and do not maintain PTK7 antigen binding. No rationale was found in the art to make substitutions, particularly in the CDRs, to arrive at the instant invention. Additionally, a skilled artisan would understand that making changes to the CDR sequence(s) of a VHH antibody is a highly unpredictable, without any reasonable expectation of success. Therefore, each of the anti-PTK7 VHH antibodies comprising one of the 3 CDR sets recited above are considered non-obvious in view of the closest prior art.
Conclusion
Claim(s) 4, 13, 15-16 require anti-PTK7 VHH antibodies comprising a CDR1-3 set that is non-obvious in view of the closest prior art (see above for details). Therefore, claim(s) 4, 13, 15-16 are considered non-obvious in view of the closest prior art. For the reasons provided above, claim(s) 4, 13, 15-16 is/are allowed.
Conclusion
Claim(s) 1-3, 5-10, 14, 17-18 are NOT ALLOWED. Claim(s) 4, 13, 15-16 is/are 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.
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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.
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/AMY M. CHATTIN/Examiner, Art Unit 1643
/GARY B NICKOL/Primary Examiner, Art Unit 1643
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