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 .
Claim 17 has been cancelled.
Election/Restrictions
Applicant's election with traverse of Group I and the antibody species having the VH CDRs of SEQ ID NOS: 37, 38, and 39 and the VL CDRs of SEQ ID NOS: 40, 41, and 42 in the reply filed on 11/28/2025 is acknowledged. The traversal is on the ground(s) that the claims share a common special technical feature. This is not found persuasive because the lack of special technical feature was explained in the written lack of unity requirement and is set forth again in the art rejection set forth below.
The requirement is still deemed proper and is therefore made FINAL.
Upon further consideration of the claims, the antibody species election has been withdrawn.
Claims 12-15 and 18-20 are withdrawn from further consideration pursuant to 37 CFR 1.142(b), as being drawn to a nonelected invention, there being no allowable generic or linking claim. Applicant timely traversed the restriction (election) requirement in the reply filed on 11/28/2025.
Specification
The disclosure is objected to because of the following informalities:
The incorporation of sequence listing on page 1 of the specification should reference the size of the file in bytes not kilobytes (KB). In addition, there is no provision for an “approximate” size. The actual size in bytes must be recited. See MPEP 2422.03(I). See 12/28/2022 amendment to the specification.
Appropriate correction is required.
Claim Objections
Claim 6 is objected to because of the following informalities: Claim 6 sets forth VH/VL pairs as a list. However, the claim lacks the conjunction “or” between the final two pairs. This appears to be inadvertent omission; however, in the absence of “or” between the final two pairs, the claim appears to require all of the VH/VL pairs simultaneously Appropriate correction is required.
Claim Rejections - 35 USC § 102
In the event the determination of the status of the application as subject to AIA 35 U.S.C. 102 and 103 (or as subject to pre-AIA 35 U.S.C. 102 and 103) is incorrect, any correction of the statutory basis (i.e., changing from AIA to pre-AIA ) for the rejection will not be considered a new ground of rejection if the prior art relied upon, and the rationale supporting the rejection, would be the same under either status.
The following is a quotation of the appropriate paragraphs of 35 U.S.C. 102 that form the basis for the rejections under this section made in this Office action:
A person shall be entitled to a patent unless –
(a)(2) the claimed invention was described in a patent issued under section 151, or in an application for patent published or deemed published under section 122(b), in which the patent or application, as the case may be, names another inventor and was effectively filed before the effective filing date of the claimed invention.
Claims 1, 3, 7, 8, 10, 11 and 16 are rejected under 35 U.S.C. 102(a)(2) as being anticipated by Tian et al. (U.S. Patent No. 12,258,419, of record).
Instant claim 1 requires CDRs "comprising a sequence set forth" in particular SEQ ID NOS. The recitation of "a sequence" includes subsequences of the recited sequences, including single amino acids. This language does not require the full and complete sequences recited in instant claim 1. (This is in contrast to a recitation such as “comprising the sequence set forth in SEQ ID…” or “comprising SEQ ID…” which would require the entirety of the recited sequence.) Tian et al. discloses an anti-FX1/FX1A antibody having the CDRS of SEQ ID NOS: 3, 4, 5, 6, 7, and 8. See at least claim 1, part (a). Each of SEQ ID NOS: 3, 4, 5, 6, 7, and 8 contain at least one amino acid in common with instant SEQ ID NOS: 63, 64, 9, 10, 65, and 66, respectively, particularly in view of the variability permitted by the wild-cards in instant SEQ ID NOS: 63, 64, 65, and 66. Murine, humanized and chimeric antibodies are disclosed. See at least issued claim 3 and instant claim 3. The antibody can be a full length antibody (i.e. having an Fc constant domain and a CH1 domain). The light chain can have a κ constant domain. See at least issued claims 4 and 26 and instant claims 7-8. The antibody can be a fragment such as an scFv or an Fab. See at least issued claim 7 and instant claim 10. The antibody can be administered intravenously or subcutaneously. See at least column 27, lines 18-33, and instant claim 11. Pharmaceutical compositions are disclosed. See at least issued claim 17 and instant claim 16.
The disclosure of Tian et al. anticipates instant claims 1, 3, 7, 8, 10, 11, and 16.
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, 3-5, 7-8, 10-11 and 16 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.
Claim 6 is directed to anti-FXI/FXIA antibody or antigen-binding fragments having the following VH/VL pairs as a list.
The VH/VL of SEQ ID NOS: 58/51 corresponds to a modified form of antibody 3807 with the CDRs of SEQ ID NOS: 37-42. It is also referenced as antibody 3882. See paragraphs [0179 and 0189-0190]. This corresponds to instant claim 2, part (a). SEQ ID NO: 58 corresponds to amino acids 1-117 of SEQ ID NO: 61. SEQ ID NO: 51 corresponds to amino acids 1-106 of SEQ ID NO: 62. See instant claim 9.
The VH/VL of SEQ ID NOS: 5/6 corresponds to antibody 0012 with CDRs of SEQ ID NOS: 7-12. See Table 1. This corresponds to instant claim 2, part (b).
The VH/VL of SEQ ID NOS: 17/21 corresponds to F-VH/3-VL with CDRs of SEQ ID NOS: 22, 23, 9, 10, 29, and 12. See Table 2. It is an affinity matured version of antibody 0012. This corresponds to instant claims 2, part (c).
The VH/VL of SEQ ID NOS: 18/21 corresponds to corresponds to H-VH/3-VL with CDRs of SEQ ID NOS: 24, 25, 9, 10, 29, and 12. See Table 2. It is an affinity matured version of antibody 0012. This corresponds to instant claim 2, part (d).
The VH/VL of SEQ ID NOS: 19/21 corresponds to corresponds to J-VH/3-VL with CDRs of SEQ ID NOS: 26, 27, 9, 10, 29, and 12. See Table 2. It is an affinity matured version of antibody 0012. This corresponds to instant claim 2, part (e).
The VH/VL of SEQ ID NOS: 20/21 corresponds to corresponds to K-VH/3-VL with CDRs of SEQ ID NOS: 28, 25, 9, 10, 29, and 12. See Table 2. It is an affinity matured version of antibody 0012. SEQ ID NO: 20 corresponds to amino acids 1-129 of SEQ ID NO: 15. SEQ ID NO: 21 corresponds to amino acids 1-108 of SEQ ID NO: 16. See instant claim 9.
The VH/VL of SEQ ID NOS: 30/34 corresponds to Fg3g. It is a modified version of antibody 0012. See paragraphs [0145 and 0149]. It has the CDRs of SEQ ID NOS: 22, 23, 9, 10, 29, and 12. This corresponds to instant claim 2, part (f).
The VH/VL of SEQ ID NOS: 31/34 corresponds to Hg3g. It is a modified version of antibody 0012. See paragraphs [0146 and 0149]. It has the CDRs of SEQ ID NOS: 24, 25, 9, 10, 29, and 12.
The VH/VL of SEQ ID NOS: 32/34 corresponds to Jg3g. It is a modified version of antibody 0012. See paragraphs [0147 and 0149]. It has the CDRs of SEQ ID NOS: 26, 27, 9, 10, 29, and 12.
The VH/VL of SEQ ID NOS: 35/36 corresponds to antibody 3807 with the CDRs of 37-42. See Example 6.
The VH/VL of SEQ ID NOS: 43/44 corresponds to a humanized form of antibody 3807 with the CDRs of SEQ ID NOS: 37-42. See Example 7.
The VH/VL of SEQ ID NOS: 45/51 corresponds to a modified version of antibody 3807 with the CDRs of SEQ ID NOS: 37-42. See paragraph [0172] and [0179]. It is also referenced as antibody 3871. See paragraph [0181].
The VH/VL of SEQ ID NOS: 49/51 corresponds to a modified form of antibody 3807 with the CDRs of SEQ ID NOS: 37-42. See paragraphs [0176] and [0179]. It is also referenced as antibody 3875. See paragraph [0181].
Claim 6 ultimately depends upon claim 1 and the VH/VL recited must retain the CDRs recited in claim 1 for proper dependency. The variation permitted by the “at least 90% identity thereto” limitations in claim 6 cannot be within the CDRs.
Claim 9 depends upon claim 1 and the VH/VL recited must retain the CDRs recited in claim 1 for proper dependency. The variation permitted by the “at least 80% identity thereto” limitations in claim 9 cannot be within the CDRs.
The anti-FXI/FXIA antibodies or antigen-binding fragments thereof of claims 2, 6, and 9 are adequately described and these claims are free of the prior art. The prior art does not disclose anti-FXI/FXIA antibodies or antigen-binding fragments having these CDRs and VH/VL sequences.
However, the genus of antibodies encompassed by independent claim 1 and dependent claim 5 are not adequately described.
Claim 1 requires the following CDRs:
The HCDR1 of SEQ ID NO: 63. SEQ ID NO: 63 is five amino acids in length and has three wild-card positions where each wild-card position has four possible choices.
The HCDR2 of SEQ ID NO: 64 is 17 amino acids in length and has seven wild-card positions where six of the wild-card positions have two possible choices and one wild-card position has four possible choices.
The HCDR3 of SEQ ID NO: 9 is 20 amino acids in length. The HCDR3 of SEQ ID NO: 39 is eight amino acids in length.
The LCDR1 of SEQ ID NO: 10 is 12 amino acids in length. The LCDR1 of SEQ ID NO: 40 is ten amino acids in length
The LCDR2 of SEQ ID NO: 65 is seven amino acids in length and has five wild-card positions where three of the wild-card positions have three possible choices and two of the wild-card positions have two possible choices.
The LCDR3 of SEQ ID NO: 66 is nine amino acids in length and has six wild-card positions where each wild-card position has two possible choices.
Claim 5 recites a list of VH and VL sequences where any VH sequence can be paired with any VL sequence.
In the instant application, the specification and claims draw a fence around a perceivedgenus but the genus is not adequately described. The specification exemplifies antibodies as discussed above with respect to claims 2, 6, and 9; however, the structural variability for the antibodies encompassed by claims 1 and 5 and dependent claims 3-4, 7-11, and 16 is large. No reasonable structure-function correlation has been established that is commensurate in scopewith the claims. The specification does not describe representative examples to support the fullscope of the claims, particularly for antibodies having all or subsets of the properties recited in claim 11.
At least for example, claim 1 includes mixing CDRs from antibody 0012 with CDRs from antibody 3807. At least for example, claim 5 includes pairing a VH from one antibody with a VL from a different antibody. With respect to the combinations of CDRs permitted by claim 1, the exemplified antibodies do not provide representative examples to support the full scope of the claims. Many of the exemplified embodiments have the same CDRs and do not reflect a representative variety of the sets of CDRs encompassed by claim 1. There is no description of those other embodiments that would have the anti-FXI/FXIa binding activity or all of the activities in claim 11.
It would have been well established in the art that the formation of an intact antigen- binding site as well as the maintenance of the antigen binding specificity and affinity critically depends on the amino acid sequence and conformations of each of the CDRs of the heavy and light chains. It is further expected that all CDRs in their proper order and in the context of framework sequences which maintain their required conformation, are required to produce an antibody having a functional antigen binding site and having specific functional characteristics. Even a single, conservative amino acid substitution in only one CDR may have an impact on antigen binding, and even more so on the functional characteristics of an antibody. The CDRs recited in the claims do not individually provide the specific antigen-binding. It is the collective whole of all of six CDRs.
Iwashashi et al. discloses that the effect of CDR replacement or a single amino acid change on the antigen binding site structure can only be known by actual structural analysis.
Kranz et al. (Proc. Natl Acad. Sci, USA, 78(9):5807-5811, 1981) showed that in mixing heavy and light chains from six monoclonal anti-fluorescyl antibodies, heterologous heavy and light chain mixtures did not form anti-fluorescyl active sites (p. 5809, col. 1, first part of second paragraph). In another experiment (supra, p. 5809, col. 1, third paragraph), "Of the 30 possible heterologous H and L chain combinations, 13 did not reassociate within detectable limits..., 13 reassociated but with less affinity than the homologous association,.. and 4 associated with greater affinity than the homologous reassociation "
Herold et al. (Scientific Reports, 7:12276, DO1:10.1038/s41598-01 7-12519-9, Sept. 2017, p. 2, end of second paragraph), looked at VH/VL interfaces and how changes effected antigen binding and found, "Our results on the effects of mutations on domain structure, stability, association and antigen binding together with CDR exchange experiments reveal complex relationships between structural and functional properties within the VL and VH domains." It was discussed that (p. 11, start of 3rd paragraph), "The relationship between structure, stability and binding affinity of VH and VL is still unclear. This is an important aspect for understanding antibody architecture both as the basis of our immune system and also in the context of the engineering of antibodies for therapeutic purposes. In this context, it was found that in mutants an increase in affinity is often accompanied by a decrease in stability and vice versa - and these consequences are difficult to predict." The reference concludes (p. 14, end of 2nd paragraph and 3rd paragraph), "[B]inding to the antigen is affected by each CDR loop differently and changes in loop mobility can in principle affect antigen binding affinity in an unpredictable way Taken together our data indicate that multiple determinants regulate the VH/VL association and the affinity for the antigen. The interplay between interface interactions and CDRs turned out to be complex with mutual influences on VH/VL association and antigen binding."
Iwahashi et al., Herold et al., and Kranz et al. illustrate the unpredictability of mixing antibody VH/VL chains (and implicitly their CDRs) with respect to binding properties.
Different combinations of amino acids in the CDRs permitted by the wild-card positions would result in unpredictability with respect to the binding properties of the resulting protein. Combining CDRs from different antibodies would result in unpredictability with respect to the binding properties of the resulting protein. Pairing VH and VL from different antibodies would result in unpredictability with respect to the binding properties of the resulting protein. The exemplified embodiments cannot be extrapolated to support all of the variable embodiments embraced by the claims.
The genus of antibodies claimed is not adequately described.
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.
Claim 4 is 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 4 is confusing in reciting “a VH having a back mutation of any one or any combination of Y27F, T28N, F29I, T30K, A93L, R94Y, E73T, R66K, V67A, T75A and T76N, and/or a VL having a back mutation of any one or any combination of R45K, L46R, L47W, I58V and F71Y.” Claims 1 and 3 do not recite or require any particular VH or VL sequence. Without a base sequence for comparison, the recited positions and changes to them as recited in claim 4 are meaningless. The metes and bounds of the claim cannot be determined.
Claims 2, 6, and 9 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
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/Marianne P Allen/Primary Examiner, Art Unit 1647
mpa