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 .
DETAILED ACTION
Status of the Clams
1. Two claim sets are filed for claims 1-43 on 4/24/2023. There are no apparent differences between the claim sets. In the Reply of 12/11/2023, Claims 1, 2, 5, 9, 11-14, 16-18, 23, 24, 27, 34, and 38-41 are amended, claims 3, 6-8, 10, 15, 19-22, 25, 26, 28-33, 35-37, 42, and 43 are canceled and new claims 44-46 are added.
Claims 1-2, 4-5, 9, 11-14, 16-18, 23-24, 27, 34, 38-41, and 44-46 are all the claims.
Priority
2. USAN 18/250,347, filed 04/24/2023, is a National Stage entry of PCT/ US2021/038086, International Filing Date: 06/18/2021, PCT/US2021/038086, Claims Priority from Provisional Application 63/106,329, filed 10/27/2020.
Election/Restrictions
3. Applicant’s election without traverse of species for Therapy or treatment” in the reply filed on 1/12/2026 is acknowledged.
4. Claimed species for prophylaxis (prevention) are withdrawn from further consideration pursuant to 37 CFR 1.142(b) as being drawn to a nonelected invention, there being no allowable generic or linking claim.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 1/12/2026.
5. Claims 1-2, 4-5, 9, 11-14, 16-18, 23-24, 27, 34, 38-41, and 44-46 are the pending claims.
Information Disclosure Statement
6. As of 3/13/2026, one (1) IDS is filed: 12/11/2023. The corresponding initialed and dated 1449 form is considered and of record.
Objections
Specification
7. The abstract of the disclosure is objected to because:
a) it contains both parenthetical text and exemplary language “(for example, T-cells)”. It is unclear if the phrase in intended subject matter of the invention or exemplary. A corrected abstract of the disclosure is required and must be presented on a separate sheet, apart from any other text. See MPEP § 608.01(b); and
b) it exceeds 150 words.
Applicant is reminded of the proper content of an abstract of the disclosure.
A patent abstract is a concise statement of the technical disclosure of the patent and should include that which is new in the art to which the invention pertains. The abstract should not refer to purported merits or speculative applications of the invention and should not compare the invention with the prior art.
If the patent is of a basic nature, the entire technical disclosure may be new in the art, and the abstract should be directed to the entire disclosure. If the patent is in the nature of an improvement in an old apparatus, process, product, or composition, the abstract should include the technical disclosure of the improvement. The abstract should also mention by way of example any preferred modifications or alternatives.
Where applicable, the abstract should include the following: (1) if a machine or apparatus, its organization and operation; (2) if an article, its method of making; (3) if a chemical compound, its identity and use; (4) if a mixture, its ingredients; (5) if a process, the steps.
Extensive mechanical and design details of an apparatus should not be included in the abstract. The abstract should be in narrative form and generally limited to a single paragraph within the range of 50 to 150 words in length.
See MPEP § 608.01(b) for guidelines for the preparation of patent abstracts.
8. The disclosure is objected to because of the following informalities:
a) The use of the term Biacore, DNASTAR, Megalign, RNeasy, GeneRacer, NORMOSOL, PLASMA-LITE, lipofectin, sonitron, NCBI, which is a trade name or a mark used in commerce, has been noted in this application. The term should be accompanied by the generic terminology; furthermore the term should be capitalized wherever it appears or, where appropriate, include a proper symbol indicating use in commerce such as ™, SM , or ® following the term.
Although the use of trade names and marks used in commerce (i.e., trademarks, service marks, certification marks, and collective marks) are permissible in patent applications, the proprietary nature of the marks should be respected and every effort made to prevent their use in any manner which might adversely affect their validity as commercial marks.
b) The specification refers to a peptide sequence > 4 amino acids in length: see [00162]
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. Pursuant to 37 CFR 1.821-1.825 the sequence identifier should be included.
c) The specification and sequence listing define SEQ ID NO:1 as residues NY-ESO-1:157-165 and SEQ ID NO: 28 as residues NY-ESO-1:157-167. The specification does not define the residues corresponding to the LAGE-1a protein that share identity with SEQ ID NOS: 1 and 28, respectively.
Appropriate correction is required.
Claim Objections
9. Claims 9, 12-13, 34 and 39 are objected to because of the following informalities:
a) Amend claim 9 to recite “wherein the immunoreactivity to the epitope of the sequence SLLMWITQC (SEQ ID NO: 1)...”
b) Claim 13 is inconsistent for the phrase “associated with a therapeutic agent” in depending from claim 12 “further comprising a detectable label.” A therapeutic agent is not related to a detectable label. The structural relationship of the agent being associated with a detectable label is unclear.
c) Claim 34 is unclear for the phrase “an epitope of an NY-ESO-1 and/or LAGE-1 a protein and/or with an epitope of a LAGE-1 a protein.” The LAGE-1 a protein is recited in duplicate.
d) Claim 39 recites “capable of inhibiting”. The phrase implies that some undefined structure or condition is what predicates whether inhibiting does or does not occur. Capacity and capability suggest that the inhibiting may sometimes occur but not always, and what determines the degree or amount of inhibition is indefinite.
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.
10. Claims 1-2, 4-5, 11-14, 16-18, 23-24, 27, 34, 38-41, and 44-46 are rejected under 35 U.S.C. 112(b) or 35 U.S.C. 112 (pre-AIA ), second paragraph, as being incomplete for omitting essential elements, such omission amounting to a gap between the elements. See MPEP § 2172.01. The omitted elements are: the immunoreactivity to the epitope SLLMWITQC (SEQ ID NO: 1) and/or SLLMWITQCFL (SEQ ID NO: 28) is (a) HLA-A2 restricted; and/or (b) HLA-A*0201 or HLA-A*0202 restricted. The specification defines immunoreactivity for the TCR invention as comprising binding an epitope in an HLA-restricted manner at:
[0046] The present invention provides T-cell receptors, as well as fragments and variants thereof, that bind to the NY-ESO-1 and/or the LAGE-1a antigens expressed on the surface of cancer cells in an HLA-restricted manner. An exemplary T-cell receptor of the invention is immunoreactive with the NY-ESO-1 and/or LAGE-1a epitope SLLMWITQC (SEQ ID NO: 1) and/or SLLMWITQCFL (SEQ ID NO: 28). The binding can be in association with recognition of HLA-A2 restricted antigens. For example, the binding can be restricted to HLA-A*0201, HLA-A*0202 or potentially other HLA-A2 subtype-expressing cells. The expression of NY-ESO-1 and/or LAGE-1a on the surface of cancer cells provides a target for specific binding of the T-cell receptor, as well as fragments and variants thereof, to the surface of cancer cells. As used herein, the term “immunoreactive” is understood to mean that a T-cell receptor, for example, a T-cell receptor of the invention, as well as fragments and variants thereof, can bind specifically to an epitope present in an antigen, for example, an NY-ESO-1 antigen or a LAGE-1a antigen, optionally in a MHC-restrictive manner.
[0062] Furthermore, in certain embodiments of the foregoing aspects, the T-cell receptor is immunoreactive with the epitope SLLMWITQC (SEQ ID NO: 1) and/or SLLMWITQCFL (SEQ ID NO: 28) in an HLA-A2 restricted manner. For example, the immunoreactivity to the epitope SLLMWITQC (SEQ ID NO: 1) and/or SLLMWITQCFL (SEQ ID NO: 28) can be (i) HLA-A*0201 or (ii) HLA-A*0202 restricted. The T-cell receptor may potentially be restricted by other HLA-A2 subtypes, and other HLA class I molecules.
HLA-restricted binding to epitopes is art-recognized as taught in (Wong et al (Front. Immunol. 10:2454 (2019)).
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.
Written Description
11. Claims 1-2, 4-5, 9, 11-14, 16-18, 23-24, 27, 34, 38-41 and 44-46 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.
Claim interpretation
Claim(s) 1(iii)-(v), 16 drawn to a recombinant a-chain of a T-cell receptor immunoreactive with an epitope of a NY-ESO-1 and/or LAGE-la protein comprising the amino acid sequence SLLMWITQC (SEQ ID NO: 1) and/or SLLMWITQCFL (SEQ ID NO: 28), wherein the a-chain comprises one or more of the following amino acid sequences: (iii) an a-chain CDR3 amino acid sequence of SEQ ID NO: 7; (iv) an a-chain CDRI amino acid sequence of SEQ ID NO: 5; and (v) an a-chain CDR2 amino acid sequence of SEQ ID NO: 6.
Claim(s) 2(iii)-(v), 17 drawn to a recombinant b-chain of a T-cell receptor immunoreactive with an epitope of a NY-ESO-1 and/or LAGE-1a protein comprising the amino acid sequence SLLMWITQC (SEQ ID NO: 1) and/or SLLMWITQCFL (SEQ ID NO: 28), where the b-chain comprises one or more of the following amino acid sequences: (iii) a b-chain CDR3 amino acid sequence of SEQ ID NO: 13; a b-chain CDR1 amino acid sequence of SEQ ID NO: 11; and (v) a b-chain CDR2 amino acid sequence of SEQ ID NO: 12.
Claim(s) 4-5, 9, 11-14, 18, 23-24, 27, 34, and 38-41 drawn to isolated, recombinant T-cell receptor immunoreactive with an epitope of a NY-ESO-1 and/or LAGE-la protein comprising the amino acid sequence SLLMWITQC (SEQ ID NO: 1) and/or SLLMWITQCFL (SEQ ID NO: 28), the T-cell receptor comprising an a-chain and a b-chain, the a and b chains each comprising a CDR1, CDR2, and a CDR3, wherein the a- chain CDR3 comprises the amino acid sequence of SEQ ID NO: 7, and the b-chain CDR3 comprises the amino acid sequence of SEQ ID NO: 13.
Here, the language in claims 1-2, 4-5, 9, 11-14, 16-18, 23-24, 27, 34, and 38-41 requires single CDR domains to recognize and bind to a NY-ESO-1 and/or LAGE-la protein comprising the amino acid sequence SLLMWITQC (SEQ ID NO: 1) and/or SLLMWITQCFL (SEQ ID NO: 28).
Here the language in claims 39-41 require the method to be performed using an engineered T cell expressing the a-chain and b-chain according to claim 4 where in addition the T-cell is required to: inhibit the growth of cancer cells expressing an NY-ESO-1 and/or LAGE-1a protein (claim 39); and treat any cancer in a subject (claims 40-41).
“immunoreactive”: the meaning of the term is defined and inferred throughout the specification as binding in an HLA-restricted manner:
[0046] The present invention provides T-cell receptors, as well as fragments and variants thereof, that bind to the NY-ESO-1 and/or the LAGE-1a antigens expressed on the surface of cancer cells in an HLA-restricted manner. An exemplary T-cell receptor of the invention is immunoreactive with the NY-ESO-1 and/or LAGE-1a epitope SLLMWITQC (SEQ ID NO: 1) and/or SLLMWITQCFL (SEQ ID NO: 28). The binding can be in association with recognition of HLA-A2 restricted antigens. For example, the binding can be restricted to HLA-A*0201, HLA-A*0202 or potentially other HLA-A2 subtype-expressing cells. The expression of NY-ESO-1 and/or LAGE-1a on the surface of cancer cells provides a target for specific binding of the T-cell receptor, as well as fragments and variants thereof, to the surface of cancer cells. As used herein, the term “immunoreactive” is understood to mean that a T-cell receptor, for example, a T-cell receptor of the invention, as well as fragments and variants thereof, can bind specifically to an epitope present in an antigen, for example, an NY-ESO-1 antigen or a LAGE-1a antigen, optionally in a MHC-restrictive manner.
[0062] Furthermore, in certain embodiments of the foregoing aspects, the T-cell receptor is immunoreactive with the epitope SLLMWITQC (SEQ ID NO: 1) and/or SLLMWITQCFL (SEQ ID NO: 28) in an HLA-A2 restricted manner. For example, the immunoreactivity to the epitope SLLMWITQC (SEQ ID NO: 1) and/or SLLMWITQCFL (SEQ ID NO: 28) can be (i) HLA-A*0201 or (ii) HLA-A*0202 restricted. The T-cell receptor may potentially be restricted by other HLA-A2 subtypes, and other HLA class I molecules.
Here, but for claim 9, is there no indication in any of the claims that the immunoreactivity not only requires binding to the epitope but that it is HLA-restricted.
Because applicant seeks patent protection for all such anti-NY-ESO-1 epitope +/- anti-LAGE-1a epitope TCR, this genus must be adequately described. A description adequate to satisfy 35 U.S.C. § 112(a) must clearly allow persons of ordinary skill in the art to recognize that the inventor invented what is claimed (Ariad Pharms., Inc. v. Eli Lilly & Co., 598 F.3d 1336, 1351 (Fed. Cir. 2010) (en banc) (citation omitted, alteration in original). The purpose of the written description requirement is to “ensure that the scope of the right to exclude, as set forth in the claims, does not overreach the scope of the inventor’s contribution to the field of art as described in the patent’s specification” (In re Katz Interactive Call Processing Patent Litig. 639 F.3d 1303, 1319 (Fed. Cir 2011).
Scope of the claimed genus
For purposes of clarity, and pursuant to Official Notice under MPEP 2144.03, the analysis of the claims is set forth as follows: T-cell Receptor (TCR) Complementarity-Determining Regions (CDRs) functionally correspond to Antibody CDRs as they both act as the main antigen-recognition sites consisting of six loop motifs, but they structurally differ in length, conformation, and binding properties, occupying distinct structural spaces. Insofar as binding differences, antibody CDRs (especially HCDR3) adapt to bind diverse shapes, while TCR CDRs (specifically CDR3α/CDR3β) are specialized for binding MHC-presented peptides. (Wong et al (Front. Immunol. 10:2454 (2019)). Accordingly, the analysis is analogized to the state of the art for antibody CDRs to advance prosecution on the merits.
State of the Relevant Art
Here, and absent to the contrary, the formation of complete a-chain and b-chain CDR1-3 for a TcR is analogized to the chains for antibody.
Methods of preparing antibodies from a variety of species to a protein or peptide of interest were well-established in the art at the time the invention was made. But application of those methods to any given antibody was still a matter of trial-and-error testing, and the skilled person could not automatically predict which residues in the CDRs would be tolerant of mutations, or which amino acid substitutions would maintain antigen binding. Overall, at the time the invention was made, the level of skill for preparing antibodies and then selecting those antibodies with desired functional properties was high. For example, it is generally the case that absent the fundamental structure provided for by all six CDRs of a parental antibody in the context of appropriate VH and VL framework sequences, a person of ordinary skill cannot visualize or otherwise predict, what an antibody with a particular set of functional properties would look like structurally.
Moreover, persons of ordinary skill in the art have long since acknowledged that even minor changes in the amino acid sequences of the VH and VL, particularly in the CDRs, may dramatically affect antigen-binding function. Moreover, persons of ordinary skill in the art have long since acknowledged that even minor changes in the amino acid sequences of the VH and VL, particularly in the CDRs, may dramatically affect antigen-binding function. Lippow, for example, teaches that a single point mutation in the CDR of a parent antibody led to as much as an eightfold improvement in binding affinity in the resulting mutant (p. 1172, left col., lines 7-8 from end of first full paragraph and Table 1a) (Lippow et al., “Computational design of antibody-affinity improvement beyond in vivo maturation,” Nature Biotechnology, 25(10):1171-1176 (2007) (PTO-892).
Sulea teaches that individual point mutations gave an improvement of one order of magnitude in binding affinity, which in turn, generated a 6-fold enhancement of efficacy at the cellular level (Abstract) (Sulea et al., “Application of Assisted Design of Antibody and Protein Therapeutics (ADAPT) improves efficacy of a Clostridium difficile toxin A single-domain antibody," Scientific Reports, 8(260):1-11 (2018) (PTO-892). Hasegawa et al. reports that a single amino acid substitution in the variable region was sufficient to alter the efficiency of biosynthesis and the variant antibody acquired stronger binding affinity to its antigen than the parent (Hasegawa et al., “Single amino acid substitution in LC-CDR1 induces Russell body phenotype that attenuates cellular protein synthesis through elF2a phosphorylation and thereby downregulates IgG secretion despite operational secretory pathway traffic,” MABS, VOL. 9, NO. 5, pp. 854-873 (2017) (PTO-892)). Altshuler teaches that generally, “CDR mutations should not involve residues that can play structural functions (form parts of the domain ‘internal core’, internal salt bridges, hydrogen bonds, etc.).” “Usually these are conservative residues, and any substitution of these residues causes decrease[s] in affinity” (Altshuler et al., “Generation of Recombinant Antibodies and Means for Increasing Their Affinity,” Biochemistry (Moscow), 75(13):1584-1605 (2010) at p. 1600, col. 1, para. 2, lines 1-5 (PTO-892). Accordingly, a person of ordinary skill in the art would have recognized that it was highly unpredictable that any of the CDRs or FRs could be modified to create an unlimited change in amino acids for both the CDRs and FRs of the claimed antibodies, without increasing, eliminating, or in some way altering antigen binding.
Summary of species disclosed in the specification
Applicant’s specification fully discloses a clone 806TCR and mutations shown in Example 4, and the display of its functions in Examples 1-5. The in vitro cell-killing effect on a cancer cell is depicted in Example 5. No data are shown for cancer cell killing in vivo following administration of an engineered TC to the subject.
Are the disclosed species representative of the claimed genus?
It is asserted that the specification shows nothing less than full length a-chain variable domains and b-chain variable domains. The specification discloses no example of a single CDR domain functioning in the capacity of TCR required of the instant claims.
Has Applicant provided a common structure sufficient to visualize the genus?
As recently as 2020, researches were still speculating as to how to reliably identify further putative binders from antibody sequence data, see, e.g., Marks et al., “How repertoire data are changing antibody science,” J. Biol. Chem. 295(29) 9823-9837 (2020 (PTO 892)), acknowledging that “there is a vast amount of the antibody sequence space that remains unknown,” p. 9831, col. 2, para. 2.
Computational and machine learning approaches for sequence-based prediction of paratope-epitope interactions are accumulating, but “it remains unclear whether antibody-antigen binding is predictable” (Akbar et al., Cell Reports 34, 108856, Mar. 16, 2021 at p. 2, col. 2, para. 2 (PTO 892)). The current state of the art continues to work toward finding an effective and efficient prediction tool for reliably assigning antibody structure based on known target epitopes. See e.g., Lo et al., “Conformational epitope matching and prediction based on protein surface spiral features,” BMC Genomics volume 22, Article number: 116 (2021 (PTO 892)) (disclosing new algorithms that calculate physicochemical properties, such as polarity, charge or the secondary structure of residues within the targeted protein sequences, and then applying quantitative matrix analyses or machine-learning algorithms to predict linear and conformational epitopes).
It is asserted that neither the specification nor the state of art at the time of filing disclosed structural features common to the members of the genus for reliably assigning different TCR structures based on the limited sequence data for 806TCR and disclosed variants thereof much less those not defined by HLA-restriction, which would support the premise that the inventors possessed the full scope of the claimed invention.
Conclusion
12. No claims are allowed.
13. The search of amino acid sequences in commercial and interference databases shows the following sequences to be free from the art: LINKED SEQ ID NO: 5-6-7; 11-12-13; and SEQ ID NOs. 2-3, 9, 37, 39, 83, 85, 87, 95 and 99.
14. Any inquiry concerning this communication or earlier communications from the examiner should be directed to LYNN A. BRISTOL whose telephone number is (571)272-6883. The examiner can normally be reached Mon-Fri 9 AM-5 PM.
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If attempts to reach the examiner by telephone are unsuccessful, the examiner’s supervisor, Wu Julie 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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LYNN ANNE BRISTOL
Primary Examiner
Art Unit 1643
/LYNN A BRISTOL/Primary Examiner, Art Unit 1643