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 .
Status of Claims
Claims 1, 4, 11, 13, 14, 22-25, 30-32, 38, 42, 43, 48, 59, 65, 77 and 80 are pending.
Claims 1, 11, 13, 14, 22-25, 30-32, 38, 42, 43, 48, 59, 65, 77 and 80 are amended.
Claims 1, 4, 11, 13, 14, 22-25, 30-32, 38, 42, 43, 48, 59, 65, 77 and 80 are currently 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 03/12/2021 based on the provisional application 63/160,558 (filed 03/12/2021).
Drawings
The drawings are objected to because there appears to be a typographical error for SEQ ID NOs: 33 and 44 in the Figure 12B (Pg. 15) and Figure 13B (Pg. 17) respectively. While these sequences are defined or labelled as “NY-ESO-1156-165”, the specification discloses that these should be NY-ESO-1157-165 (paragraphs [0064] and [0065]). The typographical error is in the numbering of “156” which should be “157”.
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 deficiency - The Incorporation by Reference paragraph required by 37 CFR 1.821(c)(1) is missing. See item 1) a) or 1) b) above.
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 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.
Specification
The disclosure is objected to because of the following informalities:
There appears to be a typographical error for SEQ ID NOs: 33 and 44 in the Sequence Listing. While these sequences are defined or labelled as “Synthetic NY-ESO-1156-165”, the specification discloses that these should be NY-ESO-1157-165 (paragraphs [0064] and [0065]). The typographical error is in the numbering of “156” which should be “157”.
In paragraph [0075], the instant specification discloses that the TCR-T comprises a T-cell receptor a-chain comprising an amino acid sequence encoded by a nucleic acid sequence of SEQ ID NOs: 5, 16, 27, or 38; a T-cell receptor beta-chain comprising an amino acid sequence encoded by a nucleic acid sequence of SEQ ID NOs: 10, 21, 32, or 43; or both. It is noted in the Sequence Listings that SEQ ID NOs: 5, 16, 27, 38, 10, 21, 32, and 43 are amino acid sequences, not nucleic acid sequences. As such, the phrase “a nucleic acid sequence of” should be deleted in this paragraph.
In paragraphs [00262] to [00266], the instant specification discloses that the TCR-T comprises a T-cell receptor α-chain comprising an amino acid sequence encoded by a nucleic acid sequence of SEQ ID NOs: 5, 16, 27, or 38; a T-cell receptor β-chain comprising an amino acid sequence encoded by a nucleic acid sequence of SEQ ID NOs: 10, 21, 32, or 43. This is a similar objection to the one above, wherein, it is noted in the Sequence Listings that SEQ ID NOs: 5, 16, 27, 38, 10, 21, 32, and 43 are amino acid sequences, not nucleic acid sequences. As such, the phrase “a nucleic acid sequence of” should be deleted in these paragraphs.
Appropriate correction is required.
Claim Objections
Claims 25, 32, 42 and 48 are objected to because of the following informalities:
Claim 25 appears to have a typographical error. The word “vector” should be inserted in line 3 after “myxoma virus”.
Claim 32 appears to have a typographical error. A space should be inserted before the term “LAGE-1” and after the comma “,” at the beginning of line 6.
Claim 42 appears to have a typographical error. The phrase “the absence of the tumor haplotype” is suggested to be amended to “is absent of the tumor haplotype”.
Claim 48 appears to have a typographical error. The phrase “or use” in line 2 should be deleted.
Appropriate correction is required.
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 4, 25, and 59 are rejected under 35 U.S.C. 112(b) or 35 U.S.C. 112 (pre-AIA ), second paragraph, as being indefinite for failing to particularly point out and distinctly claim the subject matter which the inventor or a joint inventor (or for applications subject to pre-AIA 35 U.S.C. 112, the applicant), regards as the invention.
Claim 4 recites in line 3 “…the HLA haplotype.”. There is insufficient antecedent basis for “the HLA haplotype” in the claim.
Claim 25 recites in line 2 “(pox)” and line 4 “(including lentivirus vector or a pseudotyped vector)”. The words in the parentheses in the claim can be read as being required as a limitation or not required as a limitation of the claim. Therefore, the metes-and-bounds of the claims are unclear because it is unclear whether the claim is to read on a pox virus vector or a lentivirus vector or a pseudotyped vector as recited in parentheses in claim 25.
Claim 59 recites “The method of claim 1, wherein the TCR comprises….” Claim 1 does not recite a “TCR”; rather, claim 1 recites a “TCR-T” – which involves one or more TCRs. There is insufficient antecedent basis for “the TCR” in the claim. In an effort to expedite prosecution, the following amendment to claim 59 is suggested to obviate this rejection: “The method of claim 1, wherein the TCR-T comprises a TCR that comprises….”
Claim Rejections 35 U.S.C.112(a)
The following is a quotation of the first paragraph of 35 U.S.C. 112(a):
(a) IN GENERAL.—The specification shall contain a written description of the invention, and of the manner and process of making and using it, in such full, clear, concise, and exact terms as to enable any person skilled in the art to which it pertains, or with which it is most nearly connected, to make and use the same, and shall set forth the best mode contemplated by the inventor or joint inventor of carrying out the invention.
The following is a quotation of the first paragraph of pre-AIA 35 U.S.C. 112:
The specification shall contain a written description of the invention, and of the manner and process of making and using it, in such full, clear, concise, and exact terms as to enable any person skilled in the art to which it pertains, or with which it is most nearly connected, to make and use the same, and shall set forth the best mode contemplated by the inventor of carrying out his invention.
Claim 65 is 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, the claim is inclusive of a genus of T-cell receptor (TCR) α-chains encoded by sequences that have at least 90% sequence identity to the nucleic acid sequence of SEQ ID NOs: 6, 17, 28 or 39; and/or T cell receptor β-chains encoded by sequences that have at least 90% sequence identity to the nucleic acid sequence of SEQ ID NOs: 1, 12, 23, or 34. In addition, the claim is inclusive of variability in the CDRs of the α-chains and β-chains that provide specificity for binding to antigens, wherein it is known in the art that structural mutations in the CDRs of T-cell receptors can lead to highly unpredictable functional outcomes. The number of possible TCR α-chains and b-chains would be enormous when up to 10% sequence variation could be included in nucleic acid sequences encoding both the α-chain and β-chains. However, the written description in this case only sets forth four species of T-cell receptor α-chains encompassed by the claim, namely SEQ ID NOs: 5, 16, 27 and 38 T-cell receptor a-chains encoded by nucleic acid sequence of SEQ ID NOs: 6, 17, 28 and 39, and four species of T cell receptor β-chains encompassed by the claim, namely SEQ ID NOs: 10, 21, 32 and 43 T-cell receptor β -chains encoded by nucleic acid sequence of SEQ ID NOs: 1, 12, 23, and 34. Further, the Sequence Listings also discloses only four species of TCR encompassed by the claim, namely:
KKLC-1-TCR:
alpha-chain: SEQ ID NO: 10 (amino acid) and SEQ ID NO: 6 (nucleic acid)
beta-chain: SEQ ID NO: 5 (amino acid) and SEQ ID NO: 1 (nucleic acid)
HERVE-TCR:
alpha-chain: SEQ ID NO: 21 (amino acid) and SEQ ID NO: 17 (nucleic acid)
beta-chain: SEQ ID NO: 16 (amino acid) and SEQ ID NO: 12 (nucleic acid)
NY-ESO-1-TCR:
alpha-chain: SEQ ID NO: 32 (amino acid) and SEQ ID NO: 28 (nucleic acid)
beta-chain: SEQ ID NO: 27 (amino acid) and SEQ ID NO: 23 (nucleic acid)
1G4-LY-TCR:
alpha-chain: SEQ ID NO: 43 (amino acid) and SEQ ID NO: 39 (nucleic acid)
beta-chain: SEQ ID NO: 38 (amino acid) and SEQ ID NO: 34 (nucleic acid)
Therefore, the specification does not disclose, and the art does not teach, the genus of T-cell receptor α-chains and T cell receptor β-chains as broadly encompassed in the claim.
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. Further, disclosure that does not adequately describe a product itself logically cannot adequately describe a method of using that product. See Ariad, 598 F.3d at 1354-55 (“Regardless whether the asserted claims recite a compound, Ariad still must describe some way of performing the claimed methods... the specification must demonstrate that Ariad possessed the claimed methods by sufficiently disclosing molecules capable of reducing NF-kB activity so as to ‘satisfy the inventor’s obligation to disclose the technologic knowledge upon which the patent is based, and to demonstrate that the patentee was in possession of the invention that is claimed.’”) (internal citation omitted); see also Univ. of Rochester v. G.D. Searle& Co., Inc., 358 F.3d916,918 (Fed.Cir.2004) (applying the same analysis to assess written description for claims to a “method for selectively inhibiting” a particular enzyme by administering a functionally defined compound, i.e., a “non-steroidal compound that selectively inhibits activity” of the gene product for that enzyme).
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 T-cell receptor α-chains and T cell receptor β-chains that encompass the genus of α-chains and β-chains encoded by sequences that have at least 90% sequence identity to the recited nucleic acid sequences, 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.
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 four species disclosed in the instant 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.
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)
Claims 59 and 65 are rejected under 35 U.S.C. 112(a) or 35 U.S.C. 112 (pre-AIA ), first paragraph, because the specification, while being enabled for the method of increasing sensitivity of a tumor cell to TCR-T therapy of instant claim 1, wherein the tumor cell is genetically modified to express a particular haplotype wherein: (a) the tumor cell is genetically modified to express HLA-A*01 peptide and the peptide as set forth in SEQ ID NO:11, and TCR of the TCR-T comprises the α-chain and β-chain comprising the amino acid of SEQ ID NOs: 10 and 5, respectively encoded by the nucleic acids of SEQ ID NOs: 6 and 1, respectively as described in Example 2 and Figures 10A and 10B in the specification; (b) the tumor cell is genetically modified to express HLA-A*11 peptide and the peptide as set forth in SEQ ID NO:22 and TCR of the TCR-T comprises the α-chain and β-chain of SEQ ID NO:21 and 16, respectively as described in Example 1 and Figures 11A & 11B in the specification; and (c) the tumor cell is genetically modified to express HLA-A*02 peptide and the peptide as set forth in SEQ ID NO: 33 and TCR of the TCR-T comprises the α-chain and β-chain of SEQ ID NOs: 32 and 27, respectively as described in Example 3 and Figures 12A and 12B in the specification. However, the claims are not enabled for methods of increasing sensitivity of a TCR-T therapy of instant claim 1, wherein the tumor cell of the claim is genetically modified to express just any haplotype and where the TCR-T therapy comprise just any imaginable TCR encompassed by claims 59 and 65 . The specification does not enable any person skilled in the art to which it pertains, or with which it is most nearly connected, to make and/or use 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.
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).
The breadth of instant claim 59 is a method of increasing sensitivity of a TCR-T therapy of instant claim 1, wherein the tumor cell of the claim is genetically modified to express just any haplotype where the TCR-T therapy comprise just any imaginable TCR comprising as few as one recited SEQ ID NO. SEQ ID NOs of claim 59 of TCR a and b chains.
The breadth of instant claim 65 is a method of increasing sensitivity of a TCR-T therapy of instant claim 1, wherein the tumor cell of the claim is genetically modified to express just any haplotype where the TCR-T therapy comprise just any imaginable TCR comprising as little as 90% sequence identity to a single SEQ ID NO encompassed by the claim. SEQ ID NOs of claim 65 include TCR a and b chains.
The nature of the invention is a method for increasing sensitivity of a population of tumor cells to a TCR-T therapy by modifying tumor cells to express a particular haplotype.
The level of skill of one skilled in this art is high.
The amount of direction and working examples provided in the instant specification is such that there are four species of T-cell receptor α-chains, namely nucleic acid sequence of SEQ ID NOs: 6, 17, 28 and 39 that correspond to amino acid sequence of SEQ ID NOs: 5, 16, 27 and 38 respectively, and four species of T cell receptor β-chains, namely nucleic acid sequence of SEQ ID NOs: 1, 12, 23, and 34 that correspond to amino acid sequence of SEQ ID NOs: 10, 21, 32 and 43 respectively. Further, the Examples 1-3, Figures 10 to 12 and Sequence Listings also discloses three species of TCR for TCR-T therapy such that sensitivity for TCR of each therapy was increased by modifying tumor cells to express a distinct haplotype, namely:
KKLC-1-TCR that is effective at recognizing the HLA-A*01 peptide of SEQ ID NO: 11 expressed in tumor cells modified to express HLA-A*01 peptide (Example 2 and Figures 10A and 10B):
alpha-chain: SEQ ID NO: 10 (amino acid) and SEQ ID NO: 6 (nucleic acid)
beta-chain: SEQ ID NO: 5 (amino acid) and SEQ ID NO: 1 (nucleic acid)
HERVE-TCR that is effective at recognizing the HLA-A*11 peptide of SEQ ID NO: 22 expressed in tumor cells modified to express HLA-A*11 peptide (Example 1 and Figures 11A and 11B):
alpha-chain: SEQ ID NO: 21 (amino acid) and SEQ ID NO: 17 (nucleic acid)
beta-chain: SEQ ID NO: 16 (amino acid) and SEQ ID NO: 12 (nucleic acid)
NY-ESO-1-TCR that is effective at recognizing the HLA-A*02 peptide of SEQ ID NO: 33 expressed in tumor cells modified to express HLA-A*02 peptide (Example 3 and Figures 12A and 12B):
alpha-chain: SEQ ID NO: 32 (amino acid) and SEQ ID NO: 28 (nucleic acid)
beta-chain: SEQ ID NO: 27 (amino acid) and SEQ ID NO: 23 (nucleic acid).
The state of the prior art is such that it is well established in the art that the formation of an intact antigen-binding site of TCRs generally requires the association of the complete α-chain and β-chain of a given TCR, each of which consists of three CDRs or hypervariable regions, which provide the majority of the contact residues for the binding of the TCR to its target HLA peptide (Sharma and Kranz Journal of Biological Chemistry, Volume 293, Issue 5, 2018, Pages 1820-1834; see in particular Pg. 1820 paragraph spanning columns left and right). Thus, the HLA peptide that genetically modifies the population of tumor cells to express a tumor haplotype different from the tumor haplotype endogenous to the population of tumor cells have to be expressed by the tumor cells that can be specifically recognized by the TCRs that are taught in the specification as described above.
Therefore, one cannot extrapolate the teachings of the specification to the scope of the claims because the claims are broadly drawn to methods of increasing sensitivity of a TCR-T therapy of instant claim 1, wherein the tumor cell of the claim is genetically modified to express just any haplotype and where the TCR-T therapy comprise just any imaginable TCR encompassed by claims 59 and 65 and Applicant has not demonstrate that sensitivity to TCR-T therapy of instant claim 1 wherein the TCR-T therapy comprises just any imaginable TCR encompassed by claims 59 and 65 predictably increases sensitivity of the TCR-T therapy. Rather, the specification clearly discloses that sensitivity to TCR-T therapy is specifically increased by genetically modifying tumor cells to express a particular haplotype in a TCR-specific manner. Further, undue experimentation would be required to determine which genetic modifications to tumor cells to express a tumor haplotype different from the tumor haplotype endogenous to the tumor cells would increase sensitivity of the tumor cells for every other imaginable TCR of TCR-T encompassed by claims 59 and 65 in order to perform the method as claimed.
In view of the teachings above and the lack of guidance, workable examples and or exemplification in the specification, it would require undue experimentation by one of skill in the art to determine with any predictability, that the method would function as claimed.
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.
Claim 77 is rejected under 35 U.S.C. 101 because the claimed invention is directed to judicial exception(s) (i.e., a law of nature, a natural phenomenon, and/or an abstract idea) without significantly more. The rationale for this determination is explained below:
Claim 77 is directed to natural phenomenon because the claim 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: peptides comprising the amino acid sequence NTDNNLAVY (instant SEQ ID NO: 11), ATFLGSLTWK (instant SEQ ID NO:22), or SLLMWITQC (instant SEQ ID NO:33). Said peptides are comprised within naturally occurring proteins in human cancer cells, namely Kita-Kyushu Lung Cancer Antigen 1, HERV-E antigen and NY-ESO-1 respectively.
The claim(s) does/do not include additional elements that are sufficient to amount to significantly more than the judicial exception(s). A claim that focuses on judicial exception(s) can be shown to recite something “significantly more” than the judicial exception(s) by reciting a meaningful limitation beyond the judicial exceptions. However, in the instant case, the claims do not include additional elements that are sufficient to amount to significantly more than the judicial exception because the claims are solely drawn to peptides that are not markedly different than peptides found in nature (“Step 2B”).
Claim Rejections - 35 USC § 102/103 (first)
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.
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.
Claims 1, 11, 13, 14, 22, 24, 25, 31, 32, 38, 42, 43, 77 and 80 are rejected under 35 U.S.C. 102(a)(1) and (a)(2) as being anticipated by or, in the alternative, under 35 U.S.C. 103 as obvious over Hou et al. (US20200289567A1 Date Published 2020-09-17) and as evidenced by Shaw et al. (Molecular Therapy Volume 10, Issue 6, 2004, Pages 1032-1042), He et al. (Proc. Natl. Acad. Sci. USA Vol. 95, pp. 2509–2514, March 1998), Purbhoo et al. (J Immunol. 2006 Jun 15;176(12):7308-16) and Siegfried (Cancer Res (1987) 47 (11): 2903–2910).
Hou et al. teaches a method of administering a therapeutic agent for the treatment of tumors and/or cancers of a subject (Abstract). They teach in Example 4 that the transduction of tumor cells with nucleic acids encoding labelling antigenic epitope peptides and/or exogenous HLA class I molecule can sensitize said tumor cells to be recognized by primary T cells that are transduced to express a specific TCR (paragraph [0359]). They also teach that HLA-A2 negative PBMCs were transfected with recombinant lentivirus that express NY-ESO-1 157-165 specific TCRs in T cells that had high binding affinity with NY-ESO-1 157-165/HLA-A2 complexes which are considered to be suitable for the development of adoptive T cell therapy against cancer (paragraph [0360]). They further teach that three tumor cell lines, namely A375 (NY-ESO-1 and HLA-A2 double positive), SKOV3 (NY-ESO-1 and HLA-A2 double negative) and SKOV3-NY (NY-ESO-1 positive alone) were transduced with pShuttle-EF1a-E1Ad24-A2-NY (vector encoding HLA-A2 protein and the labelling NY-ESO-1 157-165 epitope peptide) or pShuttle-EF1a-E1Ad24-A2-BM (vector expressing exogenous HLA-A2 protein alone) and utilized as target cells to assess the function of the exogenous HLA-A2 to sensitize tumor cells to be recognized by the specific TCRs expressed on primary T cells (paragraphs [0357] and [0361]). In addition, they teach in FIG. 4B that all target cell lines transduced with pShuttle-EF1a-E1A d24-A2-BM efficiently present the NY-ESO-1 156-165 peptide to activate the TCRs expressed by T cells, demonstrating that the exogenous HLA-A2 protein was expressed by the pShuttle-EF1a-E1A d24-A2-BM vector in the target cancer cell lines and that the NY-ESO-1 156-165/HLA-A2 complexes could be recognized by the primary T cells that were directed to express NY-ESO-1 specific TCRs, including TCR-NY-LY, TCR-NY-AE and TCR-NY-LI (FIG. 4A, FIG. 4B and paragraph [0361]).
Hou et al also teaches that human lung cancer cell line H1299 (NY-ESO-1+/HLA-A2-), human osteosarcoma cell line HOS-C1 (NY-ESO-1 low/HLA-A2+), and human lung cancer cell line A549 were able be sensitized by the labelling polypeptide containing NY-ESO-1 157-165 epitope peptides and the exogenous HLA-A2 protein to be recognized by the T cells expressing the NY-ESO-1 specific TCR (paragraph [0362]). Therefore, Hou et al. teaches that the method is effective in tumor cell lines that are from a solid tumor, as evidenced by Siegfried that teaches A549-1 cell line was derived from a human bronchioloalveolar carcinoma of lung which is a form of a solid lung tumor(Pg. 2905 column left paragraph second lines 1-3).
Therefore, Hou et al. anticipates above instant claims by teaching that SKOV3, a cell line that is endogenously NY-ESO-1 and HLA-A2 double negative (in other words, null or absent of NY-ESO-1 and HLA-A2 tumor haplotype), was genetically modified to stably express the NY-ESO-1 157-165 epitope peptide and the exogenous HLA-A2 molecule through contacting the tumor cells with vector encoding the NY-ESO-1 157-165 epitope peptide and exogenous HLA-A2 molecule. Similarly, Hou et al. also anticipates the instate claims by teaching that SKOV3-NY, a cell line that is only NY-ESO-1 positive (in other words, null or absent of HLA-A2 tumor haplotype), was genetically modified to stably express exogenous HLA-A2 molecule in the said manner performed on SKOV3 cell lines. Further, Hou et al. anticipates instants claims by teaching that both the said cancer cell lines could be sensitized by vectors that provided the exogenous HLA-A2 molecule to be recognized by primary T cells that were redirected to express NY-ESO-1 specific TCR that are utilized for adoptive T cell therapy against cancer (paragraphs [0095] and [0362]).
As evidenced by He et al., the pShuttle vector is a recombinant adenovirus vector (Pg. 2510 column left paragraph second lines 1-6, and paragraph fifth). In addition, as evidenced by Purbhoo et al., the HLA-A2-restricted 157–165 epitope of the NY-ESO-1 consists of the amino acid sequence of SLLMWITQC (Abstract and Pg. 7308 column left paragraph first lines 11-12). Therefore, by teaching the NY-ESO-1 157-165 epitope peptide to be introduced and expressed in tumor cell lines, Hou et al. anticipates SEQ ID NO:33 that has exactly the same amino acid sequence as taught by Purbhoo et al. Further as evidenced by Shaw et al., SKOV3 cell lines are capable of forming solid tumors and clear cell adenocarcinomas when inoculated in mice (Pg. 1032 column right lines 14-16 and Pg. 1035 column left paragraph second) therefore establishing that the tumor cells SKOV3 and SKOV3-NY taught by Hou et al. are from a solid tumor.
Hou et al. also teaches that T cells transfected with lentiviruses encoding the exogenous TCR specific for the NY-ESO-1 157-165 epitope peptide were shown to bind to the iTAg Tetramer/PE-HLA-A*02:01 NY-ESO-1 (SLLMWITQC (SEQ ID NO: 2)) using flow cytometry (paragraphs [0089] and [0331] and FIG. 1D). SEQ ID NO: 2 as taught by Hou et al. is an exact match to instant SEQ ID NO:33. Therefore, Hou et al. anticipates a TCR-T therapy that comprises a TCR having antigenic specificity for a peptide comprising the amino acid sequence SLLMWITQC (instant SEQ ID NO:33).
Regarding instant claim 14, the successful expression of exogenous HLA-A2 molecule in SKOV3 and SKOV3-NY tumor cell lines via transduction of said cells with adenoviral vectors encoding the exogenous HLA-A2 molecule as taught by Hou et al. is indicative of the stable integration of the nucleic acid or vector into the genome of the tumor cells. Further, in regards to this rejection being a rejection under 35 U.S.C. 103, one of ordinary skill in the art would have been motivated with a reasonable expectation of success to perform the method of Hou et al. wherein the HLA-A2 molecule is genomically integrated into the tumor cells, as opposed to just transiently expressed by the tumor cells, because one of skill in the art would recognize transduced genetic vectors are either transiently expressed or expressed after genomic integration and genomic integration has the benefit of stable (as opposed to “transient”) expression.
Therefore, Hou et al. fully anticipates claims 1, 11, 13, 22, 24, 25, 31, 32, 38, 42, 77 and 80 and are rejected here.
Claim Rejections - 35 USC § 102 (first)
Claims 77 is rejected under 35 U.S.C. 102(a)(1) as being anticipated by Stevanovic and Hinrichs (WO2017189254A1 Date Published 2017-11-02).
Stevanovic and Hinrichs teaches isolated T cell receptor (TCR) having antigenic specificity for Kita-Kyushu Lung Cancer Antigen 152-60 (KK-LC-152-60) (Abstract). They teach the TCR has antigenic specificity for a KK-LC- 152-60 peptide comprising, consisting of, or consisting essentially of, NTDNNLAVY (SEQ ID NO: 2) (paragraph [0018]).
SEQ ID NO: 2 as taught by Stevanovic and Hinrichs thus anticipates the instant peptide comprising the amino acid sequence NTDNNLAVY (instant SEQ ID NO:11).
Claim Rejections - 35 USC § 102 (second)
Claims 77 is rejected under 35 U.S.C. 102(a)(1) as being anticipated by Takahashi et al. (J Clin Invest. 2008;118(3):1099-1109).
Takahashi et al. teaches the recognition of an HERV-E antigen, an overexpressed immunogenic antigen in human renal cell carcinoma (RCC), by T cells (Title and Abstract). They teach the 10-mer peptide ATFLGSLTWK (named CT-RCC-1) induced dose-dependent CTL secretion of IFN-gamma consistent with said peptide being the HLA-A11–restricted antigen recognized by RCC-reactive SAUJ-CTLs (Figure 6B, Pg. 1108-1109 paragraph “Identification of the antigenic peptides” and Pg. 1102 column left paragraph spanning).
The 10-mer peptide ATFLGSLTWK as taught by Takahashi et al. thus anticipates the instant peptide comprising the amino acid sequence ATFLGSLTWK (instant SEQ ID NO:22).
Claim Rejections - 35 USC § 103 (first)
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 1, 4, 23, 30 and 48 are rejected under 35 U.S.C. 103 as being unpatentable over Hou et al. (US20200289567A1 Date Published 2020-09-17).
The teachings of Hou et al. have already been described in the first 102 rejection above.
However, Hou et al. does not specifically teach a method for increasing HLA expression to render a population of tumor cells susceptible to autologous T cells, wherein the method comprises genetically modifying the population of tumor cells to express the HLA haplotype. They also do not specifically teach the method of instant claim 11, wherein the vector is administered to a subject in need thereof systemically, intratumorally, and/or intravenously. They further do not specifically teach the method of instant claim 1, wherein the TCR-T is administered subsequently to genetically modifying the population of tumor cells to express a tumor haplotype different from the tumor haplotype endogenous to the population of tumor cells. They also further do not specifically teach the method of instant claim 1, wherein the method is for the treatment of cancer in a subject in need thereof. These deficiencies are remedied by the teachings of Hou et al.
Hou et al. teaches that TCR-T cell therapy is a type of ACT (also known as “adoptive cell transfer” or “adoptive cell therapy”) where a subject or patient's own immune cells (e.g., autologous T cells), or immune cells from healthy donors (e.g., allogeneic T cells) are collected to treat their cancer (paragraph [0224]). They also teach that the term “autologous” refers to any material derived from the same individual to whom it is later to be reintroduced into the individual (paragraph [0230]).
Hou et al also teaches that the nucleic acid encoding a labelling antigenic epitope peptide and/or a HLA class I protein can be formulated and administered intratumorally (paragraphs [0011], [0023], [0037] and [0215]).
Hou et al. teaches a therapeutic agent and method of administering the therapeutic agent for the treatment of tumors and/or cancers of a subject, wherein the therapeutic agent comprises a first agent or composition comprising nucleic acids encoding a labelling antigenic epitope polypeptide, and/or a MHC protein that can be a HLA class I protein, to be delivered into tumor cells and cause the tumor cells and/or cancer cells to express said specific target polypeptide and/or protein, and a second agent or composition that contains TCR-modified T cells that can be from the subject's own T cells modified to express a specific TCR receptor that is subsequently administered after the first composition (Abstract, paragraphs [0004], [0011], [0012] and [0205]).
One of ordinary skill in the art would have been motivated, with a reasonable expectation of success, to perform a combined method for increasing HLA expression to render a population of tumor cells susceptible to autologous T cells as taught by Hou et al., wherein the method comprises genetically modifying the population of tumor cells to express the HLA haplotype also as taught by Hou et al. because Hou et al. teaches that autologous T cells are commonly used TCR-T cell therapy (paragraph [0224]).
One of ordinary skill in the art would have been motivated, with a reasonable expectation of success, to perform a combined method to introduce the nucleic acid or vector encoding the exogenous tumor haplotype into the population of tumor cells such that there is stable expression of the tumor haplotype that is different from the tumor haplotype endogenous to the population of tumor cells as taught by Hou et al., wherein the vector is administered to a subject in need thereof intratumorally also as taught by Hou et al. because Hou et al. teaches that the direct injection of plasmid DNA within the tumor can be used to deliver DNA into tumor cells (paragraph [0166]).
One of ordinary skill in the art would have been motivated, with a reasonable expectation of success, to perform a combined method for increasing the sensitivity of a population of tumor cells to a TCR-engineered T cell (TCR-T) therapy as taught by Hou et al., wherein the TCR-T is administered subsequently to genetically modifying the population of tumor cells to express a tumor haplotype different from the tumor haplotype endogenous to the population of tumor cells also as taught by Hou et al. because Hou et al. teaches said method of first administering the first agent which comprises nucleic acids encoding a labelling antigenic epitope polypeptide, and/or a MHC protein that can be a HLA class I protein, and subsequently administering the second composition which is the TCR-T (Abstract, paragraphs [0004], [0011], [0012] and [0205]).
One of ordinary skill in the art would have been motivated, with a reasonable expectation of success, to perform a combined method for increasing the sensitivity of a population of tumor cells to a TCR-engineered T cell (TCR-T) therapy as taught by Hou et al., wherein the method is for the treatment of cancer in a subject in need thereof also as taught by Hou et al. because Hou et al teaches that primary T cells that were redirected to express NY-ESO-1 specific TCR were sensitized to cancer cell lines that were transduced with nucleic acids encoding exogenous HLA-A2 molecule, such that secretion of IFN-gamma by the T cells was enhanced, signifying activation of said cells that can effect enhanced tumor cell killing thereby making it a useful method for the treatment of cancer in a subject in need thereof (Abstract, paragraphs [0135] and [0361] and FIG. 4B).
These are examples 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, 59, 65 and 80 are rejected under 35 U.S.C. 103 as being unpatentable over Hou et al. (US20200289567A1 Date Published 2020-09-17) as applied to claim 1 above and further in view Stevanovic and Hinrichs (WO2017189254A1 Date Published 2017-11-02), Childs et al. (WO2018006054A1 Date Published 2018-01-04) and Li and Zhou (WO2019096127 Date Published 2019-05-23).
Note that the citations of Li and Zhou is based on the translation of the WO2019096127 attached to the Office Action as an OA appendix.
The teachings of Hou et al. have already been described in the first 102 rejection above as applied to claim 1.
However, Hou et al. does not specifically teach the method of instant claim 1, wherein the TCR comprises the amino acid sequences of SEQ ID NOs: 5, 10, 16, 21, 27, 32, 38, and/or 43. They also do not specifically teach the method of instant claim 1, wherein the TCR-T comprises a T-cell receptor α-chain comprising an amino acid sequence encoded by a nucleic acid sequence comprising at least 90% sequence identity to the nucleic acid sequence of SEQ ID NO: 17; a T cell receptor β-chain comprising an amino acid sequence encoded by a nucleic acid sequence comprising at least 90% sequence identity to the nucleic acid sequence of SEQ ID NO: 12, or both. They further do not specifically teach the method of claim 1, wherein the TCR-T therapy comprises a TCR having antigenic specificity for a peptide comprising the amino acid sequence NTDNNLAVY (instant SEQ ID NO: 11).
These deficiencies are remedied by the teachings of Stevanovic and Hinrichs, Childs et al. and Li and Zhou.
The teachings of Stevanovic and Hinrichs are described in the second 102 rejection above. Briefly, they teach isolated T cell receptor (TCR) having antigenic specificity for Kita-Kyushu Lung Cancer Antigen 152-60 (KK-LC-152-60) comprising, consisting of, or consisting essentially of, NTDNNLAVY (SEQ ID NO: 2) (Abstract and paragraph [0018]). Further, they also teach a TCR comprising a full-length alpha chain comprising the amino acid sequence of SEQ ID NO: 15 and a full-length beta chain comprising the amino acid sequence of SEQ ID NO: 16 (claim 6, paragraphs [0033] and paragraphs [0102]). Alignment of the amino acid sequence of SEQ ID NOs: 15 and 16 as taught by Stevanovic and Hinrichs showed that they are an exact match to instant SEQ ID NOs: 10 and 5 respectively (alignment not shown).
Childs et al. teaches T cell receptors (TCRs) capable of binding an antigen expressed by renal cell carcinoma cells (RCC) (Abstract). They teach a RCC HERV-reactive TCR comprising α chain that comprises or consists of the amino acid sequence of SEQ ID NO: 4 and a β chain that comprises or consists of the amino acid sequence of SEQ ID NO: 5 (claim 15). Alignment of the amino acid sequence of SEQ ID NOs: 4 and 5 as taught by Childs et al. showed that they are an exact match to instant SEQ ID NOs: 21 and 16 respectively (alignment not shown). Childs et al. also teaches a vector comprising a nucleic acid molecule encoding the T cell receptor α chain comprising the nucleic acid sequence of SEQ ID NO: 2 and a nucleic acid molecule encoding the T cell receptor β chain comprising the nucleic acid sequence of SEQ ID NO: 3 (claims 2 and 3). Alignment of the nucleic acid sequence of SEQ ID NOs: 2 and 3 as taught by Childs et al. showed that they are an exact match to instant nucleic acid sequences of SEQ ID NOs: 17 and 12 respectively (alignment not shown).
Li and Zhou teach a genetically engineered T cell that is characterized by a high-affinity αβTCR that is specific to pMHC (Abstract). They teach 1G4 TCR specific for NY-ESO-1 (paragraph [0125]). They also teach a TCR comprising an α chain with the amino acid sequence of SEQ ID NO: 10. They further teach a TCR with a β chain with the amino acid sequence of SEQ ID NO: 4 (paragraph [0096]). Alignment of the amino acid sequence of SEQ ID NO: 4 as taught by Li and Zhou showed that it is an exact match to instant SEQ ID NO: 38 (alignment not shown). While the alignment of the amino acid sequence of SEQ ID NO: 10 as taught by Li and Zhou, which consists of 273 amino acid residues, showed that it matches 100% to residues 2 to 275 of instant SEQ ID NO: 43 (alignment not shown). It is noted that residue 1 of instant SEQ ID NO: 43 is the amino acid methionine (M) which is known to be a universal initiator amino acid at the N-terminus of nascent eukaryotic polypeptide chains.
One of ordinary skill in the art would have been motivated, with a reasonable expectation of success, to perform a combined method for increasing the sensitivity of a population of tumor cells to a TCR-engineered T cell (TCR-T) therapy as taught by Hou et al., wherein the TCR comprises (i) the amino acid sequences of instant SEQ ID NOs: 10 and 5 and that has antigenic specificity for the amino acid sequence of NTDNNLAVY (identical to instant SEQ ID NO: 11) as taught by Stevanovic and Hinrichs, or (ii) the amino acid sequences of instant SEQ ID NOs: 21 and 16, or the nucleic acid sequences of instant SEQ ID NOs: 17 and 12 as taught by Childs et al., or (iii) the amino acid sequences of instant SEQ ID NOs: 43 and 38 as taught by Li and Zhou, because (i) Stevanovic and Hinrichs teaches that KK-LC-1-specific TCR transduced T cells displayed specific cytolysis of tumor cell lines in an antigen- and HLA-dependent manner in cytotoxicity assays (Figure 4B and paragraph [0136]), (ii) Childs et al. teaches that T cells transduced with TCR reactive with RCC HERV specifically killed HLA-A11+ and HERV-E+ ccRCC cells (FIGS. 6A and 6B and Pg. 21 lines 20-21), and (iii) Li and Zhou teaches that the 1G4 TCR specific for NY-ESO-1 had strong killing effect on the positive tumor cell line (paragraph [0131]). These are examples 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 (third)
Claims 1 and 65 are rejected under 35 U.S.C. 103 as being unpatentable over Hou et al. (US20200289567A1 Date Published 2020-09-17) as applied to claim 1 above and further in view Robbins et al. (US20100034834A1 Date Published 2010-02-11).
The teachings of Hou et al. have already been described in the first 102 rejection above as applied to claim 1.
However, Hou et al. does not specifically teach the method of instant claim 1, wherein the TCR-T comprises a T-cell receptor α-chain comprising an amino acid sequence encoded by a nucleic acid sequence comprising at least 90% sequence identity to the nucleic acid sequence of SEQ ID NO: 39; a T cell receptor β-chain comprising an amino acid sequence encoded by a nucleic acid sequence comprising at least 90% sequence identity to the nucleic acid sequence of SEQ ID NO: 34, or both.
These deficiencies are remedied by the teachings of Robbins et al.
Robbins et al. teaches the nucleotide sequence of the 1G4 TCR as set forth as SEQ ID NO: 25 (alpha chain) and SEQ ID NO: 21 (beta chain) (paragraph [0120]), wherein 1G4 is a NY-ESO-1-specific TCR (paragraph [0124]). Alignment of the nucleic acid sequence of SEQ ID NOs: 25 and 21 as taught by Robbins et al. showed that they are an exact match to instant nucleic acid sequences of SEQ ID NOs: 39 and 34 respectively (alignment not shown).
One of ordinary skill in the art would have been motivated, with a reasonable expectation of success, to perform a combined method for increasing the sensitivity of a population of tumor cells to a TCR-engineered T cell (TCR-T) therapy as taught by Hou et al., wherein the TCR comprises the nucleic acid sequences of instant SEQ ID NOs: 39 and 34 as taught by Robbins et al. because Robbins et al. teaches that WT 1G4 TCR was used as the basis for making modified (TCR) comprising an amino acid sequence of a wild-type (WT) TCR with no more than three amino acid substitutions, wherein the modified TCR, as compared to the WT TCR, (i) has an enhanced ability to recognize target cells when expressed by CD4+ T cells and (ii) does not exhibit a decrease in antigen specificity when expressed by CD8+ T cells (Abstract). These are examples 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 (fourth)
Claims 1 and 80 are rejected under 35 U.S.C. 103 as being unpatentable over Hou et al. (US20200289567A1 Date Published 2020-09-17) as applied to claim 1 above and further in view Takahashi et al. (J Clin Invest. 2008;118(3):1099-1109).
The teachings of Hou et al. have already been described in the first 102 rejection above as applied to claim 1.
However, Hou et al. does not specifically teach the method of claim 1, wherein the TCR-T therapy comprises a TCR having antigenic specificity for a peptide comprising the amino acid sequence ATFLGSLTWK (instant SEQ ID NO:22).
These deficiencies are remedied by the teachings of Takahashi et al.
The teachings of Takahashi et al. have been described in the third 102 rejection above.
One of ordinary skill in the art would have been motivated, with a reasonable expectation of success, to perform a combined method for increasing the sensitivity of a population of tumor cells to a TCR-engineered T cell (TCR-T) therapy as taught by Hou et al., wherein the TCR-T therapy comprises a TCR having antigenic specificity for a peptide comprising the amino acid sequence ATFLGSLTWK (instant SEQ ID NO:22) as taught by Takahashi et al. because Takahashi et al. teaches that T cells recognizing the HERV-E 10-mer peptide of ATFLGSLTWK secreted IFN-gamma in a dose dependent manner, therefore making said T cells that harbor TCR that are specific to ATFLGSLTWK a potential candidate to broaden application in immunotherapy (Figure 6B, Pg. 1022 column left paragraph spanning and Pg. 1107 column right paragraph second). These are examples 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