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 .
Continued Examination Under 37 CFR 1.114
A request for continued examination under 37 CFR 1.114, including the fee set forth in 37 CFR 1.17(e), was filed in this application after final rejection. Since this application is eligible for continued examination under 37 CFR 1.114, and the fee set forth in 37 CFR 1.17(e) has been timely paid, the finality of the previous Office action has been withdrawn pursuant to 37 CFR 1.114. Applicant's submission filed on 4/01/2026 has been entered.
Applicant’s amendment, filed on 4/01/2026, is acknowledged.
Claims 1-44, 46-48, and 100 are cancelled.
Claims 45 and 49-102 are currently pending.
After consideration, the search and examination has been extended to the unelected Species of invention.
Claims 82-84, 87-91, 97-99 are withdrawn from further consideration pursuant to 37 CFR 1.142(b), as being drawn to nonelected inventions. Please note that the inventions of Groups II and IV (i.e., claims 82-84, 97-91, and 97-99) are not eligible for rejoinder because these inventive Groups do not have unity of invention with the invention of Groups I and III, as stated in the Restriction Requirement mailed on 4/18/2025.
Claims 45, 49-81, 85, 86, 92-96, 101, and 102 are under examination as reading on a protein comprising a TCR Cα and Cß domains with the point mutations recited in claim 45.
Nucleotide and/or Amino Acid Sequence Disclosures
REQUIREMENTS FOR PATENT APPLICATIONS CONTAINING NUCLEOTIDE AND/OR AMINO ACID SEQUENCE DISCLOSURES
Items 1) and 2) provide general guidance related to requirements for sequence disclosures.
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. This "Sequence Listing" part of the disclosure may be submitted:
In accordance with 37 CFR 1.821(c)(1) via the USPTO patent electronic filing system (see Section I.1 of the Legal Framework for Patent Electronic System (https://www.uspto.gov/PatentLegalFramework), hereinafter "Legal Framework") as an ASCII text file, together with an incorporation-by-reference of the material in the ASCII text file in a separate paragraph of the specification as required by 37 CFR 1.823(b)(1) identifying:
the name of the ASCII text file;
ii) the date of creation; and
iii) the size of the ASCII text file in bytes;
In accordance with 37 CFR 1.821(c)(1) on read-only optical disc(s) as permitted by 37 CFR 1.52(e)(1)(ii), labeled according to 37 CFR 1.52(e)(5), with an incorporation-by-reference of the material in the ASCII text file according to 37 CFR 1.52(e)(8) and 37 CFR 1.823(b)(1) in a separate paragraph of the specification identifying:
the name of the ASCII text file;
the date of creation; and
the size of the ASCII text file in bytes;
In accordance with 37 CFR 1.821(c)(2) via the USPTO patent electronic filing system as a PDF file (not recommended); or
In accordance with 37 CFR 1.821(c)(3) on physical sheets of paper (not recommended).
When a “Sequence Listing” has been submitted as a PDF file as in 1(c) above (37 CFR 1.821(c)(2)) or on physical sheets of paper as in 1(d) above (37 CFR 1.821(c)(3)), 37 CFR 1.821(e)(1) requires a computer readable form (CRF) of the “Sequence Listing” in accordance with the requirements of 37 CFR 1.824.
If the "Sequence Listing" required by 37 CFR 1.821(c) is filed via the USPTO patent electronic filing system as a PDF, then 37 CFR 1.821(e)(1)(ii) or 1.821(e)(2)(ii) requires submission of a statement that the "Sequence Listing" content of the PDF copy and the CRF copy (the ASCII text file copy) are identical.
If the "Sequence Listing" required by 37 CFR 1.821(c) is filed on paper or read-only optical disc, then 37 CFR 1.821(e)(1)(ii) or 1.821(e)(2)(ii) requires submission of a statement that the "Sequence Listing" content of the paper or read-only optical disc copy and the CRF are identical.
Specific deficiencies and the required response to this Office Action are as follows:
Specific deficiency – Nucleotide and/or amino acid sequences appearing in the specification are not identified by sequence identifiers in accordance with 37 CFR 1.821(d).
Specifically, an amino acid sequence is disclosed on pg. 45, line 5 without the corresponding sequence identifier.
Required response – Applicant must provide:
A substitute specification in compliance with 37 CFR 1.52, 1.121(b)(3) and 1.125 inserting the required sequence identifiers, consisting of:
A copy of the previously-submitted specification, with deletions shown with strikethrough or brackets and insertions shown with underlining (marked-up version);
A copy of the amended specification without markings (clean version); and
A statement that the substitute specification contains no new matter.
Specification
The disclosure is objected to because it contains an embedded hyperlink and/or other form of browser-executable code. Specifically, an embedded hyperlink is disclosed on pg. 46, line 11. Applicant is required to delete the embedded hyperlink and/or other form of browser-executable code; references to websites should be limited to the top-level domain name without any prefix such as http:// or other browser-executable code. See MPEP § 608.01.
The use of the terms:
EpiMatrix® (pg, 26, lines 5, 10, 11; pg. 27, lines 2, 6);
ImmTAC® (pg. 32, line 7; pg. 34, line 2);
gBlocks™ (pg. 36, line 24; pg. 37, line 15);
In-Fusion (pg. 36, lines 25-26);
Octet® (pg. 37, line 25);
ÄKTA pure™ (pg. 37, line 37);
Vivaspin® (pg. 38, line 8);
LightCycler® (pg. 38, lines 15, 25);
SYPRO™ (pg. 38, lines 16, 19, 21);
SpectraMax® (pg. 44, line 24);
CellTiter-Glo® (pg. 45, line 12);
Accutase™ (pg. 45, line 22); and
AffiniPure® (pg. 46, line 3);
which are trade names or marks 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.
Claim Objections
Claims 51-81 and 92-96 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.
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 45, 49, 50, and 101 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 inventors, at the time the application was filed, had possession of the claimed invention.
Claims 45, 49, and 50 encompass a genus of TCR Cα domains with the S139F, T150I, and A190T point mutations and Cß domains with the E134K, H139R, D155P, and S170E point mutations, all according to Kabat numbering (claim 45), further comprising an interchain disulfide bond (claim 49), and further comprising point mutations to C at the Cα position 166 and Cß position 173, according to Kabat numbering (claim 46), all with the recited function “higher unfolding temperature (Tm)”. The genera encompasses TCR Cα and Cß sequences from any species and not just human TCR constant domain sequences with the recited point mutations.
Claim 101 encompasses a method of stabilizing a TCR comprising inserting at least one amino acid substitution in the Cα domain selected from S139F, T150I, and A190T; and/or inserting at least one amino acid substitution into the Cß domain selected from E134K, H139R, D155P, and S170E, wherein the stabilized TCR has at least one superior property selected from higher Tm, increased stability, increased expression level, improved assembly, or reduced glycosylation when compared to the same domains lacking said mutation(s).
Regarding the genera of TCR Cα and Cß domains (claims 45, 49, 50, and 101),
The specification fails to provide adequate written description support for a genus of TCR Cα and Cß domains with the recited point mutations according to Kabat numbering from any species and not only human TCRs that lead to the function of “higher unfolding Tm”.
The claims are not supported by a description that satisfies 35 U.S.C. § 112(a) or 35 U.S.C. § 112, first paragraph. "[T]he test for sufficiency [of the written description] is whether the disclosure of the application relied upon reasonably conveys to those skilled in the art that the inventor had possession of the claimed subject matter as of the filing date." Ariad Phanns., Inc. v. Eli Lilly & Co., 598 F.3d 1336, 1351 (Fed. Cir. 2010) (en bane).
A "sufficient description of a genus ... requires the disclosure of either a representative number of species falling within the scope of the genus or structural features common to the members of the genus so that one of skill in the art can 'visualize or recognize' the members of the genus." Id. at 1350. "[A]n adequate written description requires a precise definition, such as by structure, formula, chemical name, physical properties, or other properties, of species falling within the genus sufficient to distinguish the genus from other materials." Id.
"[F]unctional claim language can meet the written description requirement when the art has established a correlation between structure and function." Id. "But merely drawing a fence around the outer limits of a purported genus is not an adequate substitute for describing a variety of materials constituting the genus and showing that one has invented a genus and not just a species." Id.
"A sufficient description of a genus ... requires the disclosure of either a representative number of species falling within the scope of the genus or structural features common to the members of the genus so that one of skill in the art can "visualize or recognize" the members of the genus" (AbbVie, 759 F.3d at 1297, reiterating Eli Lilly, 119 F.3d at 1568-69) (emphasis added).
The specification discloses point mutations in TCR Cα and Cβ regions that increase thermal stability by increasing the temperature of unfolding (Tm) for the constant domains, leading to more stable TCR constant domains and increased expression (pg. 3, lines 12-20).
The specification further discloses screening Cα and Cβ point mutations to find specific variants that have increased stability/Tm (pg. 22, lines 15-25). Seven stabilizing mutations were chosen to introduce into the wild-type TCR α and β constant regions (instant SEQ ID NO: 1 and 2) with and without known point mutations to introduce a disulfide bond between the constant regions to generate TCR Cα and Cβ regions that are more thermally stable than the wild-type counterparts (Fig. 1B and 1C, Tables 1 and 2, SEQ ID NO: 5-8). Mutants with decreased stability/Tm were also found (Table 1). No other amino acid positions were altered in these mutants to test for changes in Tm or if the function of “higher unfolding temperature” would be retained when these other positions were substituted with different amino acid residues.
Notably, all of these mutants were generated from the IG4_122 constant domain soluble TCR (pg. 36, lines 23-27): “NY-ESO-1 1G4_122 soluble TCR, and the individual NY-ESO-1 Va/Vß and Ca/Cß…and subcloned into mammalian expression vectors…” Fig. 2 discloses the sequence of the IG4_122 constant domain sequence, along with the Kabat numbering positions and introduced point mutations to increase Tm. The specification discloses that the sequence of IG4_122 Cα and Cß of SEQ ID NO: 3 and 4, respectively (pg. 17, lines 15-20). These point mutations were not tested with other constant region from different species, such as mouse.
With respect to representative number of species, see AbbVie Deutschland GmbH & Co. v. Janssen Biotech, Inc. (Fed. Cir. 2014). Also, see MPEP 2163 Il(A)(3)(a))(ii):
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. 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. See Abb Vie Deutschland GmbH & Co., KG v. Janssen Biotech, Inc., 759 F.3d 1285, 1300, 111 USPQ2d 1780, 1790 (Fed. Cir. 2014) (Claims directed to a functionally defined genus of antibodies were not supported by a disclosure that "only describe[d] one type of structurally similar antibodies" that "are not representative of the full variety or scope of the genus.").
Satisfactory disclosure of a "representative number" depends on whether one of skill in the art would recognize that the applicant was in possession of the necessary common attributes or features possessed by the members of the genus in view of the species disclosed. For inventions in an unpredictable art, adequate written description of a genus which embraces widely variant species cannot be achieved by disclosing only one species within the genus. See, e.g., Eli Lilly, 119 F.3d at 1568, 43 USPQ2d at 1406. Instead, the disclosure must adequately reflect the structural diversity of the claimed genus, either through the disclosure of sufficient species that are "representative of the full variety or scope of the genus," or by the establishment of "a reasonable structure-function correlation." Such correlations may be established "by the inventor as described in the specification," or they may be "known in the art at the time of the filing date." See AbbVie, 759 F.3d at 1300-01, 111 USPQ2d 1780, 1790-91 (Fed. Cir. 2014) (Holding that claims to all human antibodies that bind IL-12 with a particular binding affinity rate constant (i.e., koff) were not adequately supported by a specification describing only a single type of human antibody having the claimed features because the disclosed antibody was not representative of other types of antibodies in the claimed genus, as demonstrated by the fact that other disclosed antibodies had different types of heavy and light chains, and shared only a 50% sequence similarity in their variable regions with the disclosed antibodies.).
In the instant case, the one example of a human TCR with the claimed point mutations to increase Tm does not adequately represent TCRs from other species with these point mutations, such as from mouse, that have these mutations. For example, the amino acid sequence of the mouse TCR Cα region shares little sequence identity with the human TCR Cα disclosed with the mutations that increase Tm (the residues that correspond arrows pointing to residue positions to be altered to increase Tm; top sequence is instant SEQ ID NO: 3 and bottom is the sequence from mouse TRAC PDB entry P01849):
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Note that the mouse TCR Cα sequence does not have the wild-type residues recited in instant claim 45 (i.e., “serine at position 139, threonine at position 150, and alanine at position 190”), and the instant specification does not disclose any examples of engineering TCR constant regions to contain amino acid residues at specific positions which are then mutated to increase the Tm. The instant specification only discloses alterations to a wild-type human TCR sequence to increase Tm.
Moreover, there is insufficient written description of the required kind of structure-identifying information about the corresponding makeup of the claimed antigen binding constructs to demonstrate possession. Also, see Amgen Inc. v. Sanofi, Aventisub LLC, No. 2017-1480 (Fed. Cir. 2017). The Court reiterated that adequate written description must “contain enough information about the actual makeup of the claimed products . . . .” The Court simultaneously suggested that the “newly characterized antigen” test “flouts” section 112 because it “allows patentees to claim antibodies by describing something that is not the invention, i.e., the antigen.” The Court concluded that for written description of an antibody to be adequate when presented with “functional” terminology, there must be an established correlation in the art between structure and function.
Given the broadly claimed class of TCR constant regions from any species with the recited amino acid mutations and the function of “higher Tm”, and in the absence of sufficient disclosure of relevant identifying characteristics for the broadly claimed classes of TCR constant regions from any species, the patentee must establish “a reasonable structure-function correlation” either within the specification or by reference to the knowledge of one skilled in the art with functional claims. AbbVie Deutschland GmbH & Co. v. Janssen Biotech, Inc. (Fed. Cir. 2014), MPEP 2163.
Neither the instant specification nor the prior art provides sufficient guidance to take TCR constant domain sequences from other species, such as mouse (see supra), and first altering the amino acid sequences at the particular positions indicated first to serine at position 139, threonine at position 150, and alanine at position 190, and then substituting these residues again with the indicated amino acids recited in claim 45, would lead to a higher Tm for that TCR sequence. The specification only discloses substituting the recited amino acids into wild-type human TCR constant regions.
Amending the claims 45 and 101 to recite human TCR constant domains, instead of generic TCR constant domains from any organism, would resolve this issue.
Additionally, regarding the claimed method of stabilizing TCRs comprising substituting at least one of the recited amino acids into the Cα and/or Cß domains (claim 101), the recitation of “and/or” when referring to the TCR Cα and Cβ domains without the recited mutations in the claim leaves the claim without adequate written description support for the function of “stabilizing a TCR”, or any of the other recited functions in instant claim 101.
For example, the instant claim encompasses methods of introducing a genus of TCR Cα and Cβ domains with the mutations recited in claim 101 that are stabilized when compared to an identical Cα domain and a Cβ domain without the recited mutations, as well as methods of stabilizing a genus TCR Cα and Cβ domains with the all of mutations recited in the claims when compared to a Cα without the recited mutations and an identical Cβ.
The instant specification discloses Tm of different TCRs with mutated residues with either all seven of the mutations recited in instant claim 101, or only four mutations, in Table 2. Nowhere in the instant specification is there adequate support demonstrating that a TCR with all of the Cα and Cβ mutations recited in the claim would have a higher melting temperature over a TCR with the recited mutations in either only the Cα or the Cβ domains. Instant table 2 demonstrates that an NY-ESO-1 TCR with only four mutants (Cα with T150I and A190T and a Cβ with E134K and H139R) does not have a lower Tm that the same TCR with all seven recited mutations (Table 2 cropped below):
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The 28820s2 mutant has a higher Tm than the 30754s1 mutant (i.e., 59.7 vs 59.5 C), and the average Tm of these two mutants is identical (62.35 C). However, the TCRs with 7 mutations has a higher Tm than a TCR without any of the mutations.
Absent any teaching or structure-function relationships, the skilled in the art cannot determine if a TCR with all of the mutations recited in claims 45, 49, and 50 would have the function of “higher melting temperature (Tm)” when compared to a TCR with all of the recited mutations in only the Cα or the Cβ domains.
Amending instant claim 101 to recite “and” in place of “and/or”, as well as removing the “at least one” language from the amino acid substitutions would resolve this issue.
Possession is not be shown by merely describing how to obtain possession of members of the claimed genus or how to identify their common structural features. See University of Rochester, 358 F.3d at 927, 69 USPQ2d at 1895. Sufficient description to show possession of such a genus may be achieved by means of a recitation of a representative number of anti-TMPRSS6 antibodies or antigen binding fragments thereof falling within the scope of the genus or of a recitation of structural features common to members of the genus, which features constitute a substantial portion of the genus. See Eli Lilly, 119F.3d at 1568, 43 USPQ2d at 1406.
Claims 45, 49, 50, and 101 do not meet the requirements of 35 U.S.C. 112(a) for written description.
Vas-Cath Inc. v. Mahurkar, 19 USPQ2d 1111, makes clear that "applicant must 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." (See page 1117.) The specification does not "clearly allow persons of ordinary skill in the art to recognize that [he or she] invented what is claimed." (See Vas-Cath at page 1116.). Consequently, Applicant was not in possession of the instant claimed invention. See University of California v. Eli Lilly and Co. 43 USPQ2d 1398.
Applicant is invited to point to clear support or specific examples of the claimed invention in the specification as-filed.
Claim Rejections - 35 USC § 102
In the event the determination of the status of the application as subject to AIA 35 U.S.C. 102 and 103 (or as subject to pre-AIA 35 U.S.C. 102 and 103) is incorrect, any correction of the statutory basis (i.e., changing from AIA to pre-AIA ) for the rejection will not be considered a new ground of rejection if the prior art relied upon, and the rationale supporting the rejection, would be the same under either status.
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)(1) the claimed invention was patented, described in a printed publication, or in public use, on sale, or otherwise available to the public before the effective filing date of the claimed invention.
(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 101 is rejected under 35 U.S.C. 102(a)(1) as being anticipated by Sommermeyer et al. (J Immunol. 2010 Jun 1;184(11):6223-31. doi: 10.4049/jimmunol.0902055. Epub 2010 May 5, in Office Action mailed on 8/20/2025).
Sommermeyer et al. teaches TCR Cα and Cβ amino acid substitutions to increase human TCR stability and expression (Abstract): “…TCR variants (harboring only nine residues of the mouse sequence) enhanced expression of human TCRs by supporting preferential pairing of transferred TCR chains and a more stable association with the CD3 protein…”
Sommermeyer et al. teaches the following modified Cβ domains, three of which (h1, h2, h3) contain the E134K mutation (Fig. 2, cropped with mutation annotated below):
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Sommermeyer et al. additionally teaches the following modified Cα domains, one of which (h3) contains the T150I and A190T mutations (cropped with mutation annotated below):
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Sommermeyer et al. teaches methods of introducing these mutations (pg. 6224, “Construction of retroviral vectors” section). Therefore, Sommermeyer et al. teaches a method of increasing TCR stability comprising incorporating the T150I and A190T Cα mutations (i.e., “at least one”) and the E134K Cß mutation, wherein the stabilized TCR has increased expression level (i.e., “at least one superior property”), anticipating instant claim 101.
The reference teachings anticipate the claimed invention.
Conclusion
Claim 102 is allowed.
Claims 51-81 and 92-96 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.
Co-pending application 19/100,231 has been amended and no longer claims overlapping subject matter to the instant application, and therefore the non-statutory double patenting rejection with this reference has been withdrawn.
Any inquiry concerning this communication or earlier communications from the examiner should be directed to ALEC JON PETERS whose telephone number is (703)756-5794. The examiner can normally be reached Monday-Friday 8:30am - 6:00pm EST.
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If attempts to reach the examiner by telephone are unsuccessful, the examiner’s supervisor, Misook Yu can be reached at (571) 272-0839. The fax phone number for the organization where this application or proceeding is assigned is 571-273-8300.
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/ALEC JON PETERS/Examiner, Art Unit 1641
/MISOOK YU/Supervisory Patent Examiner, Art Unit 1641
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