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 .
Restriction/Election
Applicant’s election without traverse of Group I, drawn to an ISVD which specifically binds to a constant domain of a T cell receptor and corresponding to claims 1-3, 7, 9-10, 12, 14-15, 17-18, 21, 28-29, 33, and 40 in the reply filed 01/02/2026 is acknowledged.
Applicant has further elected examination of the following species:
3 CDRs: CDR1 is SEQ ID NO: 79; CDR2 is SEQ ID NO: 160 (wherein X1 of SEQ ID NO: 80 is E); and CDR3 is SEQ ID ON: 168 (wherein X2 SEQ ID NO: 81 is Y); and
Full ISVD sequence: SEQ ID NO: 37.
Claim Status
Claims 1-3, 7, 9-10, 12, 14-15, 17-18, 21, 28-29, 33, 36-37, 39-40, and 43 are pending. Claim 2 is withdrawn for being directed to a non-elected species as it does require the elected CDR2. Claims 36-37, 39, and 43 are withdrawn for being directed to non-elected inventions.
Claims 1, 3, 7, 9-10, 12, 14-15, 17-18, 21, 28-29, 33, and 40 are under examination.
Claim Rejections - 35 USC § 112(b)
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 3, 7, 10, 12, 14-15, 17-18, 21, 28, 33, and 40, 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.
Regarding claims 3, 7, 10, 15, 17-18, 21, 33, and 40, the phrase "optionally" renders the claim indefinite because it is unclear whether the limitation(s) following the phrase are part of the claimed invention. See MPEP § 2173.05(d).
Regarding claim 28, the phrase "essentially" renders the claim indefinite because it is unclear whether the limitation(s) following the phrase are part of the claimed invention. See MPEP § 2173.05(d).
Claims 10, 12, and 14 claim variable amino acids at positions 1 and 103 in the ISVD of claim 1 according to Kabat numbering. However, claim 1 discloses only the CDRs of the ISVD and does not provide the base structure from which the amino acid substitutions are occurring. The specification teaches mutations to the parental ISVD “T0170007000” set forth in SEQ ID NO:1, however, the base sequence of the parental ISVD is not provided in the claims.
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.
Claims 1-3, 7, 9-10, 14-15, 17-18, 21, 28-29, 33, and 40 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.
MPEP § 2163 states that 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, 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.
A “representative number of species” means that the species which are adequately described are representative of the entire genus. See, e.g., AbbVie Deutschland GMBH v. Janssen Biotech, 111 USPQ2d 1780, 1790 (Fed. Cir. 2014). Thus, when there is substantial variation within the genus, one must describe a sufficient variety of species to reflect the variation within the genus to provide a "representative number” of species. The “structural features common to the members of the genus” needed for one of skill in the art to ‘visualize or recognize’ the members of the genus takes into account the state of the art at the time of the invention.
The teachings of the specification and the claimed invention
In the instant case, the claim 1 is drawn to an ISVD which specifically binds to a constant domain of a human and/or non-human primate TCR, wherein the ISVD comprises any combination of disclosed CDRs in the context of four framework regions. CDR2 and CDR3 each have an amino acid position with 16 variations, resulting in 16 different CDR2 and CDR3 regions and 256 distinct ISVDs.
Claims 10 and 21 provide additional positions with variable amino acid identity, resulting an even larger genus of ISVs.
Importantly, each claimed ISVD variation has the required function of binding a constant domain of a human and/or non-human primate TCR.
The specification provides evidence that the applicants were in possession of a subset of the claimed ISVD, set forth for example, in Tables 1-3, Pgs. 77-80.
The state of the relevant art
Production of VHH with a particular binding specificity requires extensive experimentation as the current in silico optimization techniques have no direct comparison with conventional wet-lab approaches. (de Marco Protein Expr Purif. 2020 Aug;172:105645, Page 5, Section “In silico optimization”). Adding to the complexity of modeling VHH binding, de Marco adds that VHH do not possess a single highly uniform paratope shape, but rather paratopes may be built by combining a large spectrum of different 3D conformations that can also involve framework residues and confer several alternative surfaces for interacting with antigens (Page 5, Section “Conclusions”).
While ISVs are structurally distinct from “conventional,” four chain antibodies as found in humans, many principals of adaptive immunity are shared, and thus the knowledge in the art of conventional antibodies is also relevant to the claimed molecules. Muyldermans et al., Annu. Rev. Biochem. 2013. 82:775–97, (2013) teaches the use of an immunoglobulin fold comprising CDRs that contributes the majority of antigen binding residues supported by framework domains that contribute to both antigen binding residues and residues critical for the proper positioning of the CDRs, the use of recombination to produce CDR3 loops of diverse structure and length, and the presence of somatic hypermutation affinity maturation (for example, Pg. 783, Promiscious VH Genes Contribute to the VHH Repertoire).
Almagro et al. (Front. Immunol. 2018; 8:1751) teach that while affinity maturation techniques can result in differences in the CDRs of the antibody compared to its parental antibody (page 3 “The IgG Molecule, second and third paragraphs), those techniques involve trial-and-error testing and the changes that maintain or improve affinity are not predictable a priori. E.g., id., (page 6 ending paragraph onto page 7).
Pertaining to the structural basis of antigen-antibody recognition, it is aptly 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, the unpredictability of single amino acid changes in an antibody is underscored by Winkler (J Immunol. 2000 Oct 15;165(8):4505-14) who teaches that a single amino acid change in a CDR can result in unpredictable and substantial changes in antibody specificity; see entire document (e.g., the abstract).
Claim analysis
Based on the teachings of the specification and the state of the relevant art, the claims have the following written description issues:
Claim 1 is directed to 16 different CDR2 and 16 different CDR3, with the combinations resulting in 256 ISVD. The claim requires that each of the ISVD have the ability to bind a human and/or non-human primate TCR constant region. The specification has support for just a subset of these ISVD shown, for example in Tables 1-3 of the instant specification.
Claims 10, 14, and 21 introduce additional regions of amino acid variability, expanding the claimed ISVD genus.
The instant specification does not establish that the various species displayed in Tables 1-3 are representative of the genus of all ISVs that bind to the constant domain of the T cell receptor, wherein the molecule can be isolated from any experimental animal, such as a llama, immunized with any constant domain containing TCR in any context, e.g., expressed on the surface of a cell or as a soluble protein in solution, or wherein the molecule may be isolated via any in vitro / in silico method including, e.g., any library-based phage selection or ribosomal display, any molecular modeling effort etc., insofar as said molecule has the claimed TCR constant domain binding ability.
Since the disclosure fails to describe the common attributes or characteristics that identify members of the genus, and because the genus is highly variant, the artisan cannot envision the detailed structure of the encompassed antibodies and non-antibody proteins and therefore Applicant was not in possession of the instant claimed invention. See Regents of the University of California v. Eli Lilly and Co. 119 F.3d 1559, 43 USPQ2d 1398 (Fed. Cir. 1997). Adequate written description of genetic material “'requires a precise definition, such as by structure, formula, chemical name, or physical properties,' not a mere wish or plan for obtaining the claimed chemical invention.” Id. 43 USPQ2d at 1404 (quoting Fiers, 984 F.2d at 1171, 25 USPQ2d at 1606). The disclosure must allow one skilled in the art to visualize or recognize the identity of the subject matter of the claim. Id. 43 USPQ2d at 1406. A description of what the genetic material does, rather than of what it is, does not suffice. Id.
In general, absent at least the conserved structure provided by all three CDRs of a parental antibody in the context of appropriate VH and VL framework sequences, the skilled artisan generally would not be able to visualize or otherwise predict, a priori, what an antibody with a particular set of functional properties would look like structurally. One of skill in the art would neither expect nor predict the appropriate functioning of the antibodies as broadly as is claimed. There is no disclosure of a correlation between structure and function that would allow those of skill in the art to recognize other members of the claimed genus from the disclosure.
Claims 3, 7, 9, 15, 17-18, 28-29, 33, and 40 are rejected for being dependent on claim 1 and not providing limitations that overcome the written description rejection.
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, 3, 7, 9-10, 12, 14-15, 17-18, 21, 28-29, 33, and 40 are provisionally rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1-2, 4-9, 13, 17-18, 21, 25, 37-39, 41-42, 45, and 47 of copending Application No. 19/319,929 (reference application). Although the claims at issue are not identical, they are not patentably distinct from each other because the co-pending application discloses the ISVD of the instant application.
Regarding instant claims 1, 3, 7, 9, 10, 12, 14, 17, and 18, 21 pertaining to an ISVD which specifically binds to a constant domain of a human and/or non-human primate comprising CDR1 SEQ ID NO:79, CDR2 SEQ ID NO:160, and CDR3 SEQ ID NO: 168 and 85% sequence identity with SEQ ID NO:37, ‘929 claim 13 claims an ISVD SEQ ID NO:56, which comprises the instant claimed CDRs. The alignment with instant SEQ ID NO:37 with CDRs underlined is shown below:
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Instant SEQ ID NO:37, co-pending ‘929 SEQ ID NO:56:
Regarding instant claim 15, ‘929 claim 4 discloses the ISVD is a heavy-chain ISVD and claim 5 discloses the ISVD is selected from the group consisting of VHH, a humanized VHH, a camelized VH, a domain antibody, a single domain antibody, and a dAb.
Regarding instant claims 28, 29 and 33, pertaining to a first ISVD according to claim 1 and a second ISVD capable of binding an antigen on a target cell (claims 28 and 29) and further comprising a third ISVD, ‘929 claims a first (‘929 claim 1), second (‘929 claim 9), and third ISVD (‘929 claim 13), wherein the third ISVD is specific for a TCR constant domain.
Regarding instant claim 40, pertaining to a composition comprising the ISVD according to claim 1, ‘929 claim 42 claims a composition comprising the ISVD of the disclosure.
This is a provisional nonstatutory double patenting rejection because the patentably indistinct claims have not in fact been patented.
Conclusion
No claims are allowed.
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/CAROL ANN CHASE/Examiner, Art Unit 1646
/HONG SANG/Primary Examiner, Art Unit 1646