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
Claim 2 is cancelled. Claims 1, 3-10, 14, and 16-22 are pending and are examined on the merits.
OBJECTIONS WITHDRAWN
Objection to Claim 14 is withdrawn in view of applicant’s amendment italicizing Pichia pastoris.
REJECTIONS WITHDRAWN
Claim 2 is cancelled, rendering all rejections of Claim 2 moot.
Rejection of Claim 4 made under 35 USC 112(a) written description is withdrawn in view of applicant’s amendment requiring a defined set of CDR sequences.
NEW/UPDATED REJECTIONS AS NECESSITATED BY CLAIM AMENDMENTS
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, 6-10, 14, and 17-22 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.
The rejection below has been updated to reflect the new scope of the claims.
Scope of the claimed genus
The claims are drawn to a large number of immunoglobulin single variable domains (ISVD) that specifically bind CD13 and are internalized by CD13-expressing cells comprising a CDR1, CDR2, and CDR3 corresponding to SEQ ID NOs: 1, 3, and 4 or 2, 3, and 5, respectively, wherein the ISVDs may comprise any combination of the specified amino acid substitutions at positions 4, 6, and/or 7 of CDR1 (SEQ ID NO: 1 or 2) and positions 6, 10, and/or 12 of CDR3 (SEQ ID NO: 4 or 5). Accordingly, the claims encompass thousands of possible sequence combinations for each set of CDRs – all while requiring the resulting antibodies both specifically bind CD13 and drive internalization by CD13-expressing cells.
State of the relevant art
At the time of filing (01/15/2021), single domain antibodies (sdAbs) specific for CD13 (also known as APN) were known. Hua et al. 2019 (WO 2019/210155 A1; of record) teaches a llama-derived sdAb termed “Nb157/VHH157” (Hua SEQ ID NO: 19), which exhibits high specificity towards CD13 and is capable of redirecting T cells to kill CD13 positive cells when incorporated as the binding domain in a CAR construct (Fig. 4; Example 5, Pg. 81-82). However, anti-CD13 sdAbs comprising the sequences of instant Claim 1 were not known in the art, and the antibody arts are well known to be unpredictable. For example, Edwards 2003 (Journal of molecular biology 334.1 (2003): 103-118.; of record) teaches over 1000 structurally diverse antibodies targeting a single antigen, each comprising a unique amino acid sequence – highlighting that neither knowledge of the antigen sequence nor the antibody sequence is necessarily predictive of its function.
Further 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 (PNAS 79.6 (1982): 1979-1983.; of record). 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). Similarly, Brown et al. 1996 (The Journal of Immunology, 156(9), 3285-3291.; PTO-892) teaches that while antibodies may tolerate single mutations in a VH CDR2, pairs of amino acid substitutions resulted in loss of binding (Table I), and certain positions were intolerant of single amino acid changes, including conservative substitutions (Abstract; Table II).
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.; of record) 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). Accordingly, the skilled artisan recognized that it was highly unpredictable that any of the CDRs could be modified without altering or abolishing antigen binding.
Camelid-derived single-domain antibodies (sdAb, also known as nanobodies or VHH), while lacking a light chain, share many similarities with conventional antibodies, including comprising 3 CDRs important for antigen recognition (Mitchell and Colwell, Protein Engineering, Design and Selection 31.7-8 (2018): 267-275.; Figure 1; of record). However, recent works have highlighted even greater complications when considering structure-function relationship of camelid single-domain antibodies (sdAb, also known as nanobodies or heavy chain antibodies). Mitchell 2018 teaches that predicting which residues are involved in antigen recognition (paratope) is even more difficult for sdAbs than for conventional antibodies. Unlike the well accepted three-loop consensus for paratopes on conventional antibodies, the distinction between paratope and non-paratope regions of sdAbs is less clear, the “framework” region often contributes directly to binding, and the only structural segment that is always part of the paratope in an sdAb is CDR3 (designated “H3” in Mitchell; Pg. 275, Conclusion).
Therefore, in view of the high degree of unpredictability inherent to the antibody arts, including as related to sdAbs, a skilled artisan would be unable to envisage the structure of a sdAb or ISVD that binds CD13 comprising 1 or more amino acid substitutions in the CDRs or mix-and-match CDRs, as required by the claims.
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 specification discloses immunization of llamas with porcine APN (aka CD13) followed two rounds of panning a VHH phage display library wherein 28 unique candidate anti-CD13 VHHs were identified (¶0163). However, among these candidates, only the sequences for four clones are disclosed (2L65, 3L2, 3L73, 3L94; Fig. 8), of which only three belong to the claimed genus (2L65, 3L2, 3L73), two of which comprise identical CDRs (2L65, 3L2).
In view of the prior art discussed above, wherein the antibody repertoire for any given antigen is vast and structurally diverse (See Edwards 2003), the capacity for single amino acid changes to completely disrupt antibody function (See Rudikoff 1982) even in the case of conservative substitutions (See Brown 1996), and the outsized contribution of the framework regions to the function of sdAbs (See Mitchell 2018), the disclosure of only 3 species belonging to the claimed genus, which collectively encompass only two of the thousands of possible sets of claimed CDRs, would not reasonably be considered representative of the claimed genus by one of ordinary skill in the art.
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 activity.
Among the disclosed ISVDs, clones 2L65, 3L73, and 3L2 were noted to have “high sequence similarity” (¶0179), and indeed both 2L65 and 3L2 comprise identical CDR sequences (Fig. 8). A competition assay performed with clones 2L65, 3L73, and 3L2 (Pg. 51-52, § 7. Competition Assay) suggest that these three binding domains may recognize the same or overlapping epitopes, but the epitope itself is not described and neither is there a disclosure of which particular residues and in which combinations are important or sufficient to support CD13 binding nor CD13-dependent internalization. Notably clone 3L73, which comprises amino acid substitutions at positions 4, 6, and 7 of CDR1 and 6, 10, and 12 of CDR2 relative to related clones 2L65 and 3L2, had reduced CD13 binding when compared to other members of the same sequence “family” (Fig. 2, Fig. 4). It is therefore unclear which particular amino acid substitutions could be made or whether the CDRs could be interchanged with other species while still retaining the claimed CD13 binding activity and induce internalization by CD13-expressing cells.
As such, one of ordinary skill in the art would be unable to envisage an antibody that both binds CD13 and is internalized by CD13-expressing cells having any mutations in the CDRs relative to the disclosed clones, and would therefore not reasonably conclude that the inventors were in possession of a genus if ISVDs commensurate in scope with the claims.
Response to Arguments
Applicant's arguments filed 10/10/2025 have been fully considered but they are not persuasive because:
Applicant points to clone 3L73, which retains CD13 binding activity and comprises substitutions at positions 4, 6, and 1 of CDR1 and 6, 10, and 12 of CDR3 relative to clones 2L65 and 3L2 as evidence that “some variation is permitted at the indicated positions of CDR1 and 3 without loss of function” (Remarks Pg. 9). However, as pointed out in the rejection above, the impact of any particular mutation – even conservative substitutions – on antibody function is unpredictable (See Edwards, Rudikoff, Brown, Chiu, and Mitchell cited above), and the single example in the specification of a functional variant comprising substituted CDRs is not alone sufficient to support a genus of CDR sequences comprising any “conservative” substitution in any combination at any/all of the positions recited in the claims.
Further of note, the CDRs comprised within clone 3L73 do not exclusively comprise conservative substitutions as claimed but rather a mixture of both conservative and nonconservative amino acid substitutions (see alignment below), and therefore fails to support even a single species of variant recited in claim 1(i), which, for example, requires an Asp, Glu or Gln at position 6 of SEQ ID NO: 1.
SEQ ID NO: 1 1 GRTISNHAMG 10
||| |::|||
SEQ ID NO: 2 1 GRTFSSNAMG 10
SEQ ID NO: 4 1 RQSGYVSKFVDDYGY 15
||||| |||:|:|||
SEQ ID NO: 5 1 RQSGYASKFLDEYGY 15
Accordingly, it is maintained that although the specification contains sufficient written support for an immunoglobulin single variable domain (ISVD) that specifically binds CD13 comprising CDRs 1-3 corresponding to SEQ ID NOs: 1, 3, and 4 respectively or SEQ ID NOs: 2, 3, and 5, respectively, there is insufficient written support for ISVDs comprising any amino acid substitutions thereof that satisfy the claimed function of CD13 binding.
Allowable Subject Matter
Claims 3-5 and 16 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.
The reasons for indicating allowable subject matter are the same as stated in the previous office action. Briefly, each of claims 3-5 and 16 are drawn to anti-CD13 immunoglobulin single variable domain binders comprising novel CDR sequences absent from the prior art of record.
Conclusion
No claim is allowed.
Applicant's amendment necessitated the new ground(s) of rejection presented in this Office action. Accordingly, THIS ACTION IS MADE FINAL. See MPEP § 706.07(a). Applicant is reminded of the extension of time policy as set forth in 37 CFR 1.136(a).
A shortened statutory period for reply to this final action is set to expire THREE MONTHS from the mailing date of this action. In the event a first reply is filed within TWO MONTHS of the mailing date of this final action and the advisory action is not mailed until after the end of the THREE-MONTH shortened statutory period, then the shortened statutory period will expire on the date the advisory action is mailed, and any nonprovisional extension fee (37 CFR 1.17(a)) pursuant to 37 CFR 1.136(a) will be calculated from the mailing date of the advisory action. In no event, however, will the statutory period for reply expire later than SIX MONTHS from the mailing date of this final action.
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