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 1-2, 7, 9, 11, 13, 15-21, 23-24, 30-31, 34, 41 and 50 are pending and under consideration.
Specification
The disclosure is objected to because of the following informalities: The specification filed 12/21/2023 is objected (see at least pages 37-47) for recitation of amino acid sequences in the absence of a sequence identifier. See 37 CFR 1.821(c). 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.
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 2 and 7 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.
The term “increased expression level” in claim 2 is a relative term which renders the claim indefinite. The term “increased expression level” is not defined by the claim and the specification does not provide a standard for ascertaining the requisite degree, and one of ordinary skill in the art would not be reasonably apprised of the scope of the invention.
Claim 7 is indefinite for requiring CDR sequences (CDR1, CDR2, and CDR3) without specifying the particular sequences associated with each CDR or the method by which they are meant to be determined (e.g. Chothia, Kabat, IGMT, etc.). The recited SEQ ID NO in the claim corresponds only to a variable domain, and it is unclear which subsequences thereof are intended to correspond to which CDR. As such, it is unclear what is intended to be encompassed by the claimed CDR sequences or how one is to determine the metes and bounds for CDR1, CDR2, and CDR3.
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 1-2, 9, 11, 13, 19-21, 23-24, 31, 34, 41, and 50 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. This is a written description rejection.
The rejected claims are broadly drawn to CD8α binding polypeptides comprising a variable domain (Claim 1) wherein the variable domain can have mutations (substitutions, deletions, or additions) compared to SEQ ID NO:1. According to the as-filed sequence listing, SEQ ID NO:1 is a VHH antibody (referred to as C37). Also see example 1 on page 36 of the specification. Thus, claims 1-2, 19-21, 23-24, 31, 41, and 50 comprise a genus of CD8α binding polypeptides with a structurally undefined variable domain. For example, there are no amino acid sequences defining the complementary determining regions (CDRs) of the variable domain. Regarding claims 9, 11, 13, and 34, such claims only define one complementary determining region to describe the variable region. Thus, the claims encompass a large genus of extremely diverse polypeptide variable domains that retain functional binding to CD8α with or without the added functions listed in Claim 2. The diversity is of high concern because the variable region of the claimed binding polypeptide comprises an extremely large genus of undefined complementary determining regions (CDRs). Moreover, the specification does not provide an adequate representative description for the entire claimed genus as one skilled in the art would be unable to envision, recognize, or distinguish which CDRs or mutations are comprised within the claimed generic structures. Thus, as further detailed below, applicant’s disclosure does not satisfy the written description requirement of 35 U.S.C. 112(a).
The specification teaches (page 11) that the term "CD8" (cluster of differentiation 8) refers to cell surface glycoproteins expressed primarily on cytotoxic T lymphocytes, and also on subsets of dendritic cells, natural killer cells, natural killer T cells, and γδ T cells. The glycoproteins are composed of two isoforms α and ß (which are encoded by different genes) and are expressed as αα homodimers or aß heterodimers, with the latter predominant. The specification further teaches (page 14) that the variable domain of an antibody has an “antigen binding site”, endowing the antibody with specificity to an antigen. The "variable domains" have the same general structure, and each domain comprises four framework regions (FRs) with highly conserved sequences. The variable domains also comprise the "complementarity-determining region 1" or "CDR1", the "complementarity- determining region 2" or "CDR2", and the "complementarity-determining region 3" or "CDR3" in which the FR is linked.
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. 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. However, given the substantial antibody structure variation within the genus, as well as the high level of unpredictability in the art, the disclosure of a few species comprised within the claimed genus is not sufficiently representative of the entire genus.
It is well established in the art that the formation of an intact antigen-binding site generally requires the association of the complete heavy and light chain variable regions of a given antibody (in this case, the three CDRs comprising the variable heavy domain), each of which consists of three CDRs which provide the majority of the contact residues for the binding of the antibody to its target epitope. The amino acid sequences and conformations of each of the heavy and light chain CDRs are critical in maintaining the antigen binding specificity and affinity which is characteristic of the parent immunoglobulin. For example, Vajdos et al. (J. Mol. Biol. 320, 415–428, 2002) teach that antigen binding is primarily mediated by the CDRs and that the more highly conserved framework segments which connect the CDRs are mainly involved in supporting the CDR loop conformations although in some cases framework residues also contact the antigen (page 416, left col.). Thus, even minor changes in the amino acid sequences of the heavy and light variable regions, particularly in the CDRs, may dramatically affect antigen-binding function. Further, Chiu et al. (Antibodies 2019 8(4);55, 1-80) taught the antigen binding of antibodies often results in conformational changes in the contact surface areas of both the antibody and the antigen (page 5, first paragraph). Thus, the prediction of CDR binding to the epitope is difficult to predict. Chiu further taught antibody modeling has been shown to be accurate for the framework region sequences, but CDR modeling requires further development and improvements (page 6, second paragraph). Prediction of the structure of HCDR3 could not be accurately produced when given the Fv structures without their CDR-H3s (page 6, second paragraph). Chiu taught the quality of antibody structure prediction, particularly regarding CDR-H3, remains inadequate, and the results of antibody–antigen docking are also disappointing (page 11, paragraph 2). Thus, in view of Vajdos et al. and Chiu et al., it is apparent that antibodies having less than all six CDRs (or less than 3 CDRs for a VHH) 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 at least minimal structural features correlating with a functional ability to bind an antigen which are shared by members of the genus, it is submitted that the skilled artisan could not envision, recognize, or distinguish the genus of possible CDR amino acid sequences (including possible mutations compared to SEQ ID NO:1) that may be formed into a VHH such that the resultant genus of binding proteins would confer the ability to bind CD8α.
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)(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.
Claim(s) 1-2, 19-21, 23-24, 41 and 50 are rejected under 35 U.S.C. 102(a)(2) as being anticipated by Koerber et al. (“Cd8 Binding Agents and Uses Thereof” US20230192853A1, filed 09/04/2019)
As to claim 1, Koerber et al. teach a CD8α binding polypeptide comprising a variable domain [0005], wherein an amino acid sequence of said variable domain has a substitution, a deletion, or an addition of an amino acid compared with an amino acid sequence as set forth in SEQ ID NO:1. For example, Koerber et al. teach [0013] a VHH CD8α binding polypeptide comprising the amino acids of SEQ ID NO:2. See alignment below: Compared to SEQ ID NO:1 (Qy) below, SEQ ID NO:2 (Db) has a substitution, addition or deletion of an amino acid sequence.
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As to claim 2, Koerber et al. teach [0011] that the CD8α binding polypeptide is capable of binding to a Protein A affinity chromatographic column.
As to claims 19-21, the alignment above shows that the prior art (Db) has a S60Y substitution. Claim 21 is interpreted as any ONE substitution selected from the group consisting of any of the substitutions listed as the “/” is not defined and could represent “and/or”.
As to claims 23-24, the alignment above shows that the prior art (Db) has an L2V substitution.
As to claim 41 and 50, Koerber et al. teach [0150] an immunoconjugate comprising the CD8α binding polypeptide and [0241] compositions.
Double Patenting
The nonstatutory double patenting rejection is based on a judicially created doctrine grounded in public policy (a policy reflected in the statute) so as to prevent the unjustified or improper timewise extension of the “right to exclude” granted by a patent and to prevent possible harassment by multiple assignees. A nonstatutory double patenting rejection is appropriate where the conflicting claims are not identical, but at least one examined application claim is not patentably distinct from the reference claim(s) because the examined application claim is either anticipated by, or would have been obvious over, the reference claim(s). See, e.g., In re Berg, 140 F.3d 1428, 46 USPQ2d 1226 (Fed. Cir. 1998); In re Goodman, 11 F.3d 1046, 29 USPQ2d 2010 (Fed. Cir. 1993); In re Longi, 759 F.2d 887, 225 USPQ 645 (Fed. Cir. 1985); In re Van Ornum, 686 F.2d 937, 214 USPQ 761 (CCPA 1982); In re Vogel, 422 F.2d 438, 164 USPQ 619 (CCPA 1970); In re Thorington, 418 F.2d 528, 163 USPQ 644 (CCPA 1969).
A timely filed terminal disclaimer in compliance with 37 CFR 1.321(c) or 1.321(d) may be used to overcome an actual or provisional rejection based on nonstatutory double patenting provided the reference application or patent either is shown to be commonly owned with the examined application, or claims an invention made as a result of activities undertaken within the scope of a joint research agreement. See MPEP § 717.02 for applications subject to examination under the first inventor to file provisions of the AIA as explained in MPEP § 2159. See MPEP § 2146 et seq. for applications not subject to examination under the first inventor to file provisions of the AIA . A terminal disclaimer must be signed in compliance with 37 CFR 1.321(b).
The filing of a terminal disclaimer by itself is not a complete reply to a nonstatutory double patenting (NSDP) rejection. A complete reply requires that the terminal disclaimer be accompanied by a reply requesting reconsideration of the prior Office action. Even where the NSDP rejection is provisional the reply must be complete. See MPEP § 804, subsection I.B.1. For a reply to a non-final Office action, see 37 CFR 1.111(a). For a reply to final Office action, see 37 CFR 1.113(c). A request for reconsideration while not provided for in 37 CFR 1.113(c) may be filed after final for consideration. See MPEP §§ 706.07(e) and 714.13.
The USPTO Internet website contains terminal disclaimer forms which may be used. Please visit www.uspto.gov/patent/patents-forms. The actual filing date of the application in which the form is filed determines what form (e.g., PTO/SB/25, PTO/SB/26, PTO/AIA /25, or PTO/AIA /26) should be used. A web-based eTerminal Disclaimer may be filled out completely online using web-screens. An eTerminal Disclaimer that meets all requirements is auto-processed and approved immediately upon submission. For more information about eTerminal Disclaimers, refer to www.uspto.gov/patents/apply/applying-online/eterminal-disclaimer.
Claims 1-2, 11, 13, 19, 23-24, 41, and 50 are provisionally rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1, 3, 5-7, and 10 of copending Application No. 18/017236 (reference application). Although the claims at issue are not identical, they are not patentably distinct from each other because the claimed CD8 binding proteins overlap in sequence identity.
This is a provisional nonstatutory double patenting rejection because the patentably indistinct claims have not in fact been patented.
Claim 1 of the current application is drawn to: A CD8α binding polypeptide, comprising at least one a variable domain, wherein an amino acid sequence of said variable domain has a substitution, a deletion or an addition of one or more an amino acids acid compared with an amino acid sequence as set forth in SEQ ID NO. 1.
Claim 1 of the reference application is drawn to a CD8 binding polypeptide comprising at least one immunoglobulin single variable domain capable of specifically binding to CD8a, the at least one immunoglobulin single variable domain comprises CDR1, CDR2 and CDR3 of any one of SEQ ID NOs: 5, 9, 13, 17, 21, 25, 29, 33, 37, 41, 45, 49, 53, 57, 61, 65, 69, 73, 77 and 81.
Claim 3 of the reference application is drawn to the CD8 binding polypeptide according to claim 1, wherein the immunoglobulin single variable domain comprises an amino acid sequence having at least 80%, preferably at least 90%, more preferably at least 95%, even more preferably at least 99% sequence identity to an amino acid sequence of one of SEQ ID NOs: 5, 9, 13, 17, 21, 25, 29, 33, 37, 41, 45, 49, 53, 57, 61, 65, 69, 73, 77 and 81.
Claim 5 of the reference application is drawn to the CD8 binding polypeptide according to claim l, wherein the immunoglobulin single variable domain is a VHH.
A below sequence comparison of the current application’s SEQ ID NO:1 (Qy) and the reference application’s SEQ ID NO:5 (Db) revealed 95.5% sequence identity:
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Although the claims are not identical, the claimed CD8 binding proteins overlap with each other such that one would anticipate the other. In this case, claim 1 of the current application anticipates SEQ ID NO:5 of the reference application. Further, both binding proteins are VHH. Further, SEQ ID NO:1 of the reference application contains an E at the 30th position which is substituted with a D in the reference application. Hence, an E30 substitution (reads on current Claim 19). Similarly, there is an L2V substitution which reads on current claims 23-24. Both sets of claims also include immunoconjugates. Further, the functional activities ascribed to the CD8 binding polypeptide in the current application’s Claim 2 are natural properties that would be inherent to the reference application’s CD8 binding molecule.
Regarding current claim 11, both sequences comprise a CDR2 sequence of “RIYDXX”- SEQ ID NO:23 in the current application.
Regarding current claim 13, both sequences comprise a CDR3 sequence of “GSYYSCSVYPXYDXDY” SEQ ID NO:27 in the current application.
Regarding nucleic acids encoding the CD8 binding protein and methods of making the binding protein, the nucleic acids are inherent to their encoded products and using them to make the proteins is routine in molecular biology.
Allowable Subject Matter
Claims 15-18 and 30 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.
Any inquiry concerning this communication or earlier communications from the examiner should be directed to GARY B NICKOL, Ph.D. whose telephone number is (571)272-0835. The examiner can normally be reached M-F 9AM-5:30PM.
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If attempts to reach the examiner by telephone are unsuccessful, the examiner’s supervisor, Julie Wu can be reached at 571-272-5205. The fax phone number for the organization where this application or proceeding is assigned is 571-273-8300.
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/GARY B NICKOL/Primary Examiner, Art Unit 1643
Prosecution Insights