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 .
Status of Claims
Claims 2 and 4 are amended. Claims 1, 3, 5-46, and 49 are cancelled. Claims 57-67 are added. Claims 55 and 56 are withdrawn. Claims -----2, 4, 47-48, 50-54, 57-67 are currently pending and under examination.
Priority
Applicant’s claim for the benefit of a prior-filed application under 35 U.S.C. 119(e) or under 35 U.S.C. 120, 121, 365(c), or 386(c) is acknowledged. The claims have an earliest effective filing date of 12/17/2021, corresponding to application 63/291,305.
Information Disclosure Statement
The Information Disclosure Statements filed on 10/20/2023 and 02/12/2026 have been considered.
Election/Restrictions
Claims 55 and 56 are withdrawn from further consideration pursuant to 37 CFR 1.142(b) as being drawn to a nonelected method, there being no allowable generic or linking claim. Election was made without traverse in the reply filed on 02/12/2026.
Notes on the Prior Art
The closes prior art is Nelson et al. (US PG PUB 2020/0199196, publication date: 06/25/2020). Nelson et al. teach a single chain polypeptide comprising multiple TNFSF family members - Claim 1 recites a recombinant single chain polypeptide comprising a first TNF superfamily (TNFsf) monomer, a second TNFsf monomer, and a third TNFsf monomer operably linked with peptide linkers, wherein the recombinant single chain polypeptide forms a trimer;
the trimer comprises: (i) a first receptor binding site comprising a first gain of function variant (increases binding avidity to a target TNFsfR); (ii) a second receptor binding site comprising a second gain of function variant (increases binding avidity to a target TNFsfR); and
(iii) a third receptor binding site comprising a loss of function variant (decreases binding avidity or blocks binding to target receptor); and the trimer has a high avidity for a target TNFsf receptor (e.g., RANK) and a low avidity to non-target TNFsf receptors (e.g., OPG).
Nelson et al. do not teach or suggest an antigen binding polypeptide complex comprising a first polypeptide and a second polypeptide; wherein:(i) the first polypeptide has a structure represented by:VL1-L13-VH1-L14-Fc-L15-TNF1-L16-TNF2-L17-TNF3; VH1-L18-VL1-L19-Fc-L20-TNF 1-L21-TNF2-L22-TNF3; VL1-L23 -VH1-L24-CL-L25 -CH1-L26-Fc-L27-TNF1-L28-TNF2-L29-TNF3; VL1-L23-VH1-L24-CH1-L25-CL-L26-Fc-L27-TNF1-L28-TNF2-L29-TNF3; VH1-L23-VL1-L24-CL-L25-CH1-L26-Fc-L27-TNF1-L28-TNF2-L29-TNF3; VH1-L23-VL1-L24-CH1-L25-CL-L26-Fc-L27-TNF1-L28-TNF2-L29-TNF3; VL1-VH1-L14-Fc-L15-TNF1-L16-TNF2-L17-TNF3;VH1-VL1-L19-Fc-L20-TNF1-L21-TNF2-L22-TNF3; VL1-VH1-L24-CL-L25-CHi-L26-Fc-L27-TNF1-L28-TNF2-L29-TNF3;VL1-VH1-L24-CH1-L25 -CL-L26-Fc-L27-TNF1-L28-TNF2-L29-TNF3;VH1-VL1-L24-CL-L25-CH1-L26-Fc-L27-TNF1-L28-TNF2-L29-TNF3;VH1-VL1-L24-CH1-L25-CL-L26-Fc-L27-TNF1-L28-TNF2-L29-TNF3;VL1-L3 0-CL-L3 1 -VH1-L32-CH1 -L33 -Fc-L34-TNF1-L3 5-TNF2-L3 6-TNF3;VL1-L30-CH1-L31 -VH1-L32-CL-L33-Fc-L34-TNF1-L35-TNF2-L3 6-TNF3; VH1-L30-CL-L31-VL1-L32-CH1-L33-Fc-L34-TNF1-L35-TNF2-L36-TNF3; or VH1-L30-CH1-L31-VL1-L32-CL-L33-Fc-L34-TNF1-L35-TNF2-L36-TNF3; and the second polypeptide has a structure represented by:VL2-L37-VH2-L3 8-Fc-L3 9-TNF1-L40-TNF2-L41-TNF3;VH2-L42-VL2-L43-Fc-L44-TNF1-L45-TNF2-L46-TNF3;VL2-L47-VH2-L48-CL-L49-CH1-L50-Fc-L51-TNF 1-L52-TNF2-L53-TNF3; VL2-L54-CL-L55-VH2-L56-CH1-L57-Fc-L58-TNF1-L59-TNF2-L60-TNF3; VL2-L47-VH2-L48-CH1-L49-CL-L50-Fc-L51-TNF1-L52-TNF2-L53-TNF3; VL2-L54-CH1-L55-VH2-L56-CL-L57-Fc-L58-TNF1-L59-TNF2-L60-TNF3; VL2-VH2-L38-Fc-L39-TNF1-L40-TNF2-L41-TNF3;VH2-VL2-L43 -Fc-L44-TNF1-L45 -TNF2-L46-TNF3; VL2-VH2-L48-CL-L49-CH1-L50-Fc-L51-TNF1-L52-TNF2-L53-TNF3; VL2-CL-L55-VH2-L56-CH1-L57-Fc-L58-TNF1-L59-TNF2-L60-TNF3; VL2-VH2-L48-CH1-L49-CL-L50-Fc-L51-TNF1-L52-TNF2-L53-TNF3; or VL2-CH1-L55-VH2-L56-CL-L57-Fc-L58-TNF1-L59-TNF2-L60-TNF3;
wherein: VL1 is a first immunoglobulin light chain variable region; VL2 is a second immunoglobulin light chain variable region; VH1 is a first immunoglobulin heavy chain variable region; VH2 is a second immunoglobulin heavy chain variable region; Fc is a region comprising an immunoglobulin heavy chain constant region 2 (CH2), an immunoglobulin heavy chain constant region 3 (CH3), and optionally, an immunoglobulin hinge; CH1 is an immunoglobulin heavy chain constant region 1; CL is an immunoglobulin light chain constant region; TNF1 is a first extracellular domain of a TNFSF ligand; TNF2 is a second extracellular domain of a TNFSF ligand; TNF3 is a third extracellular domain of a TNFSF ligand; and L13-L60 are amino acid linkers.
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.
Claims 2, 4, 47-48, 50-59, 63, 66-67 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 pre-AIA the inventor(s), at the time the application was filed, had possession of the claimed invention.
The purpose of the written description requirement is to ensure that the inventor had possession, at the time the invention was made, of the specific subject matter claimed. To satisfy the written description requirement, a patent specification must describe the claimed invention in sufficient detail that one skilled in the art can reasonably conclude that the inventor had possession of the claimed invention. See, e.g., Moba, B.V. v. Diamond Automation, Inc., 325 F.3d 1306, 1319, 66 USPQ2d 1429, 1438 (Fed. Cir. 2003); Vas-Cath, Inc. v. Mahurkar, 935 F.2d at 1563, 19 USPQ2d at 1116.
Claim 1 is drawn to an antigen binding polypeptide complex comprising a first polypeptide and a second polypeptide; wherein:(i) the first polypeptide has a structure represented by:VL1-L13-VH1-L14-Fc-L15-TNF1-L16-TNF2-L17-TNF3; VH1-L18-VL1-L19-Fc-L20-TNF 1-L21-TNF2-L22-TNF3; VL1-L23 -VH1-L24-CL-L25 -CH1-L26-Fc-L27-TNF1-L28-TNF2-L29-TNF3; VL1-L23-VH1-L24-CH1-L25-CL-L26-Fc-L27-TNF1-L28-TNF2-L29-TNF3; VH1-L23-VL1-L24-CL-L25-CH1-L26-Fc-L27-TNF1-L28-TNF2-L29-TNF3; VH1-L23-VL1-L24-CH1-L25-CL-L26-Fc-L27-TNF1-L28-TNF2-L29-TNF3; VL1-VH1-L14-Fc-L15-TNF1-L16-TNF2-L17-TNF3;VH1-VL1-L19-Fc-L20-TNF1-L21-TNF2-L22-TNF3; VL1-VH1-L24-CL-L25-CHi-L26-Fc-L27-TNF1-L28-TNF2-L29-TNF3;VL1-VH1-L24-CH1-L25 -CL-L26-Fc-L27-TNF1-L28-TNF2-L29-TNF3;VH1-VL1-L24-CL-L25-CH1-L26-Fc-L27-TNF1-L28-TNF2-L29-TNF3;VH1-VL1-L24-CH1-L25-CL-L26-Fc-L27-TNF1-L28-TNF2-L29-TNF3;VL1-L3 0-CL-L3 1 -VH1-L32-CH1 -L33 -Fc-L34-TNF1-L3 5-TNF2-L3 6-TNF3;VL1-L30-CH1-L31 -VH1-L32-CL-L33-Fc-L34-TNF1-L35-TNF2-L3 6-TNF3; VH1-L30-CL-L31-VL1-L32-CH1-L33-Fc-L34-TNF1-L35-TNF2-L36-TNF3; or VH1-L30-CH1-L31-VL1-L32-CL-L33-Fc-L34-TNF1-L35-TNF2-L36-TNF3; and the second polypeptide has a structure represented by:VL2-L37-VH2-L3 8-Fc-L3 9-TNF1-L40-TNF2-L41-TNF3;VH2-L42-VL2-L43-Fc-L44-TNF1-L45-TNF2-L46-TNF3;VL2-L47-VH2-L48-CL-L49-CH1-L50-Fc-L51-TNF 1-L52-TNF2-L53-TNF3; VL2-L54-CL-L55-VH2-L56-CH1-L57-Fc-L58-TNF1-L59-TNF2-L60-TNF3; VL2-L47-VH2-L48-CH1-L49-CL-L50-Fc-L51-TNF1-L52-TNF2-L53-TNF3; VL2-L54-CH1-L55-VH2-L56-CL-L57-Fc-L58-TNF1-L59-TNF2-L60-TNF3; VL2-VH2-L38-Fc-L39-TNF1-L40-TNF2-L41-TNF3;VH2-VL2-L43 -Fc-L44-TNF1-L45 -TNF2-L46-TNF3; VL2-VH2-L48-CL-L49-CH1-L50-Fc-L51-TNF1-L52-TNF2-L53-TNF3; VL2-CL-L55-VH2-L56-CH1-L57-Fc-L58-TNF1-L59-TNF2-L60-TNF3; VL2-VH2-L48-CH1-L49-CL-L50-Fc-L51-TNF1-L52-TNF2-L53-TNF3; or VL2-CH1-L55-VH2-L56-CL-L57-Fc-L58-TNF1-L59-TNF2-L60-TNF3;
wherein: VL1 is a first immunoglobulin light chain variable region; VL2 is a second immunoglobulin light chain variable region; VH1 is a first immunoglobulin heavy chain variable region; VH2 is a second immunoglobulin heavy chain variable region; Fc is a region comprising an immunoglobulin heavy chain constant region 2 (CH2), an immunoglobulin heavy chain constant region 3 (CH3), and optionally, an immunoglobulin hinge; CH1 is an immunoglobulin heavy chain constant region 1; CL is an immunoglobulin light chain constant region; TNF1 is a first extracellular domain of a TNFSF ligand; TNF2 is a second extracellular domain of a TNFSF ligand; TNF3 is a third extracellular domain of a TNFSF ligand; and L13-L60 are amino acid linkers.
The claims encompass a large number of antibodies having diverse heavy and light chain CDR amino acid sequences. Following a review of the specification, it appears that Applicant has disclosed 12 binding domains, specifically: MX169, MX170, MX306, MX318, MX368, MX369, MX424, MX425, MX485, MX487, MX620, and MX622. However in view of this disclosure, Applicant is claiming a broad genus of molecules that would be expected to encompass multiple binding domains having diverse heavy and light chain CDR sequences. Even though Applicant has disclosed twelve species within said genus, the specification does not provide adequate written description for the entire claimed genus, because one skilled in the art would be unable to immediately envision, recognize, or distinguish at least most of the members comprised within the genus claimed, specifically, which light and heavy chain CDR sequences (and combinations of said CDR sequences) give rise to antibody molecules. As detailed below Applicant’s disclosure is not sufficient to demonstrate possession of the entire claimed genus, and as such Applicant’s disclosure does not satisfy the written description requirement of 35 U.S.C. 112(a).
The written description requirement for a claimed genus may be satisfied through sufficient description of a representative number of species by actual reduction to practice, reduction to drawings, or 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. See Eli Lilly, 119 F.3d at 1568, 43 USPQ2d at 1406.
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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. In the instant case, Applicant has disclosed twelve species within the genus claimed; however given the substantial antibody structure variation within the genus, as well as the high level of unpredictability in the art, the disclosure of twelve species comprised within the claimed genus is not sufficiently representative of the entire genus.
Furthermore Applicant has not disclosed relevant, identifying characteristics of CDR region amino acid sequences (or combinations thereof) that confer upon an antibody the ability to bind an antigen, because the instant specification does not provide structural antibody features that correlate with a functional ability to bind an antigen. To elaborate on why the claimed antibodies lack adequate written description, Mariuzza (Annu. Rev. Biophys. Biophys. Chem., 16: 139-159, 1987) reviews the structural basis of antigen-antibody recognition and teach that naturally occurring conventional antibodies comprise two polypeptides, the so-called light and heavy chains. The antigen-combining site of an antibody is a three-dimensional structure that fully comprises six CDRs, three each from the light and heavy chains. The amino acid sequences of the CDRs are hypervariable, as the amino acid residues contained within the CDRs determine much of the antibody’s antigen-binding specificity. In view of Mariuzza, it is apparent that antibodies having less than all six CDRs that form the antigen binding site of a conventional antibody in their proper context of heavy and light chain variable domains do not describe the particularly identifying structural feature of the antibody that correlates with the antibody’s ability to bind antigen. Absent a description of the at least minimal structural features correlating with a functional ability to bind an antigen which are shared by members of a genus commonly sharing this function, it is submitted that the skilled artisan could not immediately envision, recognize, or distinguish which heavy and light chain CDR amino acid sequences (or combinations thereof) may be combined such that the resultant heavy and light chain variable regions comprise six CDRs that confer the ability to bind an antigen.
Furthermore while the prior art teaches some understanding of the structural basis of antigen-antibody recognition, it is noted that the art is characterized by a high level of unpredictability, since the skilled artisan still cannot accurately and reliably predict the consequences of amino acid substitutions, insertions, and deletions in the antigen-binding domains. For example in a series of experiments involving a monoclonal antibody to Legionella pneumophilia serotype 1, McCarthy et al. (J. Immunol. Methods, 251(1-2): 137-149, 2001) demonstrated that a single VH CDR3 substitution of tyrosine to serine at position 95 resulted in the total loss of antigen recognition in an ELISA. Lin et al. (African Journal of Biotechnology, 10(79):18294-18302, 2011) teach that a single amino acid substitution in the VL CDR3 of an anti-avian infectious bronchitis virus (IBV) single-chain antibody (ZL.80) may abrogate binding. For example at Figure 3, Lin et al. demonstrate that replacing either the Cys105 or Asp106 residue in the VL CDR3 of ZL.80 with an alanine residue reduces binding to near negative control levels. Lin et al. also teach that some single amino acid substitutions in the VL CDR3 of ZL.80 may significantly improve binding. For example replacing the Val108 residue in the VL CDR3 of ZL.80 with a tyrosine residue results in a 12.9-fold increase in affinity compared to parental ZL.80. Accordingly absent empirical determination, one skilled in the art would be unable to predict or envision which CDR residues of could be incorporated such that the resultant CDR residues form an antigen-binding site capable of binding an antigen. The general knowledge and level of skill in the art does not adequately supplement the omitted description, because specific, not general, guidance is needed. Since the disclosure fails to describe relevant, identifying structural characteristics, in the form of heavy and light chain CDR amino acid sequences, that correlate with the ability to bind an antigen, and because the twelve disclosed species detailed above are not sufficient to describe the claimed genus, it is submitted that the written description requirement of 35 U.S.C. 112(a) has not been met.
Although screening techniques can be used to isolate sets of six heavy and light chain CDRs that possess the ability to bind an antigen, Applicant is reminded that the written description requirement of 35 U.S.C. 112 is severable from the enablement provision. As stated in Vas-Cath Inc. v. Mahurkar (CA FC) 19 USPQ2d 1111, 935 F2d 1555, “The purpose of the ‘written description’ requirement is broader than to merely explain how to ‘make and use’; the applicant must also convey with reasonable clarity to those skilled in the art that, as of the filing date sought, he or she was in possession of the invention. The invention is, for purposes of the ‘written description’ inquiry, whatever is now claimed.”
Accordingly given the unpredictability associated with antibody CDR region changes on antigen binding and given the lack of particularity with which the claimed antibodies are described in the specification, it is submitted that the skilled artisan could not immediately envision, recognize, or distinguish at least most of the members of the genus to which the claims are directed, and therefore the specification would not reasonably convey to the skilled artisan that Applicant was in possession of the claimed invention at the time the application was filed.
Allowable Subject Matter
Claims 60-62 and 64-65 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
No claim is allowed.
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/J.K.D./Examiner, Art Unit 1642
/NELSON B MOSELEY II/Primary Examiner, Art Unit 1642