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
Applicant’s election without traverse in the reply filed on 05/07/2026 is acknowledged. The following are Applicant’s election:
the HLA-PEPTIDE antigen of a RAS_G12C MHC Class I antigen comprising HLA-A*02:01 and the restricted peptide KLVVVGACGV, which corresponds to SEQ ID NO: 14954 (which is also identical to SEQ ID NO: 14954 and SEQ ID NO: 29366), wherein SEQ ID NO: 14954 refers to the KRAS G12C restricted peptide KLVVVGACGV in the context of being presented by HLA-A*02:01; and
the sequences associated with clone O1CA019_064_FOS_0005, which is also referred to as "TCR66", wherein the corresponding sequences are as follows:
SEQ ID NO: 29400 for the TCR alpha sequence and SEQ ID NO: 29404 for the TCR beta sequence; and
TRAV14DV4; TRAJ12; TRBV9; TRBD1; TRBJ2-3; TRBC2; CAMREESSYKLIF (SEQ ID NO: 29452) for the alpha-CDR3 amino acid sequence; and CASSVAGDSLTDTQYF (SEQ ID NO: 29456) for the beta-CDR3 amino acid sequence.
For the purpose of compact prosecution, the Examiner rejoins all species of HLA-PEPTIDE and all species of ABP encompassed by the claims.
Status of Claims
Claims 1, 4, 8, 51, 52, 56, 57, 62, 64, 71, 73, 76, 155-158 and 160-163 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 claims 1, 4, 8, 51, 52, 56, 57, 62, 64, 71, 73 and 76 under examination is set at 11/15/2019 based on the provisional application 62/936,303 (filed 11/15/2019), while the U.S. effective filing date of claims 155-158 and 160-163 under examination is set at 05/27/2020 based on the provisional application 63/030,774 (filed 05/27/2020).
Information Disclosure Statement
The information disclosure statements (IDS) submitted on 12/23/2022 and 05/07/2026 are being considered by the examiner.
The listing of references in the specification is not a proper information disclosure statement. 37 CFR 1.98(b) requires a list of all patents, publications, or other information submitted for consideration by the Office, and MPEP § 609.04(a) states, "the list may not be incorporated into the specification but must be submitted in a separate paper." Therefore, unless the references have been cited by the examiner on form PTO-892, they have not been considered.
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 – Amino acid sequences appearing in claims 4 and 160 are not identified by sequence identifiers in accordance with 37 CFR 1.821(d).
Required response – Applicant must provide:
Replacement and annotated claims in accordance with 37 CFR 1.121(c) inserting the required sequence identifiers;
Claim Objections
Claim 158 is objected to because of the following informalities:
Claim 158 recites the phrase "the HLA-restricted peptide” in line 3. For consistency, this phrase is suggested to be amended to “the HLA-restricted RAS peptide”.
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 155-158 and 160-163 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 four specific tables, namely Tables 1A.2, 1A.3, 1C.2 and 1C.3; 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).
Claim Rejections - 35 USC § 112
The following is a quotation of the first paragraph of 35 U.S.C. 112(a):
(a) IN GENERAL.—The specification shall contain a written description of the invention, and of the manner and process of making and using it, in such full, clear, concise, and exact terms as to enable any person skilled in the art to which it pertains, or with which it is most nearly connected, to make and use the same, and shall set forth the best mode contemplated by the inventor or joint inventor of carrying out the invention.
Claims 1, 4, 8, 51, 52, 56, 57, 62, 64, 71, 73, 76, 155, 156, 158 and 160-162 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.
Scope of the Claimed Genus
Instant claims 1, 4, 8, 51, 52, 56, 57, 62, 64, 71, 73 and 76 are inclusive of a genus of an antigen binding protein (ABP) that specifically binds to an HLA-PEPTIDE antigen comprising an HLA-restricted peptide complexed with an HLA Class I molecule, wherein the HLA-restricted peptide is located in the peptide binding groove of an α1/α2 heterodimer portion of the HLA Class I molecule, wherein the HLA Class I molecule and the HLA-restricted peptide are each selected from an HLA-PEPTIDE antigen as described in any one of SEQ ID NOs:10,755 to 29,364 (a total of 18,608 peptide antigens), and wherein the ABP comprises a T cell receptor (TCR) or antigen-binding fragment thereof. If there were one ABP for each of the 18,608 peptide antigens recited in the claims, then this means that the genus would include 18,608 ABPs at the very least. Alternatively, the genus could potentially include a smaller number of ABPs that could bind to several of the 18,608 peptide antigens since it is known in the art that a single TCR is inherently "promiscuous" or “cross-reactive” thus making it capable of recognizing and binding to numerous antigenic peptides (see Title and Abstract of Sewell Nat Rev Immunol 2012 Aug 24;12(9):669–677).
In addition, instant claims 155 and 156 are inclusive of a genus of an ABP of instant claim 1, wherein the ABP comprises an alpha-CDR3 amino acid sequence and corresponding beta-CDR3 amino acid sequence selected from the group consisting of the sequences shown in Tables 1C.2 and 1C.3. This means the genus includes ABPs comprising any alpha-CDR1 and any alpha-CDR2 that can be combined with the alpha-CDR3 amino acid sequences shown in Tables 1C.2 and 1C.3, that can in turn be matched with the corresponding beta-CDR3 amino acid sequences shown in Tables 1C.2 and 1C.3 that is to be combined with any beta-CDR1 and any beta-CDR2 amino acid sequences, that together form a functional set of six CDRs that is capable of binding to an HLA-PEPTIDE antigen comprising an HLA-restricted peptide complexed with an HLA Class I molecule, wherein the HLA-PEPTIDE antigen as described in any one of SEQ ID NOs:10,755 to 29,364.
Further, instant claims 158 and 160-162 are inclusive of a genus of an ABP that specifically binds to an HLA-PEPTIDE antigen comprising an HLA-restricted RAS peptide complexed with an HLA Class I molecule, wherein the HLA-restricted peptide is located in the peptide binding groove of an α1/α2 heterodimer portion of the HLA Class I molecule, wherein the HLA-restricted RAS peptide comprises at least one alteration that makes HLA-restricted RAS peptide sequence distinct from the corresponding peptide sequence of a wild-type RAS peptide, and wherein the ABP comprises an alpha-CDR3 amino acid sequence and corresponding beta-CDR3 amino acid sequence selected from the group consisting of the sequences shown in Tables 1C.2 and 1C.3. This means the genus includes ABPs comprising any alpha-CDR1 and any alpha-CDR2 that can be combined with the alpha-CDR3 amino acid sequences shown in Tables 1C.2 and 1C.3, that can in turn be matched with the corresponding beta-CDR3 amino acid sequences shown in Tables 1C.2 and 1C.3 that is to be combined with any beta-CDR1 and any beta-CDR2 amino acid sequences, that together form a functional set of six CDRs that is capable of binding to an HLA-PEPTIDE antigen comprising an HLA-restricted RAS peptide complexed with an HLA Class I molecule, wherein the HLA-restricted RAS peptide comprises at least one alteration that makes HLA-restricted RAS peptide sequence distinct from the corresponding peptide sequence of a wild-type RAS peptide.
In summary, the genus includes ABPs that:
have the defined function of binding to any one of HLA-PEPTIDE antigens of SEQ ID NOs:10,755 to 29,364 complexed with an HLA Class I molecule, but do not have defined structure (claims 1, 4, 8, 51, 52, 56, 57, 62, 64, 71, 73 and 76);
have the defined function of binding as in (i) with defined alpha-CDR3 amino acid sequence and corresponding beta-CDR3 amino acid, but do not have defined alpha-CDR1, alpha-CDR2, beta-CDR1 and beta-CDR2 which is equivalent to having mutations in the four out of six of the CDRs that contribute to the formation of an antigen binding pocket for its said defined function (claims 155 and 156); and
have the defined function of binding HLA-restricted RAS peptide that comprises at least one alteration that makes HLA-restricted RAS peptide sequence distinct from the corresponding peptide sequence of a wild-type RAS peptide with defined alpha-CDR3 amino acid sequence and corresponding beta-CDR3 amino acid, but do not have defined alpha-CDR1, alpha-CDR2, beta-CDR1 and beta-CDR2 which is equivalent to having mutations in the four out of six of the CDRs that contribute to the formation of an antigen binding pocket for its said defined function (claims 158 and 160-162).
Summary of Species Disclosed in the Specification
The specification in Tables 1A.1, 1A.2, 1A.3 and 1B disclose twenty-six TCR clones with defined twenty-six TCR alpha (VJ) sequences paired with corresponding twenty-six beta (V(D)J) sequences which represent the ABPs that the Applicant was in possession of at the time of filing (Pg 121-127). Tables 1C.1, 1C.2, 1C.3 and 1D disclose the V(D)J segments and CDR3 sequences for the same twenty-six TCR clones of Tables 1A.1, 1A.2, 1A.3 and 1B (Pg 128- 131). Therefore, the specification does not disclose, and the art does not teach, the genus of ABPs comprising a T cell receptor (TCR) alpha chain sequence and a TCR beta chain sequence, wherein (i) the ABP is capable of specifically binding to an HLA-PEPTIDE antigen comprising an HLA-restricted peptide complexed with an HLA Class I molecule, wherein the HLA Class I molecule and the HLA-restricted peptide are each selected from an HLA-PEPTIDE antigen as described in any one of SEQ ID NOs:10,755 to 29,364; or (ii) the ABP is capable of said function that comprises only defined alpha-CDR3 amino acid sequence and corresponding beta-CDR3 amino acid; or (iii) the ABP is capable of specifically binding to an HLA-PEPTIDE antigen comprising an HLA-restricted RAS peptide complexed with an HLA Class I molecule, wherein the HLA-restricted RAS peptide comprises at least one alteration that makes HLA-restricted RAS peptide sequence distinct from the corresponding peptide sequence of a wild-type RAS peptide, and wherein the ABP is capable of said function that comprises only defined alpha-CDR3 amino acid sequence and corresponding defined beta-CDR3 amino acid, as broadly as is encompassed in the claims. Therefore, the written description only reasonably conveys twenty six clones of TCRs.
State of the Prior Art and Structure/Function Correlation
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).
In summary, the structure of the TCR that provides its function of binding is from the structure of CDR sequences of the alpha and beta chains. The TCR epitope does not provide structure and a partial sequence of CDRs does not provide a structure/function correlation.
Guidance on When Disclosed Species are Representative of the Claimed Genus
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).
In regards to claims to a product defined by function, without a correlation between structure and function, the claim does little more than define the claimed invention by function. That is not sufficient to satisfy the written description requirement. See Eli Lilly, 119 at1568 USPQ2d at 1406 (“definition by function…does not suffice to define the genus because it is only an indication of what the gene does, rather than what it is”). Further, the functional requirements of the claimed antibodies are the sort of wish list of properties which fails to satisfy the written description requirement because “antibodies with those properties have not been adequately described.” Centocor, 636 F.3d at 1352. The “claims merely recite a description of the problem to be solved while claiming all solutions to it and . . . cover any compound later actually invented and determined to fall within the claim' s functional boundaries— leaving it to the pharmaceutical industry to complete an unfinished invention.”Ariad Pharmaceuticals, Inc. v. EliLilly and Co.,598 F.3d 1336, 1353 (Fed. Cir. 2010).
Further, 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). 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).
The instant specification fails to provide sufficient descriptive information, such as definitive structural features that are common to the genus. That is, the specification that discloses only twenty-six species provides neither a representative number of species ABPs that encompass the genus of ABPs that is capable of binding to an HLA-restricted peptide antigen of any one of SEQ ID NOs: 10,755 to 29,364/HLA Class I molecule complex; or an HLA-restricted RAS peptide antigen comprising at least one alteration compared to corresponding peptide sequence of a wild-type RAS peptide/HLA Class I molecule 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.
Conclusion
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 only twenty-six species of alpha sequences paired with corresponding twenty-six species of beta sequences; or only the twenty-six species of alpha-CDR3 sequences paired with corresponding twenty-six species of beta sequences alone, 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.
Claims 157 and 163 are not included in this rejection because they recite fully defined CDRs in the TCR alpha and beta chains.
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, 4, 8, 51, 52, 56, 57, 62, 64, 71, 155-158 and 160-163 are rejected under 35 U.S.C. 101 because the claimed invention is directed to antigen-specific TCRs isolated from healthy human donors, cells expressing said TCRs, and polynucleotides encoding said TCRs (see Table 1A.2 (Pg 123-124), Table 1A.3 (Pg 124-126), Table 1C.2 (Pg 129) and Table 1C.3 (Pg 130). In addition, the specification in “Example 6: Identification of TCRs that bind HLA-PEPTIDE target neoantigens Methods” discloses that PBMCs were obtained by processing leukapheresis samples from healthy donors (paragraph [00438]). Further, frozen PBMCs were thawed and enriched for different subsets of T cells through negative depletion using the following magnetic-activated cell sorting (MACS) systems (Miltenyi Biotech), as indicated below: (i) Pan T Cell Isolation Kit to enrich for naive and memory CD4 and CD8 T cells; or a (ii) Naive CD8 T Cell Isolation Kit & CD4 depletion kit to enrich for naive CD8 T cells (paragraph [00438]).
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 “pharmaceutically acceptable excipient” 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 are not markedly different from naturally occurring counterparts and polynucleotides encoding said TCRs that are not markedly different than genes of the TCRs contained within 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 1, 4, 8, 51, 52, 56, 57, 64, 71, 73 and 76 are rejected under 35 U.S.C. 102(a)(1) as being anticipated by Rooney (CA3018748A1 Date Published 2017-10-05) as evidenced by Cruz-Tapias et al. (in Chapter 10 “Major histocompatibility complex: Antigen processing and presentation” of “Autoimmunity: From Bench to Bedside” Anaya et al. editors. Bogota (Colombia): El Rosario University Press; 2013 Jul 18; Pg 169-183).
Rooney teaches immunotherapeutic peptides, peptide binding agents, and their use in the immunotherapy of cancer (Abstract). They teach in Figure 1, exemplary graph of 562 peptides with predicted affinity for select HLA Class I molecule (paragraph [0086]). They also teach neoantigenic peptides in Table 2, specifically neoantigenic peptides from KRAS gene mutations with corresponding protein changes of G12C, G12D, G12V, Q61H, as well as the associated HLA allele peptides in Table 2A (Pg 164-165). They further teach CD8+ HLA-A02:01+ T cells were analyzed for antigen-specificity for KRAS G12C frameshift neoepitope that had been co-cultured with monocyte-derived dendritic cells loaded with the KRAS G12C neoepitope of KLVVVGACGV; HLA-A02:01 after 10 days of incubation (paragraphs [0094] and [0095] and Figures 6A and 6B). Moreover, they teach T cells that express TCRs specific to an immunogenic antigen peptide that result in cytolytic activity when incubated with autologous diseased tissue can be expanded and administered to a subject (paragraph [0507]). Therefore, Rooney teaches T cells that express TCRs that are ABPs that can specifically bind to the HLA-restricted peptide of KLVVVGACGV complexed with HLA-A02:01 on dendritic cells.
As evidenced by Cruz-Tapias et al., HLA class I molecules are expressed on all nucleated cells including dendritic cells (see Pg 169 section “History”). They teach that HLA class I molecules are heterodimers comprising an α chain that comprises a cytoplasmic region containing a peptide-binding groove made from α1 and α2 domains (see Pg 174-175 section “Structure of HLA class I” and Figure 8 (Pg 175) and Figure 9 (Pg 176)). Therefore, the dendritic cells that are loaded with neoantigenic peptides as taught by Rooney are cells that comprise the HLA Class I molecule of HLA-A02:01 which presented the HLA-restricted peptide of KLVVVGACGV that is located in the peptide binding groove of the α1/α2 heterodimer portion of said HLA Class I molecule.
Rooney also teaches cells expressing a T cell receptor (TCR) that is a neoantigen-recognizing receptor that activates an immunoresponsive cell wherein such cells include genetically modified immunoresponsive cells such as T cells, Natural Killer (NK) cells, cytotoxic T lymphocytes (CTL) cells and helper T lymphocyte (HTL) cells (paragraphs [0497] and [0498]). They teach that T cells can be autologous subject T cells (paragraphs [0030], [0036] and [0500]), where the subject is a human and has a tumor or the human subject had a tumor which was at least partially removed (paragraph [0525]). They also teach nucleic acid comprising a promoter operably linked to a polynucleotide encoding the TCR (paragraph [0027]). They further teach modified cells that are transfected or transduced with said nucleic acid encoding said TCR (paragraph [0030]). They also further teach a method for stimulating an immune response in a subject, comprising administering an effective amount of modified cells expressing said TCR which is an ABP (paragraph [0079]). Therefore, Rooney teaches a method of stimulating an immune response comprising administering to the subject an ABP that that comprises a TCR that specifically binds to the HLA-restricted peptide of KLVVVGACGV complexed with HLA-A02:01.
Rooney further teaches that TCRs comprising antigen binding proteins that specifically bind neoantigens can be included in a pharmaceutical composition (paragraph [0477]). They also teach pharmaceutically acceptable or physiologically acceptable compositions including solvents (aqueous or non-aqueous), solutions, emulsions, dispersion media, coatings, isotonic and absorption promoting or delaying agents, compatible with pharmaceutical administration (paragraph [0387]).
Therefore, the teachings of Rooney anticipate instant claims above.
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 1, 51, 56 and 62 are rejected under 35 U.S.C. 103 as being unpatentable over Rooney (CA3018748A1 Date Published 2017-10-05) and Cruz-Tapias et al. (in Chapter 10 “Major histocompatibility complex: Antigen processing and presentation” of “Autoimmunity: From Bench to Bedside” Anaya et al. editors. Bogota (Colombia): El Rosario University Press; 2013 Jul 18; Pg 169-183) as applied to claims 1, 51 and 56 above, and further in view of Roth et al. (WO2019084552A1 Date Published 2019-05-02).
The teachings of Rooney and Cruz-Tapias et al. have been discussed in the 102 rejection above.
Rooney and Cruz-Tapias et al. do not specifically teach the engineered cell of instant claim 56, wherein the ABP comprises a T cell receptor (TCR) or an antigen-binding portion thereof, and wherein a polynucleotide encoding the T cell receptor (TCR) or antigen-binding portion thereof is inserted in an endogenous TCR locus.
However, these deficiencies are made of in the teachings of Roth et al.
Roth et al. teaches methods and compositions for editing the genome of a human T cell (Abstract). They teach insertion of a heterologous TCR-β chain and a heterologous TCR-α chain into the exon 1 of a TCR subunit constant gene (e.g. TRAC) in the genome of the cell (Abstract and Figure 1a).
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 engineered cell that is an autologous cell of a subject, wherein the engineered cell expresses a receptor comprising the ABP that specifically binds to an HLA-PEPTIDE antigen comprising an HLA-restricted peptide complexed with an HLA Class I molecule, wherein the HLA-restricted peptide is located in the peptide binding groove of an α1/α2 heterodimer portion of the HLA Class I molecule, wherein the HLA Class I molecule is HLA-A02:01 and the HLA-restricted peptide is the HLA-PEPTIDE antigen of KLVVVGACGV, and wherein the ABP comprises a TCR as taught by Rooney and Cruz-Tapias et al., and wherein the polynucleotide encoding the said TCR is inserted into an endogenous TCR locus as taught by Roth et al. because Roth et al. teaches that insertion of a heterologous TCR (having the desired antigen specificity) into the endogenous Exon 1 of a TCR constant gene region in the genome of a T cell has the advantage of ensuring that the heterologous TCR is under the control of an endogenous TCR promoter (paragraph [0003]). Further, Roth et al. teaches their non-viral genome editing method was confirmed to be able to generate neoantigen binding-TCR-expressing cells at scale and that said cells have in vivo anti- tumor function (Fig. 8c and Fig. 7a and paragraph [0161]). 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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