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 .
Election/Restriction
The response filed on 03/23/2026 to the restriction requirement of 01/27/2026 has been received. Without traverse, Applicant has elected a species of binding protein comprising alpha chain variable domain (Vα): SEQ ID NO: 3 and beta chain variable domain (Vβ): SEQ ID NO: 4, and six CDRs of:
Alpha chain CDR1 (CDR1α): DSAIYNL of SEQ ID NO: 3
Alpha chain CDR1 (CDR2α): QSSQRE of SEQ ID NO: 3
Alpha chain CDR1 (CDR3α): CAVRGGTSGTYKYIF of SEQ ID NO: 3
Beta chain CDR 1 (CDR1β): SEHNR of SEQ ID NO: 4
Beta chain CDR 1 (CDR2β): FQNEAQ of SEQ ID NO: 4
Beta chain CDR 1 (CDR3β): CASSRTAGDTQYF of SEQ ID NO: 4
For purpose of compact prosecution, the Examiner has rejoined all species recited in the claims (Table 1) of the instant application. In addition, the species of SEQ ID NO: 38 and SEQ ID NO: 37 as taught by Bleakley et al. (US20190211076A1 Date Published 2019-07-11) has been rejoined.
Status of Claims
Claims 1, 7, 31-32, 34, 42-43, 74-79, 81, 83, 86, 88, 92, and 139 are currently pending and under examination on the merits.
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 U.S. effective filing date of all claims under examination is set at 11/06/2020 based on the provisional application 63/110,851 (filed 11/06/2020).
Information Disclosure Statement
The information disclosure statements (IDS) submitted are being considered by the examiner.
Drawings
The drawings are objected to because:
Amino acid sequences appearing in the drawings are not identified by sequence identifiers in accordance with 37 CFR 1.821(d). Sequence identifiers for nucleotide and/or amino acid sequences must appear either in the drawings or in the Brief Description of the Drawings. The amino acid sequences of (a) VLHDDLLEA in Figures 1, 3B, 3C, 4A, 7A, 7B and 7C; and (b) VLRDDLLEA in Figure 2A, are not identified by sequence identifiers. See below Nucleotide and/or Amino Acid Sequence Disclosures: REQUIREMENTS FOR PATENT APPLICATIONS CONTAINING NUCLEOTIDE AND/OR AMINO ACID SEQUENCE DISCLOSURES.
Corrected drawing sheets in compliance with 37 CFR 1.121(d) are required in reply to the Office action to avoid abandonment of the application. Any amended replacement drawing sheet should include all of the figures appearing on the immediate prior version of the sheet, even if only one figure is being amended. The figure or figure number of an amended drawing should not be labeled as “amended.” If a drawing figure is to be canceled, the appropriate figure must be removed from the replacement sheet, and where necessary, the remaining figures must be renumbered and appropriate changes made to the brief description of the several views of the drawings for consistency. Additional replacement sheets may be necessary to show the renumbering of the remaining figures. Each drawing sheet submitted after the filing date of an application must be labeled in the top margin as either “Replacement Sheet” or “New Sheet” pursuant to 37 CFR 1.121(d). If the changes are not accepted by the examiner, the applicant will be notified and informed of any required corrective action in the next Office action. The objection to the drawings will not be held in abeyance.
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 deficiencies –
The Incorporation by Reference paragraph required by 37 CFR 1.821(c)(1) is missing or incomplete. See item 1) a) or 1) b) above.
Amino acid sequences appearing in the specification are not identified by sequence identifiers in accordance with 37 CFR 1.821(d). The amino acid sequences of (a) VLRDDLLEA appearing in claim 7 (two occurrences) and on Pages 5, 16, 26, 49, 160, 162 and 164 of the specification; (b) SMIDDLLGV appearing in claim 7 and on Pages 5 and 17 of the specification; (c) VLHDDLLEA appearing in claims 43 and 92, and on Pages 7, 12, 15, 16, 19, 26, 94, 100, 149, 152 (two occurrences), 153, 160, 162 and 164 of the specification; (d) ELAGIGILTV appearing on Pages 151 and 160 (two occurrences) of the specification; have not been identified by sequence identifiers.
Amino acid sequences appearing in the drawings are not identified by sequence identifiers in accordance with 37 CFR 1.821(d). Sequence identifiers for nucleotide and/or amino acid sequences must appear either in the drawings or in the Brief Description of the Drawings. The amino acid sequences of (a) VLHDDLLEA in Figures 1, 3B, 3C, 4A, 7A, 7B and 7C; and (b) VLRDDLLEA in Figure 2A, are not identified by sequence identifiers.
Required response – Applicant must provide:
Replacement and annotated drawings in accordance with 37 CFR 1.121(d) inserting the required sequence identifiers; and
A substitute specification in compliance with 37 CFR 1.52, 1.121(b)(3) and 1.125 inserting the sequence identifier and the required incorporation-by-reference paragraph 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.
Claim Objections
Claims 43, 78, 81, 83, 86, 88, 92 are objected to because of the following informalities:
Claim 43 is objected to because there appears to typographical errors. The phrase “1 µg/mL to 50 pg/mL” (line 12 of Pg 8) should be amended to “50 pg/mL to 1 µg/mL” because pg is smaller than µg.
Claim 78 is objected to because there appears to be a typographical error. The word “and” is missing before “(ii)” in line 3 of the claim.
Claim 81 is objected to because there appears to be two typographical errors. The word “comprising” in line 5 is a repeated word (see preamble) and should be deleted. In addition, the word “expressing” in line 5 should be amended to “express”.
Claim 83 is objected to because there appears to be several typographical errors on Pg 11 lines 4 and 5. First, the word “a” before “hyperproliferative disorder”, and before “relapse of a hyperproliferative disorder” should be amended to “the”. Second, punctuation of the “.” in line 11 of Pg 12 after “del(5q)” should be amended to “;”. Third, the option “v)” in line 23 of Pg 12 should be amended to “C)” and this line should be indented to align with “B)”. Fourth, the option “vi)” in line 25 of Pg 12 should be amended to “v)”.
Claims 83, 86, 88 and 92 are objected to because there appears to be typographical errors in these claims. The acronym “(MALT)” should be moved so that the claims recite “extra-nodal marginal zone B-cell lymphoma of mucosa-associated lymphoid tissue (MALT)”.
claim 139 is objected to because of a missing word in the last line of option “10)”. It is suggested that “nucleic sequence” be amended to “nucleic acid sequence”.
Appropriate correction is required.
Claim Interpretation
With regards to claims 79, 81 and 86, claim 79 recites the word “optionally” after the first phrase of “A method of detecting the presence or absence of an HA-1 antigen and/or a cell expressing HA-1,” (see lines 1-2 of Pg 10). The Examiner has interpreted all the limitations after this first phrase to be optional limitations and therefore need not be necessary for the method of detecting in particular when searching for prior art for the said claims.
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 1, 7, 31-32, 34, 42-43, 74-79, 81, 83, 86, 88, 92, and 139 are rejected under 35 U.S.C. 112(b) or 35 U.S.C. 112 (pre-AlA), 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-AlA 35 U.S.C. 112, the applicant), regards as the invention.
Claims 1, 7, 42-43, 74-79, 81, 83, 86, 88 and 92 are rejected because claim 1 is unclear on whether the binding protein has to comprise all of options 1) through 6); or the binding protein only has to comprise one of the options selected from one of 1) to 6) in the alternative because the claim is lacking any word such as “or” between recitation of the options. This rejection can be obviated if the claim were to recite the word “or” after option 5). For the purpose of the present examination, the Examiner has interpreted the claims to be in the alternative form, meaning any one of options 1) through 6) alone is a limitation that can be taken separately to fulfil the limitations of the claimed binding protein.
Claims 1, 7, 31-32, 34, 42-43, 74-79, 81, 83, 86, 88, 92, and 139 are rejected under 35 U.S.C. 112(b) or 35 U.S.C. 112 (pre-AIA ), second paragraph, because 35 U.S.C. 112(b) and 35 U.S.C. 112 (pre-AIA ), second paragraph, require claims to particularly point-out and distinctly claim subject matter. The instant claims attempt to incorporate by reference binding proteins comprising amino acid sequences listed in Table 1; however, such incorporation is permitted only in exceptional circumstances where there is no practical way to define the invention in words and where it is more concise to incorporate by reference than duplicating a drawing or table into the claim. In the instant case, there is a practical way to define the invention in words. Incorporation by reference is a necessity doctrine, not for applicant's convenience. See MPEP 2173.05(s). Similarly, claim 92 also attempts to incorporate by reference peptide epitopes listed in Table 2. Further, claim 139 also attempts to incorporate by reference polypeptide sequences listed in Table 1, TRAV, TREAJ, TRAC, TRBV, TRBJ and/or TRBC genes listed in Table 1, and nucleic acid sequences listed in Table 3.
Claim 7 recites the limitation of "… the binding domain …. " in line 3 of option 6). There is insufficient antecedent basis for this limitation in the claim. This rejection can be obviated if the claim were amended to recite “….the binding protein”.
Claim 7 contains the trademarks HaloTag and FLAG ; and claims 79, 83 and 88 contain the trademark FACS. Where a trademark or trade name is used in a claim as a limitation to identify or describe a particular material or product, the claim does not comply with the requirements of 35 U.S.C. 112(b) or 35 U.S.C. 112 (pre-AIA ), second paragraph. See Ex parte Simpson, 218 USPQ 1020 (Bd. App. 1982). The claim scope is uncertain since the trademark or trade name cannot be used properly to identify any particular material or product. A trademark or trade name is used to identify a source of goods, and not the goods themselves. Thus, a trademark or trade name does not identify or describe the goods associated with the trademark or trade name. In the present case, the trademark is used to identify/describe protein labeling (HaloTag and FLAG) and Fluorescence-Activated Cell Sorting (FACS) and, accordingly, the identification/description is indefinite.
In claim 43, the terms “lower” (line 19 on Pg 7) and “higher” (lines 1, 3, 14 and 16 on Pg 8) are relative terms which render the claim indefinite. The terms “lower” and “higher” are not defined by the claim, 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. In part 5)c) of the claim, the surface expression of an endogenous TCR has been rendered indefinite by the use of the term “lower” appearing in the sentence. In part 6)d) of the claim, the level of cytokine or a cytotoxic molecule produced by the host cell has been rendered indefinite by the use of the term “higher” appearing in the sentence. In part 6)e)iv) of the claim, the level of killing of target cells by the host cell has been rendered indefinite by the use of the term “higher” appearing in the sentence. Likewise, in claim 92, the terms “lower” in line 14 of Pg 18 and “higher” in lines 21, 23, 26 and 28 of Pg 18 also have the same issues. The metes-and-bounds of the claims cannot be determined because it is unclear, as compared to what, recited amounts are “lower” or “higher”.
Claim 43 recites the phrase "e) …..the HA-1 peptide epitope…” in line 7 on Pg 8. There is insufficient antecedent basis for "the HA-1 peptide epitope” in the claim.
Claim 43 recites the phrase "i) the MHC alpha chain” in line 23 on Pg 8. There is insufficient antecedent basis for "the MHC alpha chain” in the claim.
Claims 81, 83, 86, 88 and 92 recite the phrase "the mammal”. There is insufficient antecedent basis for "the mammal” in the claims.
Claim 83 recites the phrase "the level of a non-malignant disorder, a hyperproliferative disorder, or a relapse of a hyperproliferative disorder”. There is insufficient antecedent basis for "the level” in the claim.
Claim 83 also recites the phrase "the level of reactivity”. There is insufficient antecedent basis for "the level of reactivity” in the claim.
Claims 83, 86, 88 and 92 recite the term "(thymic)” in the claims. It is unclear if the limitation in parentheses is exemplary or a further limitation of mediastinal large B-cell lymphoma. In addition, these claims also recite the phrase “(refractory anemia, refractory neutropenia, and refractory thrombocytopenia)”. It is also unclear if the limitations in parentheses are exemplary or a further limitation of refractory cytopenia with unilineage dysplasia.
Claim 86 recites the phrase "the progression of a non-malignant disorder, a hyperproliferative disorder, or a relapse of a hyperproliferative disorder” in Pg 13. There is insufficient antecedent basis for "the progression of a non-malignant disorder, a hyperproliferative disorder, or a relapse of a hyperproliferative disorder” in the claim.
Claim 86 also recites the phrase "the level of the HA-1 antigen” in Pg 13. There is insufficient antecedent basis for “the level of the HA-1 antigen” in the claim.
Claim 86 further recites the phrase "the cell of interest expressing HA-1” in Pg 13. There is insufficient antecedent basis for "the cell of interest expressing HA-1” in the claim.
Claim 88 recites the phrase "the efficacy of a therapy” in line 1. There is insufficient antecedent basis for "the efficacy” in the claim.
Claim 88 also recites the phrase "the presence or level of reactivity” in line 4. There is insufficient antecedent basis for "the presence or level of reactivity” in the claim.
Claim 88 further recites the phrase "the subject” in lines 4-5. There is insufficient antecedent basis for "the subject” in the claim.
Claim 88 even further recites the phrase "the absence or a reduced level of reactivity” in line 14. There is insufficient antecedent basis for "the absence or a reduced level of reactivity” in the claim.
Claim 88 recites the phrase "A) the presence of binding” in line 20. There is insufficient antecedent basis for "the presence of binding” in the claim.
Claim 88 recites the phrase "2) the T cell binding” in line 24. There is insufficient antecedent basis for "the T cell binding” in the claim.
Claim 92 recites the phrase "15) the HLA allele” in line 3 of Pg 19. There is insufficient antecedent basis for "the HLA allele” in the claim.
Claim 92 also recites the phrase "16) the target cell” in line 5 of Pg 19. There is insufficient antecedent basis for "the target cell” in the claim.
Claim 139 recites the phrase "3) the tag” on Pg 21. There is insufficient antecedent basis for "the tag” in the claim.
Claim 139 recites the phrase "5) the TCRα and/or TCRβ” on Pg 21. There is insufficient antecedent basis for "the TCRα and/or TCRβ” in the claim.
Claim 139 recites the phrase "6) the mutated transmembrane domain and/or mutated constant domain” on Pg 21. There is insufficient antecedent basis for “the mutated transmembrane domain and/or mutated constant domain” in the claim.
Claim 139 recites the phrase "7) ….. the nucleic sequence encoding TCRα and/ TCRβ” on Pg 22. There is insufficient antecedent basis for “the nucleic sequence encoding TCRα and/ TCRβ” in the claim.
Claim 139 recites the phrase "8) the self-cleaving peptide” on Pg 22. There is insufficient antecedent basis for “the self-cleaving peptide” in the claim.
Claim 139 recites the phrase "9)…. the isolated nucleic acid molecule” on Pg 22. There is insufficient antecedent basis for “the isolated nucleic acid molecule” in the claim.
Claim Rejections 35 U.S.C.112(a) (first)
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, 7, 42-43, 74-79, 81, 83, 86, 88 and 92 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.
In the instant case, instant claim 1 and dependents are inclusive of a genus of a binding protein comprising: a) a T cell receptor (TCR) alpha chain CDR sequence with at least about 80% identity to a TCR alpha chain CDR sequence selected from the group consisting of TCR alpha chain CDR sequences listed in instant Table 1; and/or b) a TCR beta chain CDR sequence with at least about 80% identity to a TCR beta chain CDR sequence selected from the group consisting of TCR beta chain CDR sequences listed in instant Table 1, wherein the binding protein is capable of binding to an HA-1 immunogenic peptide-MHC (pMHC) complex. This means the genus includes binding proteins comprising up to 20% mutations in the alpha chain CDR sequences and/or the beta chain CDR sequences that are responsible for binding to an HA-1 immunogenic peptide-MHC (pMHC) complex.
In addition, instant claim 1 and dependents are also inclusive of a genus of a binding protein comprising: a) a TCR alpha chain variable (Vα) domain sequence with at least about 80% identity to a TCR alpha chain sequence selected from the group consisting of TCR alpha chain sequences listed in Table 1; and/or b) a TCR beta chain variable (Vβ) domain sequence with at least about 80% identity to a TCR beta chain sequence selected from the group consisting of TCR beta chain sequences listed in Table 1, wherein the binding protein is capable of binding to an HA-1 immunogenic peptide-MHC (pMHC) complex. This means the genus includes binding proteins comprising up to 20% mutations in the Vα and/or the Vβ including having mutations in the CDR sequences that are responsible for binding to an HA-1 immunogenic peptide-MHC (pMHC) complex.
Further, instant claim 1 and dependents are also inclusive of a genus of a binding protein comprising: a) a TCR alpha chain sequence with at least about 80% identity to a TCR alpha chain sequence selected from the group consisting of TCR alpha chain sequences listed in Table 1; and/or b) a TCR beta chain sequence with at least about 80% identity to a TCR beta chain sequence selected from the group consisting of TCR beta chain sequences listed in Table 1, wherein the binding protein is capable of binding to an HA-1 immunogenic peptide-MHC (pMHC) complex. This means the genus includes binding proteins comprising up to 20% mutations in the alpha chains and/or the beta chains which include having mutations in the CDR sequences that are responsible for binding to an HA-1 immunogenic peptide-MHC (pMHC) complex.
Moreover, instant claim 7 is inclusive of a genus of a binding protein comprising up to five amino acid substitutions, insertions, deletions, or a combination thereof in each of the six CDRs of the binding protein as compared to the cognate reference CDR sequence listed in Table 1.
In summary, for the claims cited above, the genus includes binding proteins that comprise mutations or variability in the amino acid sequences of the CDR sequences of the TCR alpha chain variable (Vα) domain and/or the TCR beta chain variable (Vβ) domain sequences.
The specification in Table 1 discloses fourteen TCR alpha chain sequences paired with fourteen beta chain sequences which represents the binding proteins that the applicant was in possession of at the time of filing (namely SEQ ID NOs: 1, 3, 5, 7, 9, 11, 13, 15, 17, 19, 21, 23, 25 and 27 for the alpha chains and SEQ ID NOs: 2, 4, 6, 8, 10, 12, 14, 16, 18, 20, 22, 24, 26 and 28 for the beta chains) (Pg 52-56). In particularly, it is noted that: (a) HA-1-TSC-100 wild type (also known as TSC-100) comprises the same CDRs as HA1-TSC-100 CDTM (also known as TCR-100a); (b) HA1-10-34 wild type comprises the same CDRs as HA-10-34 CDTM (also known as TCR-100b); (c) HA1-10-26 wild type comprises the same CDRs as HA1-10-26 CDTM (also known as TCR-100c) (Pg52-56). This means there are three binding proteins that each share the same set of six CDRs with their mutated counterpart which comprise variations in the amino acid outside of the CDR regions. In addition, it also means that there are only twelve unique sets of six CDRs disclosed.
In addition, the written description for alpha chain sequence and/or beta chain sequence that have more than 80% identity, when comparing the elected binding protein that comprises SEQ ID NOs: 3 and 4 with the thirteen other binding protein amino acid sequences in Table 1, the specification only sets forth alpha chains SEQ ID NOs: 1 and 3 that have 96.9% match, alpha chains SEQ ID NOs: 3 and 15 that are 98.9% identical and alpha chains SEQ ID NOs: 3 and 29 that are 94.1% identical, which fulfill the greater than 80% identity match, meaning only three other alpha chain sequences have at least 80% identities with SEQ ID NO:3; while each of the following twelve beta chains of SEQ ID NOs: 2, 8, 10, 14, 16, 18, 20, 22, 24, 26, 28 and 30 have between 94.8 to 98.7% identities when compared to SEQ ID NO: 4 respectively.
Unrelated to the written description issue pertaining to the TCR CDRs, Valpha, Vbeta, alpha chain or beta chain having at least 80% identity, the instant claim 1 and dependents are further inclusive of a genus of a binding protein comprising only a single TCR alpha chain or only a single TCR beta chain that are not paired. However, the written description for binding proteins comprising TCRs only sets forth fourteen binding proteins listed in Table 1 which comprises paired TCR alpha chains and TCR beta chains. In order words, there are NO species of binding protein that comprises either only a single TCR alpha chain or only a single TCR beta chain.
Therefore, the specification does not disclose, and the art does not teach, the genus of binding protein comprising a T cell receptor (TCR) alpha chain sequence; and/or a TCR beta chain sequence, wherein the binding protein is capable of binding to an HA-1 immunogenic peptide-MHC (pMHC) complex, as broadly encompassed in the claims.
A description of a genus may be achieved by means of a recitation of a representative number of species falling within the scope of the genus or by describing structural features common to that genus that “constitute a substantial portion of the genus.” See University of California v. Eli Lilly and Co., 119 F.3d 1559, 1568, 43 USPQ2d 1398, 1406 (Fed. Cir. 1997): “A description of a genus of cDNAs may be achieved by means of a recitation of a representative number of cDNA, defined by nucleotide sequence, falling within the scope of the genus or of a recitation of structural features common to the members of the genus, which features constitute a substantial portion of the genus.” The inventions at issue in Lilly were DNA constructs per se, the holdings of that case is also applicable to claims such as those at issue here.
The instant specification fails to provide sufficient descriptive information, such as definitive structural features that are common to the genus. That is, the specification provides neither a representative number of species binding proteins that encompass the genus of binding proteins that comprises up to 20% variations in the CDR sequence of the TCR alpha chain and/or up to 20% variations in the CDR sequence of the TCR beta chain; or 20% variations in the TCR variable alpha chain and/or up to 20% variations in the TCR variable beta chain; or 20% variations in the TCR alpha chain and/or up to 20% variations in the TCR beta chain; or the genus of binding proteins that comprises only a TCR alpha chain CDR sequence; or comprises only a TCR beta chain CDR sequence; wherein the binding protein is capable of binding to an HA-1 immunogenic peptide-MHC (pMHC) complex; nor does it provide a description of structural features that are common to the genus so that one of skill in the art can ‘visualize or recognize’ the members of the genus. “[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.” Ariad, 598 F.3d at 1350 (quoting Eli Lilly, 119 F.3d at 1568-69). A “representative number of species” means that those species that are adequately described are representative of the entire genus. AbbVie Deutschland GMBH v. Janssen Biotech, 111 USPQ2d 1780, 1790 (Fed. Cir. 2014) (“The ’128 and ’485 patents, however, only describe species of structurally similar antibodies that were derived from Joe-9. Although the number of the described species appears high quantitatively, the described species are all of the similar type and do not qualitatively represent other types of antibodies encompassed by the 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 to provide a "representative number” of species.
The state of the art teaches that TCR functionality is known to depend on the minimal structure comprising a full complement of six CDRs (e.g., CDRα1-3 and CDRβ1-3). It is understood by one of ordinary skill in the art that mutation to TCR CDRs is unpredictable and that each construct requires function testing. For example, Riley and Baker (Seminars in Cell & Developmental Biology 84 (2018) 30–41), reviews the structural basis of TCR-antigen recognition in the state of the art (Title and Abstract). Riley and Baker teach that TCRs in their normal function only recognize antigens bound and presented by proteins encoded by the major histocompatibility complex, a phenomenon termed MHC restriction (Pg. 30 Introduction). Riley and Baker further teach the MHC restriction of TCRs and their binding affinities are major considerations for translating TCRs into new therapies, and that TCRs are quite similar to germline antibodies, so much so that some of the same language is used to describe both TCR and germline antibody molecular recognition (Pg. 31 column first paragraph second). Riley and Baker teach that naturally occurring TCRs of alpha beta T cells have six hypervariable loops that are commonly termed complementary determining regions (CDRs), three from the alpha chain and three from the beta chain, and are widely assumed to be responsible for antigen recognition (Pg. 31, “3. Structural properties of TCR complexes).
A person of ordinary skill in the art would understand that although the above basics of TCR-antigen binding are known, the specifics of TCR structure within the CDRs that underlie the antigen recognition are not well characterized and that mutation(s) in the CDRs are unpredictable as the roles various CDR loops play in binding are dependent of the structural details unique to each interface (Pg. 34 column first, paragraph first). Therefore, making changes to the CDR sequences of a TCR sequence is a highly unpredictable process and one skilled in the art could not make any predications regarding such mutations with any reasonable expectation of success nor envisage the breadth of structurally unrelated CDR combinations that would still possess the required function(s).
Since the disclosure fails to describe common attributes or characteristics that adequately identify members of the genus, and because the genus is highly variant, the disclosure of:
three species of alpha chain CDRs that have 100% identity and three species of beta chain CDRs that have 100% identity;
a few species of alpha chain sequence or beta chain sequence that have 80% identity;
no species that comprise only the TCR alpha chain; or no species that comprise only TCR beta chain,
found in the specification is insufficient to describe the genus. Thus, one of skill in the art would reasonably conclude that the disclosure fails to provide a representative number of species to describe the genus as broadly claimed. Written description can be met if the claims recite the minimal structure that is needed to perform the function recited in the claims without any variability.
Vas-Cath Inc. v. Mahurkar, 19USPQ2d 1111, clearly states “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). As discussed above, even though Applicant may propose methods of screening for possible members of the genus, the skilled artisan cannot envision the detailed chemical structure of the encompassed genus, and therefore conception is not achieved until reduction to practice has occurred, regardless of the complexity or simplicity of the method of isolation. Adequate written description requires more than a mere statement that it is part of the invention and reference to a potential method of isolation. The compound itself is required. See Fiers v. Revel, 25 USPQ2d 1601 at 1606 (CAFC 1993) and Amgen Inc. v. Chugai Pharmaceutical Co. Ltd., 18 USPQ2d 1016. See Ariad, 94 USPQ2d at 1161; Centocor at 1876 (“The fact that a fully-human antibody could be made does not suffice to show that the inventors of the '775 patent possessed such an antibody.”)
One cannot describe what one has not conceived. See Fiddes v. Baird, 30 USPQ2d 1481 at 1483. In Fiddes, claims directed to mammalian FGF’s were found to be unpatentable due to lack of written description for that broad class. The specification provided only the bovine sequence. Applicant is reminded that Vas-Cath makes clear that the written description provision of 35 U.S.C. §112 is severable from its enablement provision (see page 1115).
Claim Rejections 35 U.S.C.112(a) (second)
Claims 1, 7, 42-43, 74-79, 81, 83, 86, 88 and 92 are rejected under 35 U.S.C. 112(a) or 35 U.S.C. 112 (pre-AIA ), first paragraph, because the specification, while being enabling for a binding protein capable of binding to an HA-1 immunogenic peptide-MHC (pMHC) complex comprising the alpha chain CDRs and beta chain CDRs as disclosed in Table 1, does not reasonably provide enablement for a binding protein capable of binding to an HA-1 immunogenic peptide-MHC (pMHC) complex comprising variability in the alpha chain CDRs and beta chain CDRs of up to 20%; or variability in the alpha chain variable domain and beta chain variable domain of up to 20% which includes variability in the CDRs; or variability in alpha chain and beta chain of up to 20% which includes variability in the CDRs, relative to those described in Table 1.
Moreover, claims 1, 7, 42-43, 74-79, 81, 83, 86, 88 and 92 are also rejected under 35 U.S.C. 112(a) or 35 U.S.C. 112 (pre-AIA ), first paragraph, because the specification, while being enabling for a binding protein capable of binding to an HA-1 immunogenic peptide-MHC (pMHC) complex comprising: a TCR alpha chain sequence and a TCR beta chain sequence, does not reasonably provide enablement for a binding protein capable of binding to an HA-1 immunogenic peptide-MHC (pMHC) complex comprising: only a TCR alpha chain sequence or only a TCR beta chain sequence.
The specification does not enable any person skilled in the art to which it pertains, or with which it is most nearly connected, to perform the invention commensurate in scope with these claims.
Factors to be considered in determining whether undue experimentation is required are summarized in Ex parte Forman, 230 USPQ 546 (BPAI 1986). They include the nature of the invention, the state of the prior art, the relative skill of those in the art, the amount of direction or guidance disclosed in the specification, the presence or absence of working examples, the predictability or unpredictability of the art, the breadth of the claims, and the quantity of experimentation which would be required in order to practice the invention as claimed.
Nature of the Invention
The above instant claims are drawn to a binding protein that comprises TCR alpha chain and/or TCR beta chain that are capable of binding to an HA-1 immunogenic peptide-MHC (pMHC) complex.
This invention is in a class of invention which the CAFC has characterized as "the unpredictable arts such as chemistry and biology". Mycogen Plant Sci., Inc. v. Monsanto Co., 243 F.3d 1316, 1330 (Fed. Cir. 2001).
Breadth of Claims
The claims are broad in that they encompass binding proteins that can have: (1) TCR alpha chains and/or TCR beta chains with up to 20% mutations in any of the CDR sequences compared to those recited in the claims; or (2) TCR alpha chains and/or TCR beta chains with up to 20% mutations in any of the variable sequences compared to those recited in the claims; or (3) TCR alpha chains and/or TCR beta chains with up to 20% mutations in any of the sequences compared to those recited in the claims; or (4) TCRs with only three CDRs, which is effectively half of a TCR binding site, as being sufficient for functional TCR binding. In addition, claim 7 encompasses binding proteins that comprises in each of the six CDRs, up to five amino acid substitutions, insertions, deletions or a combination thereof as compared to the cognate reference CDR sequence recited .
One of ordinary skill in the art would understand that one cannot expect mutations in the any of the TCR CDRs and/or expect the use of half of TCR binding domain and still reasonably expect to maintain HA-1 peptide-MHC complex binding function.
The amount of direction provided by the inventor/the existence of working examples
The specification in Table 1 discloses fourteen TCR alpha chain sequences paired with fourteen beta chain sequences which represents the binding proteins that the applicant was in possession of at the time of filing (namely SEQ ID NOs: 1, 3, 5, 7, 9, 11, 13, 15, 17, 19, 21, 23, 25, 27 and 29 for the alpha chains that are paired with SEQ ID NOs: 2, 4, 6, 8, 10, 12, 14, 16, 18, 20, 22, 24, 26, 28 and 30 for the beta chains respectively) (Pg 52-56). In particularly, it is noted that: (a) HA-1-TSC-100 wild type (also known as TSC-100) comprises the same CDRs as HA1-TSC-100 CDTM (also known as TCR-100a); (b) HA1-10-34 wild type comprises the same CDRs as HA-10-34 CDTM (also known as TCR-100b); (c) HA1-10-26 wild type comprises the same CDRs as HA1-10-26 CDTM (also known as TCR-100c) (Pg52-56). This means there are twelve unique sets of six CDRs disclosed.
However, these teachings do not enable the full breadth of the claims because a binding protein that comprises: (1) TCR alpha chains and/or TCR beta chains with up to 20% mutations in any of the CDR sequences compared to those recited in the claims; (2) TCR alpha chains and/or TCR beta chains with up to 20% mutations in any of the variable sequences compared to those recited in the claims; or (3) TCR alpha chains and/or TCR beta chains with up to 20% mutations in any of the sequences compared to those recited in the claims; or (4) TCRs with only three CDRs, which is effectively half of a TCR binding site, as being sufficient for functional TCR binding; or (5) each of the six CDRs having up to five amino acid substitutions, insertions, deletions or a combination thereof as compared to the cognate reference CDR sequence recited, would not predictably be capable of binding to the target antigen of HA-1 immunogenic peptide-MHC complex.
The state of the art/the level of predictability in the art
The state of the art teaches that with regards to changes in the amino acid residues on binding domains, it is especially important to disclose which residues are permissive to mutation. Even minor changes in the amino acid sequences of antibody heavy and light variable regions, particularly in the CDRs, may dramatically affect antigen-binding function as evidenced by Rudikoff et al. (Proceedings of the National Academy of Sciences USA, Vol., 79, Pg. 1979-1983, 1982, see Abstract). Rudikoff et al. teaches that the alteration of a single amino acid in the CDR of a phosphocholine-binding myeloma protein resulted in the loss of antigen-binding function (see 112a written description rejection section above).
With respect to TCRs, the state of the art at the time of filing teaches that TCR functionality is known to depend on the minimal structure comprising a full complement of six CDRs (e.g., CDRα1-3 and CDRβ1-3). It is understood by one of ordinary skill in the art that mutation to TCR CDRs is unpredictable and that each construct requires function testing. For example, Riley and Baker (Seminars in Cell & Developmental Biology 84 (2018) 30–41), reviews the structural basis of TCR-antigen recognition in the state of the art (Title and Abstract). Riley and Baker teach that TCRs in their normal function only recognize antigens bound and presented by proteins encoded by the major histocompatibility complex, a phenomenon termed MHC restriction (Pg. 30 Introduction). Riley and Baker further teach the MHC restriction of TCRs and their binding affinities are major considerations for translating TCRs into new therapies, and that TCRs are quite similar to germline antibodies, so much so that some of the same language is used to describe both TCR and germline antibody molecular recognition (Pg. 31 column first paragraph second). Riley and Baker teach that naturally occurring TCRs of alpha beta T cells have six hypervariable loops that are commonly termed complementary determining regions (CDRs), three from the alpha chain and three from the beta chain, and are widely assumed to be responsible for antigen recognition (Pg. 31, “3. Structural properties of TCR complexes).
A person of ordinary skill in the art would understand that although the above basics of TCR-antigen binding are known, the specifics of TCR structure within the CDRs that underlie the antigen recognition are not well characterized and that mutation(s) in the CDRs are unpredictable as the roles various CDR loops play in binding are dependent of the structural details unique to each interface (Pg. 34 column first, paragraph first). Therefore, making changes to the CDR sequences of a TCR sequence is a highly unpredictable process and one skilled in the art could not make any predications regarding such mutations with any reasonable expectation of success nor envisage the breadth of structurally unrelated CDR combinations that would still possess the required function(s).
Further, the prior art provides the skilled artisan with insufficient guidance or direction as to which particular amino acid residues in a given CDR are required for MHC or peptide binding, or which CDR residues are required to bring about the canonical diagonal interaction of the TCR with peptide-bound MHC (see Garcia et al. (Cell, 2005, 122: 333-336), specially page 333, right column, paragraphs 1-3; page 336, col. bridging paragraph through right column, paragraph 1 and Figure 1). Indeed, one hypothesis in the art is that the CDR1 and CDR2 interactions with the MHC are dependent on the CDR3 interaction with the peptide bound to the MHC, and, if so, "there may be as many TCR/pMHC orientations as CDR3 sequences” (Garcia et al., page 336, column bridging paragraph).
The TCR interacts with two ligands simultaneously, i.e., the peptide and the MHC, and as described above there is considerable uncertainty in the art about which residues depend on which for these interactions. The instant specification provides no teachings whatsoever and the prior art does not teach as to how the skilled artisan is to go about preparing or envisioning the structural features of the claimed genus of TCRs that can bind to a given peptide:MHC complex starting from as little as 80% sequence homology to any of the six TCR CDRs, or from as little as 80% sequence homology to a TCR alpha variable or beta variable chain, or as little as 80% sequence homology to a TCR alpha chain or beta chain, or from a CDR that can have up to five amino acid substitution, insertion, deletion or a combination thereof, or from only three CDRs of the alpha chain, or only three CDRs of the beta chain.
Therefore, there is insufficient evidence or nexus that would lead the skilled artisan to predict the ability of a binding protein comprising TCR alpha and/or beta chain sequences to bind to HA-1 immunogenic peptide-MHC complex which comprises variations or mutations in any of the six CDR regions, or comprising only the alpha chain without the beta chain or vice versa, or comprising up to five amino acid substitutions, insertions, deletions or a combination thereof in the CDRs.
Note that an enabling disclosure for the preparation and use of only a few analogs of a product does not enable all possible analogs where the characteristics of the analogs are unpredictable. See Amgen Inc. v. Chugai Pharmaceutical Co. Ltd. (18 USPQ 2d 1027 (CAFC 1991)).
Not knowing and absent further experimentation, which modifications can retain antigen binding function and which cannot, even a single change of an encoded amino acid can unpredictably affect structure and function, leads to one having no predictability or expectation of success for the function of any given TCR alpha chain or beta chain modification. Such random experimentation to identify at a later time what structure or fragment or modification is or is not functional and is embraced by Applicant’s claims is undue experimentation.
The quantity of experimentation needed to make or use the invention based on the content of the disclosure
Based on the instant disclosure and prior art, there is no known method through which one of ordinary skill in the art would have been able to reliably predict or otherwise envisage (1) which amino acid mutations of up to 20% in the CDRs; (2) which amino acid mutations of up to 20% in the variable chains; (3) which amino acid mutations of up to 20% in alpha or beta chains; (4) which combinations of the fourteen alpha chains can be matched with the fourteen beta chains; and (5) which up to five substitutions, insertions, deletions or combination thereof in each of the CDRs, can retain binding function to HA-1 immunogenic peptide-MHC complex. Therefore, in order to practice the invention as claimed, one of ordinary skill in the art would have to perform undue experimentation to create and function test: (1) six CDRs with up to 20% mutations; (2) alpha and/or beta variable chains with up to 20% mutations; (3) alpha and/or beta chains with up to 20% mutations; (4) possible combinations of the fourteen alpha and fourteen beta chains; and (5) six CDRs comprising up to five amino acid up to five substitutions, insertions, deletions or combination thereof, for which retention of functional activity is still present.
The Examiner confirms that Applicant is enabled for binding proteins wherein the TCR alpha chains and beta chains are paired as recited (e.g. SEQ ID NO: 1 is paired with SEQ ID NO:2) without any variability to the amino acid sequences that has been disclosed in Table 1 of the specification.
Conclusion
One cannot extrapolate the teachings of the specification to the scope of the claims because the claims are broadly drawn to binding proteins that comprise mutations in the CDRs of the TCR alpha and/or beta chains; or the chains can be only a single alpha chain or only a single beta chain which are not paired or not matched, and Applicant has not enabled binding proteins that bind HA-1 immunogenic peptide-MHC complex that comprise mutations in the CDRs or can have only a single alpha chain or a single beta chain because it has not been shown that TCRs that comprise mutations especially in the CDRs; or TCRs that do not have paired alpha and beta chains, can function to bind HA-1 immunogenic peptide-MHC complex.
In view of the teachings above and the lack of guidance, workable examples and or exemplification in the specification, it would require an unreasonable amount of experimentation by one of skill in the art to determine with any predictability, that the method would function as claimed. This is because the art teaches that it is unpredictable whether or not CDR variants of known TCR chains will function as such, and the specification does not provide direction on which constructs below 100% identity to those disclosed in instant Table 1 have function, or do not have function, as claimed in order to perform the method as claimed. In other words, the specification does nothing to ameliorate these concerns over the breadth of the claims rejected above with respect to functional variants, therefore, one would be burdened with undue experimentation to make or use the products of instant claims as broadly as they are currently claimed.
As indicated by the art, a full complement of six CDRs are required for TCR peptide-MHC complex binding and one cannot predict which CDR residues may be changed and still result in a TCR that binds HA1 immunogenic peptide-MHC. The art as stated above, indicates that the six CDRs in a TCR antigen-binding domain are the minimal structure that binds to a target antigen.
Enablement can be met by amending instant claims to recite explicitly the amino acid sequences of all six CDRs in the TCR without any percentage identity variations, and paired alpha and beta chains that are able to provide the function of binding HA-1 immunogenic peptide-MHC complex.
Claim Rejections 35 U.S.C.112(a) (third)
Claim 92 is rejected under 35 U.S.C. 112(a) or 35 U.S.C. 112 (pre-AIA ), first paragraph, because the specification, while being enabling for methods of treating a non-malignant disorder, a hyperproliferative disorder or a relapse of a hyperproliferative disorder characterized by expression of an HA-1 antigen in a subject 1, does not reasonably provide enablement for methods of preventing a non-malignant disorder, a hyperproliferative disorder or a relapse of a hyperproliferative disorder characterized by expression of an HA-1 antigen in a subject. The specification does not enable any person skilled in the art to which it pertains, or with which it is most nearly connected, to perform the invention commensurate in scope with these claims.
Claim 92, as written, include methods of preventing a non-malignant disorder, a hyperproliferative disorder or a relapse of a hyperproliferative disorder characterized by expression of an HA-1 antigen in a subject. The specification lacks guidance and or objective evidence with regards to vaccination of a population of subjects predisposed to a non-malignant disorder, a hyperproliferative disorder or a relapse of a hyperproliferative disorder characterized by expression of an HA-1 antigen.
It is well known in the art that the prevention of a disorder, in general, is highly unpredictable and Applicant has not demonstrated, with any predictability, that the claimed binding protein would predictably prevent the occurrence of a non-malignant disorder, a hyperproliferative disorder or a relapse of a hyperproliferative disorder characterized by expression of an HA-1 antigen in a subject. Reasonable guidance with respect to preventing any non-malignant disorder, hyperproliferative disorder or relapse of a hyperproliferative disorder characterized by expression of an HA-1 antigen in a subject relies on quantitative analysis from defined populations; some of which have been successfully pre-screened and are predisposed to particular types of said disorders. This type of data might be derived from widespread genetic analysis, cancer clusters, family histories, or randomized controlled trials.
For example, Byers, T. (CA Cancer Journal for Clinicians, Vol. 49, No. 6, Nov/Dec. 1999) teaches that randomized controlled trials are commonly regarded as the definitive study for proving causality (1st col., p.358), and that in controlled trials the random assignment of subjects to the intervention eliminates the problems of dietary recalls and controls the effects of both known and unknown confounding factors. Further, Byers suggests that chemo-preventative trials be designed “long-term” such that testing occurs over many years (2nd col., p. 359). Further, the essential element towards the validation of any preventive therapeutic is the ability to test the drug on subjects monitored in advance of clinical cancer. This would require monitoring a large population with the claimed agents and linking such results with subsequent histological confirmation of the presence or absence of disease. Thus, while the specification is enabling for treating a non-malignant disorder, a hyperproliferative disorder or a relapse of a hyperproliferative disorder characterized by expression of an HA-1 antigen in a subject who has been diagnosed with a non-malignant disorder, a hyperproliferative disorder or a relapse of a hyperproliferative disorder characterized by expression of an HA-1 antigen, the specification lacks reasonable guidance, predictability, and objective evidence that enables the prevention of a non-malignant disorder, a hyperproliferative disorder or a relapse of a hyperproliferative disorder characterized by expression of an HA-1 antigen.
Claim Rejections - 35 USC § 101
35 U.S.C. 101 reads as follows:
Whoever invents or discovers any new and useful process, machine, manufacture, or composition of matter, or any new and useful improvement thereof, may obtain a patent therefor, subject to the conditions and requirements of this title.
Claims 1, 7, 31-32, 34, 42-43, 74, 75 and 139 are rejected under 35 U.S.C. 101 because the claimed invention is directed to antigen-specific TCRs isolated from healthy human donors (Pg 146 lines 10-15, Pg. 147 lines 4-8, Pg. 154 line 12-13 and Pg. 162 lines 28-29). The instant specification discloses a TCR discovery and evaluation platform which identified 329 HA-1-specific TCRs from a total of 178.3 million naive CD8+ T cells from six unique HA-1- (VLRDDLLEA, genotype RS_1801284 G/G) donors, as such they are directed to TCRs from human T cells and so are natural products which are judicial exceptions (Fig. 1, Pg. 162-163 Example 2 and Pg. 51-52 Table 1). Said platform identified the most active TCR that is named TSC-100, disclosed in Table 1, as consisting of the amino acid sequences of SEQ ID NO: 1 (alpha chain) and SEQ ID NO: 2 (beta chain), and alternatively is named “HA1-TSC-100 wild type sequence” (Pg. 51-52 Table 1 and Pg. 163 line 11 to Pg. 164 line 24). In addition, in Figures 7A, 7B and 7C, it appears that, in addition to the TCR named TSC-100, other TCRs named 10-34, 1-12, 2-21, 2-23, 6-2, 9-46, 9-105, 10-26, 10-93, 10-104 are ten other TCRs that were shown to be expressed on Donors 1, 2 and 3 Pan T cells.
The claims are drawn to natural phenomenon because the claims recite natural phenomenon (“Step 2A prong one”) and the judicial exception(s) is/are not integrated into a practical application (“Step 2A prong two”). The “natural phenomenon” is: naturally occurring antigen-specific TCRs, naturally occurring antigen-specific TCRs in combination with a “carrier” that can be water, and naturally occurring polynucleotides encoding said TCRs. MPEP 2106.04(d)(2) indicates a claim reciting a judicial exception is not directed to a judicial exception if it also recites additional elements(s) demonstrating the claim as a whole integrates the exception into a practical application by using recited judicial exceptions to effect a particular treatment or prophylaxis that has more than a nominal or insignificant relationship to the exception(s) (see aspirin example under “Whether The Limitation(s) Have More Than A Nominal Or Insignificant Relationship To The Exception(s)” at MPEP 2106.04(d)(2)). In the instant situation, there is no limitation that requires claimed products to be markedly different than products found in nature.
Therefore, the claimed invention is directed to a natural product/phenomenon without significantly more because the claims recite naturally occurring TCRs from naïve human T cells, which is not markedly different from its naturally occurring counterpart because all the genes of the selected TCRs are contained within the natural T cells of unimmunized humans.
This judicial exception is not integrated into a practical application because there is no additional claim element that prevents monopoly of the judicial exception/natural product since the claims do not require any structure other than a structure that is not markedly different from natural product.
The claims do not include additional elements that are sufficient to amount to significantly more than the judicial exception because, again, there is no element required by the claims other than structures within the natural TCR of the human donor. Therefore, the instant claims above are drawn to judicial exceptions and are rejected here.
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)(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.
Claims 79 and 81 are rejected under 35 U.S.C. 102(a)(1) as being clearly anticipated by Fujii et al. (Transplantation 73(7):p 1137-1141, April 15, 2002).
Fujii et al. teaches expression of minor histocompatibility antigen, HA-1, in tumor cells (Title). They teach HA-1 expression level in paired samples of cancerous and adjacent noncancerous tissues by standard RT-PCR analysis wherein HA-1 expression was detected in all the tissue samples (Fig. 2C). They also teach quantification of HA-1 gene expression levels in three human PBMNC, 11 leukemia/lymphoma cell lines, and 17 solid tumor cell lines obtained from subjects whereby the expression levels of human PBMNC are 14- to 19-fold higher than that of Raji (Fig. 3A).
Fujii et al. therefore teaches a method of detecting the presence or absence of an HA-1 antigen in a sample through gene expression analysis by obtaining the sample for a human subject which is a mammal. Fujii et al. thus anticipates the above instant claims.
Claim Rejections - 35 USC § 102 (second)
Claims 1, 7, 42-43, 74-78, 88, 92 and 139 are rejected under 35 U.S.C. 102(a)(1) and (a)(2) as being clearly anticipated by Bleakley et al. (US20190211076A1 Date Published 2019-07-11).
Bleakley et al. teaches TCRs specific for minor histocompatibility antigen HA-1 and uses thereof (Title). They teach compositions and methods for targeting a minor histocompatibility (H) antigen (HA-1H) to prevent or manage relapse of a hematological malignancy after allogeneic hematopoietic stem cell transplantation (HCT) (Abstract). They also teach transgene constructs encoding engineered binding proteins, such as a T cell receptor or a chimeric antigen receptor, optionally encoding additional components such as a co-receptor and/or safety switch, transduced into an immune cell and used as an immunotherapy in a subject having a hematological malignancy or at risk for recurrence of the hematological malignancy (Abstract).
Bleakley et al. teaches that an encoded binding protein comprises: TCR β-chain comprising or consisting of the amino acid sequence shown in SEQ ID NO:37, and a TCR-α chain comprising or consisting of the amino acid sequence shown in SEQ ID NO:38 (paragraph [0101]). The sequence alignment of instant SEQ ID NO: 4 with SEQ ID NO: 37 taught by Bleakley et al. shows that the latter sequence has 95.5% identity to instant SEQ ID NO: 4, thus meeting the limitation that the TCR β-chain is at least 80% identity to the instant TCR beta chain of SEQ ID NO: 4 listed in instant Table 1 (see Alignment 1 below).
In addition, the sequence alignment of instant SEQ ID NO: 3 with SEQ ID NO: 38 taught by Bleakley et al. shows that the latter sequence has 96.4% identity to instant SEQ ID NO: 3, thus meeting the limitation that the TCR α-chain taught by Bleakley et al. is at least 80% identity to the instant TCR alpha chain of SEQ ID NO: 3 listed in instant Table 1 (see Alignment 2 below).
Alignment 1: Alignment of TCR β-chains. Top sequence is instant SEQ ID NO: 4, bottom sequence is SEQ ID NO: 37 taught by Bleakley et al.
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Alignment 2: Alignment of TCR α-chains. Top sequence is instant SEQ ID NO: 3, bottom sequence is SEQ ID NO: 38 taught by Bleakley et al.
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Bleakley et al. teaches an isolated polynucleotide that encodes a binding protein that is an HA-1H-specific TCR (paragraph [0135]). They teach that binding proteins contained in engineered immune cells can specifically bind to an HA-1H peptide:HLA complex, wherein the HLA can comprise HLA-A*0201 and the HA-1H peptide comprises the amino acid sequence VLHDDLLEA (SEQ ID NO:66) (paragraph [0105]). They also teach that lentiviral (LV) vectors were used to transduce primary T cells to deliver a polynucleotide encoding engineered HA-1H specific TCR constructs (paragraph [0218]). They teach that the transduced T cells were sorted, expanded, and tested for HA-1H specificity, wherein five of the six HA-1H TCR LVs efficiently transduced primary CD8+ and CD4+ T cells (paragraph [0218] and FIGS. 4, 5A and 6A).
Bleakley et al. also teaches in Fig. 30, a diagram of a lentiviral delivery vector encoding an HA-1-TCR-RQR-CD8 co-receptor construct, wherein RQR comprises CD20 and CD34 epitope and wherein the vector construct comprises a promoter (paragraph [0035] and Fig. 30). Of note, the lentiviral vector comprises both an alpha and a beta chain for the CD8 co-receptor (Fig. 30). Therefore, Fig. 30 as taught by Bleakley et al. teaches an expression vector comprising a promoter operably linked to a nucleic acid sequence encoding CD8α and/or CDβ, which thus anticipates instant claim 139.
Bleakley et al. also teach that transduced cells were flow-sorted using HA-1H/HLA-A2 multimers and CD34 mAb 4-5 days later, and cultured in G-Rex flasks using REP (Rapid Expansion Protocol) comprising OKT3 cells, PBMC, HA-1+ LCL, and IL-2, and that the CD4+ and CD8+ transduced HA-1H TCR memory T cells were efficiently expanded, harvested and combined (total 3-6×109 cells at days 16-20), then enriched via selection for CD34 to produce an enriched population of ≥1.5×109 cells (paragraphs [0036], [0037], [0039] and [0229] and FIGs. 31, 32A and 34). They further teach compositions that comprise said engineered immune cells and a pharmaceutically acceptable carrier (paragraphs [0132], [0167] and [0208] and claim 44).
Bleakley et al. further teaches a clinical study using the HA-1H T cell therapy product wherein patients were treated with one of five dose levels of HA-1H TCR T cells to monitor whether infusion of HA-1H TCR T cells is followed by a reduction of leukemia burden; a reduction of recipient hematopoietic chimerism; and the appearance or recurrence of signs or symptoms of graft-versus-host disease (GVHD). (Example 7, paragraphs [0231] to [0233]).
Therefore Bleakley et al. anticipates instant claims 1, 7, 42-43, 74-78, 88, 92 and 139 and are they are thus rejected here.
Claim Rejections - 35 USC § 103
The following is a quotation of 35 U.S.C. 103 which forms the basis for all obviousness rejections set forth in this Office action:
A patent for a claimed invention may not be obtained, notwithstanding that the claimed invention is not identically disclosed as set forth in section 102, if the differences between the claimed invention and the prior art are such that the claimed invention as a whole would have been obvious before the effective filing date of the claimed invention to a person having ordinary skill in the art to which the claimed invention pertains. Patentability shall not be negated by the manner in which the invention was made.
The factual inquiries for establishing a background for determining obviousness under 35 U.S.C. 103 are summarized as follows:
1. Determining the scope and contents of the prior art.
2. Ascertaining the differences between the prior art and the claims at issue.
3. Resolving the level of ordinary skill in the pertinent art.
4. Considering objective evidence present in the application indicating obviousness or nonobviousness.
Claims 32 is rejected under 35 U.S.C. 103 as being unpatentable over Bleakley et al. (US20190211076A1 Date Published 2019-07-11) in view of Nakatsura et al. (WO2018143454A1 Date Published 2018-08-09) and Han et al. (Nat Biotechnol. 2015 Feb;33(2):210).
Note that the citations of Nakatsura et al. below are according to the translations obtained from Espacenet that has been attached to the current Office Action as an Appendix.
The teachings of Bleakley et al. have been described in the second 102 rejection above.
Bleakley et al. does not specifically teach an isolated nucleic acid molecule that hybridizes, under stringent conditions, with a sequence with at least about 80% homology to a nucleic acid encoding a polypeptide selected from the group consisting of the polypeptide sequences listed in instant Table 1.
However, these deficiencies are made up in the teachings of Nakatsura et al.
Nakatsura et al. teaches a T cell receptor (TCR) specific for glypican 3 (Pg. 4 line 6). They teach that isolated nucleic acid or a vector encoding the α chain and the nucleic acid encoding β chain of genetically engineered TCR can be introduced into T cells to express the α chain and β chain polypeptides of engineered TCRs (Pg. 16 lines 3-15). They also teach nucleic acids that are capable of hybridizing under stringent conditions to the complement of any nucleic acid that encodes the amino acid sequence of a CDR, variable region or constant region of said TCR having the function of being able to bind a) a GPC 3298-306 peptide or a complex thereof with HLA-A24, or b) a GPC 3144-152 peptide or a complex of said peptide and HLA-A 02 (Pg. 16 lines 15-23).
One of ordinary skill in the art would have been motivated, with a reasonable expectation of success, to perform a combined method of making an isolated nucleic acid molecule that hybridizes, under stringent conditions, with the complement of a nucleic acid as taught by Nakatsura et al. wherein the complement of a nucleic acid encodes a polypeptide sequence that comprises the amino acid sequence of SEQ ID NO: 37 or 38 as taught by Bleakley et al. which has at least 80% homology to a nucleic acid encoding a polypeptide consisting of the polypeptide sequence of instant SEQ ID NO: 4 or 3, respectively as listed in instant Table 1 because it is well known in the art that an isolated nucleic acid molecule that hybridizes to the complement of a nucleic acid is a primer, and because Han et al. teaches the use of TCR primers can be an efficient strategy for single-cell TCRα and TCRβ genes sequencing and phenotyping which retains information about individual TCRα-TCRβ pairs for functional studies, antigen discovery, or therapeutic applications (Abstract and Figure 1). This is an example of (A) Combining prior art elements according to known methods to yield predictable results; and (G) Some teaching, suggestion, or motivation in the prior art that would have led one of ordinary skill to modify the prior art reference or to combine prior art reference teachings to arrive at the claimed invention. See MPEP 2143. Therefore, the invention as a whole would have been prima facie obvious to one of ordinary skill in the art, absent unexpected results.
Claim Rejections - 35 USC § 103 (second)
Claims 1 and 76 are rejected under 35 U.S.C. 103 as being unpatentable over Bleakley et al. (US20190211076A1 Date Published 2019-07-11) in view of Irvine et al. (WO2020018715A1 Date Published 2020-01-23).
The teachings of Bleakley et al. have been described in the second 102 rejection above.
Bleakley et al. does not specifically teach a device or kit comprising: a binding protein according to instant claim 1.
However, these deficiencies are made up in the teachings of Irvine et al.
Irvine et al. teaches TCR fusion proteins and compositions for therapeutic or diagnostic use (Abstract). They teach a kit comprising a container comprising said TCR fusion proteins that can comprise pharmaceutically acceptable carrier, package insert and instructions for administration for treating various diseases (Pg. 19 seventh full paragraph to Pg. 20 third full paragraph). They also teach kits for producing a single-dose administration unit and kits containing single and multi-chambered pre-filed syringes (Pg. 76 fourth paragraph).
One of ordinary skill in the art would have been motivated, with a reasonable expectation of success, to perform a combined method of making a binding protein comprising a) the TCR alpha chain sequence of SEQ ID NO: 38 as taught by Bleakley et al. which has at least about 80% identity to the TCR alpha chain sequence as set forth in instant SEQ ID NO: 3; and b) the TCR beta chain sequence of SEQ ID NO: 37 as taught by Bleakley et al. with at least about 80% identity to the TCR beta chain sequence as set forth in instant SEQ ID NO: 4, wherein the binding protein is capable of binding to an HA-1 immunogenic peptide-MHC (pMHC) complex as taught by Bleakley et al., and including the binding protein in a kit as taught by Irvine et al. because a kit comprising said binding protein would have the advantage of simplifying the administration of the binding protein for treatment of diseases. This is an example of (A) Combining prior art elements according to known methods to yield predictable results; and (G) Some teaching, suggestion, or motivation in the prior art that would have led one of ordinary skill to modify the prior art reference or to combine prior art reference teachings to arrive at the claimed invention. See MPEP 2143. Therefore, the invention as a whole would have been prima facie obvious to one of ordinary skill in the art, absent unexpected results.
Conclusion
No claims are allowed.
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/YIE-CHIA LEE (TONYA)/Examiner, Art Unit 1642
/SEAN E AEDER/Primary Examiner, Art Unit 1642
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