DETAILED ACTION
The Examiner of your application in the USPTO has changed. To aid in correlating any papers for this application, all further correspondence regarding this application should be directed to Examiner Bryan William Heck in Art Unit 1643.
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 .
Election/Restrictions
Applicant’s election without traverse of the invention of Group 1, claim 1-17 in the reply filed on 10/03/2025 is acknowledged.
Claims Status
Claims 18-20 are withdrawn from further consideration pursuant to 37 CFR 1.142(b) as being drawn to a nonelected invention, there being no allowable generic or linking claim. Election was made without traverse in the reply filed on 12/03/2025.
Claims 1-17 are pending and are examined on the merits.
Nucleotide and/or Amino Acid Sequence Disclosures
REQUIREMENTS FOR PATENT APPLICATIONS CONTAINING NUCLEOTIDE AND/OR AMINO ACID SEQUENCE DISCLOSURES
Items 1) and 2) provide general guidance related to requirements for sequence disclosures.
37 CFR 1.821(c) requires that patent applications which contain disclosures of nucleotide and/or amino acid sequences that fall within the definitions of 37 CFR 1.821(a) must contain a "Sequence Listing," as a separate part of the disclosure, which presents the nucleotide and/or amino acid sequences and associated information using the symbols and format in accordance with the requirements of 37 CFR 1.821 - 1.825. This "Sequence Listing" part of the disclosure may be submitted:
In accordance with 37 CFR 1.821(c)(1) via the USPTO patent electronic filing system (see Section I.1 of the Legal Framework for Patent Electronic System (https://www.uspto.gov/PatentLegalFramework), hereinafter "Legal Framework") as an ASCII text file, together with an incorporation-by-reference of the material in the ASCII text file in a separate paragraph of the specification as required by 37 CFR 1.823(b)(1) identifying:
the name of the ASCII text file;
ii) the date of creation; and
iii) the size of the ASCII text file in bytes;
In accordance with 37 CFR 1.821(c)(1) on read-only optical disc(s) as permitted by 37 CFR 1.52(e)(1)(ii), labeled according to 37 CFR 1.52(e)(5), with an incorporation-by-reference of the material in the ASCII text file according to 37 CFR 1.52(e)(8) and 37 CFR 1.823(b)(1) in a separate paragraph of the specification identifying:
the name of the ASCII text file;
the date of creation; and
the size of the ASCII text file in bytes;
In accordance with 37 CFR 1.821(c)(2) via the USPTO patent electronic filing system as a PDF file (not recommended); or
In accordance with 37 CFR 1.821(c)(3) on physical sheets of paper (not recommended).
When a “Sequence Listing” has been submitted as a PDF file as in 1(c) above (37 CFR 1.821(c)(2)) or on physical sheets of paper as in 1(d) above (37 CFR 1.821(c)(3)), 37 CFR 1.821(e)(1) requires a computer readable form (CRF) of the “Sequence Listing” in accordance with the requirements of 37 CFR 1.824.
If the "Sequence Listing" required by 37 CFR 1.821(c) is filed via the USPTO patent electronic filing system as a PDF, then 37 CFR 1.821(e)(1)(ii) or 1.821(e)(2)(ii) requires submission of a statement that the "Sequence Listing" content of the PDF copy and the CRF copy (the ASCII text file copy) are identical.
If the "Sequence Listing" required by 37 CFR 1.821(c) is filed on paper or read-only optical disc, then 37 CFR 1.821(e)(1)(ii) or 1.821(e)(2)(ii) requires submission of a statement that the "Sequence Listing" content of the paper or read-only optical disc copy and the CRF are identical.
Specific deficiencies and the required response to this Office Action are as follows:
Specific deficiency – Nucleotide and/or amino acid sequences appearing in Table 1 of the specification are not identified by sequence identifiers in accordance with 37 CFR 1.821(d).
Required response – Applicant must provide:
A substitute specification in compliance with 37 CFR 1.52, 1.121(b)(3) and 1.125 inserting the required sequence identifiers, consisting of:
A copy of the previously-submitted specification, with deletions shown with strikethrough or brackets and insertions shown with underlining (marked-up version);
A copy of the amended specification without markings (clean version); and
A statement that the substitute specification contains no new matter.
Specification
The disclosure is objected to because of the following informalities:
Tables appearing in the specification (Tables 1, 3, and 5) are illegible.
In addition, Table 1 appears to contain amino acid sequences without the required corresponding sequence identifiers (see above).
Appropriate correction is required.
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 1-17 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.
Claims 1 and 5 recite the phrase “wherein n is the same number”, however it is unclear what is meant by this phrase (i.e. same as what?). For the purposes of examination, this limitation has been ignored. This rejection can be overcome by removing said language, for example: “...wherein n
Claim 5 recites the phrase “(where n is the same number that is 2 or greater)” in parentheses, and it is unclear if this parenthetical is a required limitation of the claim or merely exemplary of a possible value for n.
Claims 1-17 are rejected for reciting the phrases “functional equivalent thereof” and/or “functionally equivalent sequence thereof”. It is unclear what is meant to be encompassed by a “functional equivalent” or which function or functions in particular the “functional equivalent” must possess.
Claims 6-9 are rejected for reciting the limitations “on the same side”, “on different sides”, “on a side that binds”, “on a side that does not bind”. Antigens/proteins are not generally understood to have “sides”, and it is unclear how one would determine whether a pair of epitopes are on the same or different sides as one another or on a side that does nor does not bind a target molecule.
Although ¶0040 of the instant specification details one possible means of determining epitope “sides”, this description of antigen “sides” is specific to a single projection of the TNFR2 crystal structure as it relates to five particular epitopes, and it is unclear whether such a definition would be generalizable to other antigens or indeed to any/all epitopes of TNFR2.
Because the scope of Claims 6-9 could not be determined, they have not been treated further on the merits.
Claims 15-17 are rejected for reciting antibody clones in parentheses, for example, “(TR92 heavy chain)”. It is unclear if the terms appearing in parentheses are required parts of the claim or if they are merely exemplary of polypeptides containing the claimed sequences. This rejection can be overcome, for example, by removing the terms in parentheses.
Claims 15-17 are further rejected because it is unclear how in particular the CDRs of the claim are defined. Each of the claims requires sets of 3 heavy chain and 3 light chain CDRs, however the recited sequence identifiers correspond to full VH/VL or HC/LC sequences. The claims do not set forth which subsequences are considered to be the CDRs nor a particular method by which to define said CDRs (e.g. Chothia, IMGT, Kabat, etc.). This rejection can be overcome, for example, by directly specifying the individual CDR sequences with their corresponding SEQ ID NO.
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 1-17 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 claims contain 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. This is a written description rejection.
Scope of the claimed genus
Claims 1-11 are drawn to biparatopic antibodies wherein the antigen is defined only by its being “activated by a target molecule binding thereto”, and the antibody is defined functionally by an antibody:antigen ratio of a complex and the requirement that the antibody bind two different epitopes.
Claims 10-11 further require that the antibody is increased antagonistic or decreased agonistic activity, respectively, relative to a naturally-occurring antibody.
Claims 12-14 further specify that the antigen is a “membrane protein”, a “membrane protein belonging to a TNF receptor superfamily”, or TNFR2, respectively, however no additional structural requirements are provided for the antibody.
Claims 15-17 further specify structure partial structure of the antibody, however the claimed sequences allow for 20% variability, including within the critical CDR sequences. Moreover, Claims 15-17 allow for mix-and-match pairings of heavy chain and light chain CDRs (for example, the “TR92 heavy chain” CDR sequences of claim 16 can be paired with either the “TR92 light chain” or “TR109 light chain” CDR sequences).
Accordingly, the resulting scope of the claims is enormous, encompass a near limitless variety of biparatopic antibodies defined only by a desired binding ratio, by the antigen to which they bind, or by partial sequence identity to CDRs from anti-TNFR2 antibodies.
State of the relevant art
Biparatopic antibodies are known in the art. For example, DaSilva et al. 2020 (Clinical Cancer Research, 26(6), 1408-1419.; PTO-892) teaches a METxMET biparatopic antibody that forms a 2:2 antibody:antigen complex which both blocks binding of MET to its cognate ligand and prevents agonism of the receptor typically induced by the antibody itself. In another example Yang et al. 2019 (MAbs (Vol. 11, No. 6, pp. 996-1011). Taylor & Francis.; PTO-892) teaches biparatopic antibodies to TNFRSF member OX40 which causes higher-order receptor crosslinking and activates its downstream signaling. Thus, the properties of any given biparatopic antibody (e.g. binding ratios, agonistic/antagonistic activity, etc.) are particular to that specific antibody.
As was well known in the antibody art, the formation of an intact antigen binding site in a conventional antibody typically requires the association of the complete heavy and light chain variable regions of a given antibody, each of which comprises three CDRs (or hypervariable regions) which provide the majority of the contact residues for the binding of the antibody to its target epitope (reviewed in Sela-Culang et al. Frontiers in Immunology 4 (2013): 302.; PTO-892). It is generally understood that all six CDRs in combination and in a specific order (HCDR1, HCDR2, HCDR3, LCDR1, LCDR2, LCDR3) are required to convey an antibody’s specificity to its target, and that neither the CDRs themselves nor individual VH and VL domains are interchangeable.
For example, Julien 2017 (US 2017/0355756 A1; PTO-892) discloses an antibody specific for human TDP-43 with a heavy chain comprising 3 CDRs termed “C10-VH3” (Table A, SEQ ID NO. 4). Cassone 2008 (WO 2008/068048 A2; PTO-892) discloses an antibody with a heavy chain comprising the same 3 CDRs (“αSAP 2A8”; Pg. 18, SEQ ID NO. 2). However, the antibody of Cassone 2008 is paired with a different VL and targets an entirely different protein – secreted aspartyl protease (SAP) from pathogenic yeast in the genus Candida sp. Below is an alignment between the VH domains of these unrelated antibodies; the 3 HCDRs according to Julien 2017 are highlighted (SEQ ID NOs: 16-18):
C10-VH3 15 RKLSCAASGFTFSSFGMHWVRQAPEKGLEINVAYISSGSSTLHYADTVKGRFTISRDNPK 74
||||||||||||||||||||||||||||| |||||||||||||||||||||||||||||
αSAP 2A8 1 RKLSCAASGFTFSSFGMHWVRQAPEKGLEW-VAYISSGSSTLHYADTVKGRFTISRDNPK 59
C10-VH3 75 NTLFLQMKLPSLCYGLLGPRDHGH 98
|||||||||||||||||| |: |
αSAP 2A8 60 NTLFLQMKLPSLCYGLLGSRNLSH 83
Sela-Culang further teaches that antigens lack intrinsic properties that clearly differentiate between epitopic and non-epitopic residues, and any part of the antigen surface my become part of an epitope under some circumstances (“Ab Epitope Prediction”; Pg. 2). In the same vein, Edwards et al. 2003 (Journal of molecular biology 334.1 (2003): 103-118.; PTO-892) endeavored to uncover the breadth of the structural diversity of antibodies a single antigen can give rise to.
Edwards employed a phage display library to screen for antibodies that bind a single protein, BLyS, and isolated over 1000 unique anti-BLyS antibodies, each comprising a different amino acid sequence (Abstract). These antibodies were structurally diverse, resulted from nearly all possible Vh, D, and Jh, germlines (Pg. 105; “Vh and Vl germline usage”), and comprised 568 distinct Vh CDR3 sequences, ranging in length from 5 to 25 amino acid residues (Fig. 4; “Vh CDR3 sequence diversity”; Pg. 105). Together, these works highlight that neither knowledge of the antigen sequence nor the antibody sequence is necessarily predictive of its function.
Finally, the skilled artisan has long recognized that even minor changes in the amino acid sequences of the VH and VL, particularly in the CDRs, may dramatically affect antigen-binding function, as evidenced by Rudikoff 1982 (Proceedings of the National Academy of Sciences 79.6 (1982): 1979-1983.; PTO-892). Rudikoff teaches that the alteration of a single amino acid in the CDR of a phosphocholine-binding myeloma protein resulted in the loss of antigen-binding function (Abstract).
Although more recent advances in computational modelling of CDRs have led to improvements in rational mutagenesis of antibodies, the overall effects of any given mutation on antibody function remain unpredictable. For example, Chiu et al. 2019 (Antibodies, 8(4), 55.; PTO-892) teaches that although modeling has proven accurate for framework region sequences, CDR modeling requires further development and improvement (Pg. 6, ¶2). In particular, prediction of the structure of HCDR3 could not be accurately produced when given the Fv structures without their CDR-H3s (Pg. 6, ¶2). Chiu further states “despite the obvious development in algorithms and computer power, the quality of antibody structure prediction, particularly regarding CDR-H3, remains inadequate” (Pg. 11, ¶ 2).
Chiu further discusses the state of the art as it relates to antibody humanization and highlights the importance of VH-VL pairing to antigen-binding affinity (§2.1.3). For example, even in cases where structural analysis indicated that all the interactions between the antibody CDRs and the antigen were conserved, changes in the relative orientation of the VH and VL domains can cause a dramatic loss in antibody affinity – and a modification as small as a single back-mutation in the framework region has the potential capacity to completely restore this diminished affinity (Pg. 14, ¶3). Chiu further teaches the utility of back-mutations more generally, as “straightforward CDR grafting may result in reduced target binding even if the VH-VL interface residues are preserved” (Pg. 16, §2.1.4), and back-mutations in the framework region can both modulate binding affinity and improve antibody expression. However, although some residues are frequently targeted for back mutation – such as those in the vernier zone known to influence the structure of CDRH2 – the importance of these residues depends largely on the particular CDRs of the grafted binding domain, and it is “not always the case” that such mutations will be of benefit to the antigen-binding affinity/function.
Description of representative species in the specification
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.
The instant disclosure provides 11 examples of anti-TNFR2 biparatopic antibodies (Table 2), each comprising different combinations of binding domains derived from two of five parental anti-TNFR2 monoclonal antibodies (TR45, TR92, TR94, TR96, TR109). Of these, only a subset possessed antagonistic activity (Example 4), and only three form a 1:1 antibody:antigen ratio as required by Claim 4. No examples of biparatopic antibodies to antigens other than TNFR2 are provided. Given the breadth of the claims, such a limited number of exemplary species would not reasonably be considered representative of the entire genus.
Identifying characteristics and structure/function correlation
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 genus. To meet this requirement in the instant case, the specification must describe structural features that the skilled artisan as of the effective filing date would have expected to convey the claimed binding function.
Although the disclosure teaches the approximate epitopes bound by each of the parental TNFR2 antibodies, no structure-function relationship between the antibody sequences and their capacity to bind a particular epitope is established. Further, although Example 8 highlights tendencies to form lower and higher order antibody:antigen complexes based on the proximity of the epitopes bound by the biparatopic antibody, antagonistic activity was shown to be reliant on the parental antibody (¶0108). Moreover, despite each of the tested antibodies having 2:2 binding acting as agonists, the prior art teaches that 2:2 antibody can be a potent antagonist (see discussion of DaSilva et al. 2020 above). Accordingly, the skilled artisan would be unable to envisage the structure of a biparatopic antibody meeting the required antigen binding ratio or functional limitations commensurate with the full breadth of the instant claims.
Claim Rejections - 35 USC § 102
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)(1) the claimed invention was patented, described in a printed publication, or in public use, on sale, or otherwise available to the public before the effective filing date of the claimed invention.
Claims 1-3, 5, and 10-12 are rejected under 35 U.S.C. 102(a)(1) as being anticipated by DaSilva et al. 2020 (Clinical Cancer Research, 26(6), 1408-1419.; PTO-892), herein “DaSilva”.
DaSilva teaches a biparatopic anti-MET antibody comprising two arms derived from two different parental anti-MET antibodies wherein each arm of the antibody recognizes a different epitope of MET (Pg. 1410, Fig. 1).
Regarding the requirement in claim 1 that the antigen “is activated by a target molecule binding thereto”, DaSilva teaches that MET is activated upon binding its ligand HGF (§ Introduction).
Regarding instant Claims 1, 3, and 5, DaSilva teaches that the biparatopic anti-MET antibody forms a 2:2 antibody:antigen complex with MET (Fig. 3). As it relates to the formula in Claim 1, the antibody of DaSilva has 2 different binding domains with two different paratopes, thus the “maximum value of the number of antigen binding domains sharing a paratope” is 1 (m=1) and the number of each the antigen and antibody is 2 (n=2), therefore the complex ratio of DaSilva is (1 x 2):2.
Regarding Claims 10-11, DaSilva teaches that the biparatopic anti-MET antibody has enhanced antagonistic activity and reduced agonistic activity relative to each of the two parental antibodies used in its construction (Fig. 5A, Pg. 1413-1415, § “The biparatopic MET antibody inhibits HGF-induced signaling and does not activate MET-dependent biological processes”).
Regarding Claim 12, DaSilva teaches MET is a membrane protein (e.g. Fig. 4D).
Claim Rejections - 35 USC § 103
The following is a quotation of 35 U.S.C. 103 which forms the basis for all obviousness rejections set forth in this Office action:
A patent for a claimed invention may not be obtained, notwithstanding that the claimed invention is not identically disclosed as set forth in section 102, if the differences between the claimed invention and the prior art are such that the claimed invention as a whole would have been obvious before the effective filing date of the claimed invention to a person having ordinary skill in the art to which the claimed invention pertains. Patentability shall not be negated by the manner in which the invention was made.
The factual inquiries for establishing a background for determining obviousness under 35 U.S.C. 103 are summarized as follows:
1. Determining the scope and contents of the prior art.
2. Ascertaining the differences between the prior art and the claims at issue.
3. Resolving the level of ordinary skill in the pertinent art.
4. Considering objective evidence present in the application indicating obviousness or nonobviousness.
Claims 1-3, 5, 12-15, and 17 are rejected under 35 U.S.C. 103 as being unpatentable over Hammer et al 2019 (Cancer Res, 79(13 Supplement), 563-563.; Abstract cited on the IDS dated 09/29/2022; Full poster attached to PTO-892), herein “Hammer”, and further in view of Kondo et al. 2018 (WO 2018092907 A1; IDS dated 09/29/2022), herein “Kondo”.
Note: the machine translation of WO 2018092907 A1 provided with the IDS filed 09/29/2022 was used as the reference in this rejection.
Hammer teaches that tumor necrosis factor receptor superfamily members require high-order receptor clustering to achieve full activity (Abstract).
Hammer teaches that biparatopic antibodies can induce OX40 signaling without the need for secondary cross-linking (Abstract).
Hammer teaches that biparatopic antibodies contain two different binding domains having specificities for different epitopes of the same antigen (bottom left panel), and that the combined biparatopic antibody is a more potent agonist than either parental antibody (center, third panel).
Hammer does not teach biparatopic anti-TNFR2 antibodies comprising the instantly claimed sequences. This deficiency is cured by Kondo.
Kondo teaches anti-TNFR2 monoclonal antibodies TR92 and TR94, and their corresponding sequences (¶0474; SEQ ID NOs 3, 8, 14, and 18), which are the same as the TR92 and TR94 sequences of the instant claims (Instant SEQ ID NOs 2, 7, 3, and, 8).
Kondo teaches that TR92 and TR94 target different epitopes of TNFR2, and that both antibodies have agonist activity towards TNFR2 and activate NFkB (¶0434; Fig. 60).
Kondo teaches that agonistic anti-TNFR2 antibodies can be used to stimulate Treg proliferation and to treat autoimmune disease (¶0289-0291).
It would have been obvious to one of ordinary skill in the art to construct a biparatopic anti-TNFR2 antibody having two different binding domains derived from the monoclonal anti-TNFR2 antibodies taught by Kondo. The skilled artisan would have been motivated by the teachings of Kondo that activating TNFR2 promoted Treg proliferation and can be used to treat autoimmune disease, and the teachings of Hammer which teaches that TNFRSF members require higher-order clustering for activation. There would have been a reasonable expectation of success because Hammer teaches that biparatopic antibodies are more potent agonists than the parental monoclonal antibodies, and Kondo teaches that each TR92 and TR94 independently possess agonistic activity towards TNFR2. Although Hammer is silent on the antibody:antigen ratio, the antibodies of Kondo are the same as the parental antibodies of the instant disclosure, and thus any resulting properties would be inherent to said antibodies.
Conclusion
No claim is allowed.
Any inquiry concerning this communication or earlier communications from the examiner should be directed to BRYAN WILLIAM HECK whose telephone number is (703)756-4701. The examiner can normally be reached Mon-Fri 8:00am - 5:30pm.
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/BRYAN WILLIAM HECK/Examiner, Art Unit 1643
/JULIE WU/Supervisory Patent Examiner, Art Unit 1643