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 .
DETAILED ACTION
Continued Examination Under 37 CFR 1.114
1. A request for continued examination under 37 CFR 1.114, including the fee set forth in 37 CFR 1.17(e), was filed in this application after final rejection. Since this application is eligible for continued examination under 37 CFR 1.114, and the fee set forth in 37 CFR 1.17(e) has been timely paid, the finality of the previous Office action has been withdrawn pursuant to 37 CFR 1.114. Applicant's submission filed on 12/26/2025 has been entered.
Status of the Claims
2. Claims 1-17 are the original claims filed on 8/29/2022. In the Preliminary Amendment of 8/29/2022, Claims 1-17 are canceled and new Claims 18-22 are added. Claims 18-22 are the claims for this application. In the Response of 1/29/2025, Claims 21-22 are amended, claims 18-20 are canceled and new Claims 23-25 are added. In the Response After Final Action of 4/24/2025, claim 21 is amended and claim 22 is canceled but the amendments are not is not entered as discussed in the Advisory Action of 5/15/2025. See the PTOL-303 showing claims 21-25 rejected. See the claim set filed 4/24/2025 with the Examiner’s stamp to not enter. In the Response After Final Action of 6/7/2025, claim 21 is amended (and claim 22 is canceled) but the amendments are not entered as discussed in the Advisory Action of 6/23/2025. See the claim set filed 6/7/2025 with the Examiner’s stamp to not enter.
Claims 21-25 from the claim set of 1/29/2025 are the claims under examination.
This Office Action contains new grounds for objection.
Priority
3. USAN 17/822,959, filed 08/29/2022, and having 1 RCE-type filing therein, is a Divisional of 16/156,036, filed 10/10/2018, now U.S. Patent # 11427628, and having 1 RCE-type filing therein, 16/156,036 is a Divisional of 14/900,550, filed 12/21/2015, now U.S. Patent # 10/174,102 and having 1 RCE-type filing therein, 14/900,550 is a National Stage entry of PCT/EP2014/001730, International Filing Date: 06/26/2014, claims foreign priority to EP 13003264.2, filed 06/26/2013.
Information Disclosure Statement
4. As of 1/28/2026, a total of one (1) IDS is filed for this application: 8/29/2022. The corresponding initialed and dated 1449 form is considered and of record.
Rejections Maintained
Claim Rejections - 35 USC § 112(a)
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.
Written Description
5. The rejection of Claims 21-25 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 is maintained.
Applicants allege an existing antibody comprising human VH and VK chains and rabbit or rodent CDRs can be improved by replacing the VK framework IV region by a corresponding Vλ framework IV region; the VL framework IV region has a constant length of 11 amino acid residues and one of ordinary skill in the art would not consider mutations in VL framework IV resulting in insertions or deletions, but would understand "mutation" to be synonymous with "substitution"; and one of ordinary skill in the art would be aware of the natural repertoire of the human Vλ germline sequences (see SEQ ID NOs: 16 to 22) to identify positions in that framework region that appear to be rather conserved and positions that appear to be less conserved and appropriate for variation.
Response to Arguments
A. The disclosure in Applicants own specification is dispositive to the allegation that the POSA is drawn to mutating a framework much less a less conserved position in the framework. The specification teaches against mutating antibody frameworks to avoid creating immunogenic sites:
[0016] Thus, despite that fact that many attempts have already been made to address the issue of obtaining humanized antibody drug substances from non-human antibodies, there still remains a large unmet need to develop novel human antibody frameworks with advantageous properties, such as high stability and reduced aggregation propensity, wherein the human antibody frameworks contain as few mutations as possible, ideally none, when compared to naturally occurring sequences, in order to reduce the risk of creating immunogenic sequences as far as possible. Such stable human frameworks could also be used to stabilize fully human antibodies or fragments thereof for example by loop grafting or simply by exchanging the stability-contributing component between the parent antibody and the stable framework.
The specification teaches that while mutations used in the hand of the authors are for configuring the rabbit CDRs into the human framework, the mutations are in fact substitutions at
[0146] In addition to hu-4D5, another published framework solution was tested, namely the framework FW1.4gen (scFv2), of which extensive biophysical data is published (Borras, loc. cit.). The framework FW1.4gen includes several amino acid substitutions when compared to hu-4D5 thus deviating from the human consensus. In the VH, such differences probably result from affinity maturation, on one hand because it originates from a human cDNA library, containing sequences of mature antibodies that have undergone somatic hypermutation, rather than germline sequences, and on the other hand because several mutations have been introduced by the authors for purpose of accommodating rabbit CDRs. In the VL no or only few mutations have been deliberately introduced, suggesting that most differences result from the germ line sequence used somatic hypermutation or possibly are artifacts resulting from library cloning procedures.
The POSA could reasonably conclude that the only support in the specification is that the mutations are substitutions that effect the engraftment of the rabbit CDRs. Here is the case that none of the claims recite the kind of mutations much less the effect of the mutation on the performance of the antibody.
B. Applicants have not responded to the citation of reference art that establishes the unpredictability of mutating framework domains. For that reason, the Response is incomplete. The original grounds for rejection from the OA (10/29/2024) are excerpted herein for convenience and the record history.
“The limited disclosure in the specification does not support the genus of antibodies comprising VL domains of element (b) comprising the genus of frameworks having any manner and kind of one or two mutations in the region for IV from the Vλ SEQ ID NOS: 16-22.
“mutation”:
[0063] “…It further relates to the mutation of the κ consensus residue at position AHo101 (framework region III) and replacement by a λ consensus residue to support packing of the λ joining segment in a κ-λ chimeric variable light domain to further improve protein stability and to further reduce aggregation propensity.”
The specification does not define the mutation by the nature or kind that could include any insertion, deletion, substitution or the combination that meets the two mutations. The specification does not teach the meaning of the mutation, per se, so that is not necessarily limited to an amino acid but encompasses glycosylation, phosphorylation, lipidation, etc.
The specification does not support the genus of chimeric antibody VL domains that could accommodate the genus of all possible CDRs grafted into those frameworks (i.e., element (b) of Claim 21) based on the state of the art. The specification does not provide sufficient support demonstrating the instant claimed frameworks to provide “universal” acceptors for the insertion or grafting of just any CDRs known-and-yet to be discovered.
MPEP § 2163 states that the written description requirement for a claimed genus may be satisfied through establishment of a structure-function correlation (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) or through a sufficient description of a representative number of species. Either is considered sufficient to show the applicant was in possession of the claimed genus.
Regarding structure-function correlation, it is noted that one of skill in the art was aware that there is a lack of structure-function correlation in antibody molecules having framework mutations. Evidence of such in the form of publications in the art include the following.
Dufner (Trends Biotechnol. 24(11):523-29 (2006); IDS 8/29/2022) teaches: "specific structural information - on the antibody to be optimized, its antigen and their interaction- is rarely available or lacks the high resolution required to determine accurately important details such as side-chain conformations, hydrogen-bonding patterns and the position of water molecules" (p. 527, Col. 2, 1). Thus even with the availability of screening approaches as taught in the specification, the ordinary artisan could not predict the hotspots much less those residues critical for conferring specific binding to any antigen absent further additional information and experimentation.
Queen (USPN 5,530,101; IDS 8/29/2022) teaches and emphasizes the importance in reducing distortions in the grafted CDRs into human frameworks that could impact antigen binding affinity by analyzing adjacent framework residues compatible with the CDR substitution as follows:
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Early on, Queen recognized the loss of stability and aggregation propensity using human antibody frameworks to engineer non-human CDR insertions.
Agpar et al (IDS 8/29/2022) teach that as the CDR encodes the binding region for antibody: antigen interactions, care must be taken to maintain these interacting and loop supporting residues, where “CDR grafting onto a subset of frameworks does not always result in stable antibodies because there may be some incompatibility between the CDR and the framework residues” (p. 1303, Col. 1).
Dondelinger et al (IDS 8/29/2022) teaches an important prerequisite for antibody humanization requires standardized numbering methods to define precisely complementary determining regions (CDR), frameworks and residues from the light and heavy chains that affect the binding affinity and/or specificity of the antibody- antigen interaction with the large fluctuation of the variable chain lengths, especially in CDR3 of heavy chains (CDRH3), which complicates the comparison and analysis of antibody sequences and the identification of the antigen binding residues. Even if these humanization techniques produce mAbs with reduced immunogenicity, they frequently lead to a loss in antibody affinity and/or specificity (22). In most cases, the main causes for this affinity loss are attributed to various factors such as imprecise definition of the CDR sequences (23), inappropriate choice of the human framework scaffold used for loop grafting and erroneous identification of structural corresponding residues from different species. Indeed, the antibody engineering techniques require an accurate identification of CDRs, antigen-binding residues as well as structural corresponding residues.
“The “λ-graft” of Worn et al. (IDS 8/29/2022) differed from the κ-graft by only 7 amino acids at the VH/VL interface, and these changes were generated to aid in proper orientation of the domains, which successfully enhanced solubility, expression, and structural stability. However, the λ-graft still lost an order of magnitude in KD from the anti-GCN4 mouse antibody, suggesting that other residues within the k framework were important for maintaining CDR orientation, and thus antibody affinity.”
Regarding disclosure in the specification
Applicants specification teaches that Vλ-type joining segments over Vκ-type joining segments in FR IV are elements conferring stability for the Vκ1-VH3 (scfv) antibody construct:
Applicants specification teaches full replacement of the Vκ1 FR IV by a corresponding Vλ FR IV is what leads to favorable stability profiles and exemplified the scfv constructs as follows:
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The exemplary constructs are drawn to scFv constructs but the specification does not identify which if any of the working embodiments comprise the one or two mutations in the chimeric VL domains falling within the Vλ framework region IV of those scfv constructs. The POSA is required to ascertain which of any mutation could result in the stable antibody of the claimed invention.
Still further, the meaning of "mutation" for the phrase "not more than five mutations" are defined as nothing but specific residue substitutions in the specification, yet where no such limitations are found in the claims as filed or amended. The mutations are not identified as conservative much less the extent of variance for each mutation. The specification does not support a broad range of amino acids for just any mutation.
The instant specification fails to describe a representative number of species mutations to provide adequate written description of the claimed genus as per MPEP § 2163.
C) The amendment to claim 21 is unclear and confusing because it is not ascertainable if the sequence FGQGTKLTVLG is a proviso in the phrase:
“provided that if said mutated human VA framework region IV has the sequence FGQGTKLTVLG (SEQ ID No. 15), and if said human VK framework regions I to III belong to the VK1 subfamily according to SEQ ID NO: 23, said human VK framework regions I to III comprise not more than five mutations compared to the respective regions in the human VK sequence with SEQ ID No: 8.”
It is recognized in the art that framework and CDR domains contribute to the antigen binding and stability for antigen binding domains. Thus, and based on the scope of the instant claimed VL domains, the ordinary artisan could reasonably conclude that Applicants were not in possession of the full scope of the invention at the time of filing.
D) Claim 25 recites the species “a Bs1Ab with an scFv linked to the N- terminus of the light chain of an IgG, a Bs2Ab with an scFv linked to N-terminus of the heavy chain of an IgG, a Bs3Ab with an scFv linked to the C-terminus of the heavy chain of an IgG, a Ts1Ab with an scFv linked to the N-terminus of both the heavy chain and the light chain of an IgG, a Ts2Ab with a dsscFv linked to the C-terminus of the heavy chain of an IgG.”
The specification does not define the antibody named a Bs1Ab, a Bs2Ab, a Bs3Ab, a Ts1Ab, or a Ts2Ab. The names of the antibodies do not correspond to any known kind of antibody.
There is insufficient guidance and direction for making of the claimed antibody chimeric VL domain as broadly encompassed by the one or two mutations to the Vλ framework region IV. Given the well-known high level of polymorphism of immunoglobulin / antibody frameworks and CDRs, the skilled artisan would not have been in possession of the vast repertoire of chimeric VL Vκ(I-III)-Vλ(IV) domains encompassed by the claimed invention at the time of filing.”
The rejection is maintained.
New Grounds for Objection
Claim Objections
6. Claims 22-25 are objected to because of the following informalities:
a) Claims 22-25 are inconsistent for the phrase “of claim 21” and “according to claim 21.” Amend the claims to recite one or the other for consistency.
b) Amend claim 23 to correct improper punctuation: a colon (:) is followed by semi-colon (;) and not a comma (,).
c) Amend claim 25 in lines 3-4 to recite “said isolated antibody or functional fragment thereof according to claim 21.”
d) Claim 25 is objected to because it references claims drawn to two different inventions comprising different but overlapping features, i.e., nucleic acids and vectors comprising the nucleic acids (MPEP 608.01(n)).
e) Amend claim 25 to recite: “, or a vector or collection of vectors comprising said nucleic acid sequence or said collection of nucleic acid sequences, respectively, and optionally in a host cell.”
Appropriate correction is required.
Examiner’s Comment
7. Relevant art: Claims 1-12 of U.S. Patent No. 10,174,102 (IDS of 8/20/2020); and Claims 1-4 of U.S. Patent No. 11427628 (IDS of 8/20/2020). Claims of ‘102 and ‘628 do not recite the limitation of the instant claimed invention that the Vλ framework region IV of the VL domain results in a chimeric VL comprising Vκ(II-III)-Vλ(IV) frameworks where the Vλ(IV) framework has one or two mutations compared to the sequence for framework region of SEQ ID NOs: 16-22. Notably, that limitation was deleted during the prosecution history for each of the separate patents.
Conclusion
8. No claims are allowed.
9. Any inquiry concerning this communication or earlier communications from the examiner should be directed to LYNN A. BRISTOL whose telephone number is (571)272-6883. The examiner can normally be reached on Mon-Fri 9 AM-5 PM.
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/LYNN A BRISTOL/Primary Examiner, Art Unit 1643