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 1-15 are pending and examined herein.
Claim Objections
Claims 1, 3, 4, 6, 11, 12, and 14 are objected to because:
Claims 1, 3, 4, 6, 11, 12, and 14 contain abbreviation MHC. It should be completely spelled out in its first occurrence.
Claim 3 recites “substituted amino acid residue in the F pocket of the MHC binding groove is at position 116 or 147” and claim 6 recites “the amino acid residue at position 116 or
147 of the MHC heavy chain”. Both claims recite identical positions, but different MHC entities. Claim 1 recites “the MHC binding groove” and claim 14 recites “the MHC heavy chain”. Terminology should be consistent.
Appropriate correction is required.
Specification
The Specification is objected to because it contains disclosures of amino acid sequences that are not accompanied by SEQ ID NOS, specifically, SYFPEITHI pg. 5, line 21. Even if those sequences are included in the sequence listing, a sequence identifier must accompany each sequence each time it appears in the specification. 37 C.F.R. 1.821 (a) and (c); M.P.E.P. 2422.01-03.
Claim Rejections - 35 USC § 112
The following is a quotation of the first paragraph of 35 U.S.C. 112(a):
(a) IN GENERAL. —The specification shall contain a written description of the invention, and of the manner and process of making and using it, in such full, clear, concise, and exact terms as to enable any person skilled in the art to which it pertains, or with which it is most nearly connected, to make and use the same, and shall set forth the best mode contemplated by the inventor or joint inventor of carrying out the invention.
The following is a quotation of the first paragraph of pre-AIA 35 U.S.C. 112:
The specification shall contain a written description of the invention, and of the manner and process of making and using it, in such full, clear, concise, and exact terms as to enable any person skilled in the art to which it pertains, or with which it is most nearly connected, to make and use the same, and shall set forth the best mode contemplated by the inventor of carrying out his invention.
Claims 1-15 are rejected under 35 U.S.C. 112(a) or 35 U.S.C. 112 (pre-AIA ), first paragraph, as failing to comply with the written description requirement. The claim(s) contains subject matter which was not described in the specification in such a way as to reasonably convey to one skilled in the relevant art that the inventor or a joint inventor, or for applications subject to pre-AIA 35 U.S.C. 112, the inventor(s), at the time the application was filed, had possession of the claimed invention. This is a written description rejection.
Claim 1 recites a stabilized peptide-MHC (pMHC) complex, comprising a non-native linkage between the C terminal anchor residue of the peptide, and the MHC molecule.
The claim is broadly drawn to any MHC molecule (MHC class I or MHC class II) binding any peptide of unspecified sequence and length.
An original claim may lack written description support when a broad genus claim is presented but the disclosure only describes a narrow species with no evidence that the genus is contemplated. See Ariad Pharms., Inc. v. Eli Lilly & Co., 598 F.3d 1336, 1349-50 (Fed. Cir. 2010) (en banc) (MPEP §2163.03.V).
“[T]he disclosure must adequately reflect the structural diversity of the claimed genus, either through the disclosure of sufficient species that are "representative of the full variety or scope of the genus," or by the establishment of "a reasonable structure-function correlation." (MPEP § 2163.II.A).
A "representative number of species" means that the species which are adequately described are representative of the entire genus. Thus, when there is substantial variation within the genus, one must describe a sufficient variety of species to reflect the variation within the genus. See AbbVie Deutschland GmbH & Co., KG v. Janssen Biotech, Inc., 759 F.3d 1285, 1300, 111 USPQ2d 1780, 1790 (Fed. Cir. 2014) (Claims directed to a functionally defined genus of antibodies were not supported by a disclosure that "only describe[d] one type of structurally similar antibodies" that "are not representative of the full variety or scope of the genus.") (MPEP § 2163).
In the instant case, claim 1 is directed to a broad genus of MHC molecules of unspecified origin that bind a broad genus of peptides of unspecified sequence and length.
The instant specification discloses in details only MHC class I molecules (e.g., [0011] and [0012]), and only 7 peptides, each 9 residues long (Tables 1 and 2). The specification broadly discloses that the MHC binding peptide may be 8 to 30 amino acids in length ([0016]). However, MHC class I molecules are known for binding peptides from 8 to 10 amino acid residues long. Specifically, O'Callaghan et al. (Mol Cell. 1998 Mar;1(4):531-41) teaches that MHC class I molecules have pockets from A to F for binding peptide residues from P1 to P9 (e.g., Fig. 2 and 3). Therefore, peptides over 10 residues long are not supported by the specification or the prior art.
The potential diversity of all peptides of 8 residues long is 208 = 256 x 108. Disclosing only 7 peptides out of over 25 billion potential peptides is not sufficient to claim the entire genus of peptides.
Additionally, claim 1 is directed to a broad genus of non-native linkages between the C terminal anchor residue of the peptide, and an amino acid residue in the F pocket of the MHC binding groove. However, the specification only discloses the disulfide bond as a covalent, non-native linkage ([0010] and [0011]).
The teachings of the instant specification are insufficient to establish possession of the breadth of both classes of MHC molecules, the breadth of peptides, and the breadth of non-native linkages required to practice the claimed invention consistent with the written description requirement of 35 U.S.C. § 112(a).
Therefore, claims 1-15 are rejected under 35 U.S.C. 112(a) for failure to describe a sufficient number of different peptides, non-native linkages, and MHC molecules.
The following is a quotation of 35 U.S.C. 112(b):
(b) CONCLUSION. —The specification shall conclude with one or more claims particularly pointing out and distinctly claiming the subject matter which the inventor or a joint inventor regards as the invention.
The following is a quotation of 35 U.S.C. 112 (pre-AIA ), second paragraph:
The specification shall conclude with one or more claims particularly pointing out and distinctly claiming the subject matter which the applicant regards as his invention.
Claims 1-15 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 1 recites “stabilized peptide-MHC (pMHC) complex”. It is unclear what structural features of this complex make it stabilized. Claims 2-15 are rejected because they depend from rejected claim 1.
Claim 1 recites “peptide-MHC”, claim 3 recites “the native peptide”, and claims 7-8 and 14 recite “the peptide”. It is unclear if “peptide” in MHC complex, “the native peptide” and “the peptide” refer to the same or different molecules.
Claim 3 recites “the native peptide”. There is insufficient antecedent basis for this limitation in the claim, because claims 1 and 2 do not recite any native peptide.
Additionally, it is unclear why claim 3 recites “the native peptide” wherein this peptide is linked to MHC molecule via a non-native linkage.
Claim 3 recites “preferably in both the F pocket of the MHC binding groove and the C terminal anchor residue of the native peptide.”
A broad range or limitation together with a narrow range or limitation that falls within the broad range or limitation (in the same claim) may be considered indefinite if the resulting claim does not clearly set forth the metes and bounds of the patent protection desired. See MPEP § 2173.05(c).
In the present instance, claim 3 recites the broad recitation of amino acid residues in the F pocket of the MHC binding groove and/or the C terminal anchor residue of the native peptide, and the claim also recites “preferably in both the F pocket of the MHC binding groove and the C terminal anchor residue of the native peptide.” which is the narrower statement of the limitation. The claim(s) are considered indefinite because there is a question or doubt as to whether the feature introduced by such narrower language is (a) merely exemplary of the remainder of the claim, and therefore not required, or (b) a required feature of the claims.
For examination purposes with respect to prior art, the language following “preferably” will not be given patentable weight.
Claims 4 and 7-9 are rejected because they depend from rejected claim 3.
Claim Rejections - 35 USC § 102
In the event the determination of the status of the application as subject to AIA 35 U.S.C. 102 and 103 (or as subject to pre-AIA 35 U.S.C. 102 and 103) is incorrect, any correction of the statutory basis for the rejection will not be considered a new ground of rejection if the prior art relied upon, and the rationale supporting the rejection, would be the same under either status.
The following is a quotation of the appropriate paragraphs of 35 U.S.C. 102 that form the basis for the rejections under this section made in this Office action:
A person shall be entitled to a patent unless –
(a)(1) the claimed invention was patented, described in a printed publication, or in public use, on sale or otherwise available to the public before the effective filing date of the claimed invention.
(a)(2) the claimed invention was described in a patent issued under section 151, or in an application for patent published or deemed published under section 122(b), in which the patent or application, as the case may be, names another inventor and was effectively filed before the effective filing date of the claimed invention.
Claims 1-3, 5, 10, and 13-15 are rejected under 35 U.S.C. 102(a)(1) as being anticipated by Truscott et al. (IDS; J Immunol. 2007 May 15;178(10):6280-9) and as evidenced by Nguyen et al. (Biochem Soc Trans. 2021 Nov 1;49(5):2319-2331).
Regarding claim 1, Truscott teaches engineered MHC class I molecules expressed as single-chain trimers (SCT), comprising both the MHC I molecule and an antigenic peptide forming an MHC-peptide complex (pg. 6280, col. 2, par. 3).
Additionally, the reference teaches a disulfide trap introduced into a SCT (Abstract). One cysteine residue is introduced into the C terminus of the peptide and the other in a proximal H chain position of MHC I. The engineered SCT molecules oxidized properly in the endoplasmic reticulum indicating the formation of a disulfide bond (pg. 6281, col. 1, par. 2). The disulfide bond is the non-native linkage of claim 1.
Truscott teaches that the peptide-MHC complex is stabilized because the peptide is not easily displaced by a competitor peptide – “The disulfide-trap SCTs, or dtSCTs, did not succumb to high concentrations of competitor peptide, even when the dtSCT construct was based on a low-affinity complex” (pg. 6281, col. 1, par. 2).
Finally, the reference teaches that the non-native linkage between the C terminal anchor residue of the peptide is formed with an amino acid residue in the F pocket of the MHC. Specifically, MHC heavy chain residues were replaced with cysteine: T80C or Y84C (Table I). Nguyen provides evidence that residues T80 and Y84 are located in the F pocket of MHC (Fig. 1F).
Regarding claims 2, 3, and 5, Truscott teaches the non-native linkage is a covalent bond formed between amino acids substituted for amino acid residues in the F pocket of the MHC and the C terminal anchor residue of the peptide – the disulfide trap between cysteine residue at the C terminus of the peptide and the other in a proximal H chain position of MHC I is a covalent, disulfide bond (pg. 6281, col. 1, par. 2). Specifically, MHC heavy chain residues were replaced with cysteine: T80C or Y84C (Table I). Nguyen provides evidence that residues T80 and Y84 are located in the F pocket of MHC (Fig. 1F).
Regarding claim 10, Truscott teaches the complex of claim 1 is soluble – “It was clear from the crystal structure of the dtSCT that an analogous disulfide trap might also be incorporated into soluble, recombinant class I molecules without the SCT linkers” (pg. 6288, col. 2, par. 1). The soluble, recombinant class I molecules are recombinant MHC class I molecules.
Regarding claim 13, Truscott teaches a multimer of the complex of claim 1. Specifically, the reference teaches that “The disulfide trap forms properly upon in vitro refolding, and disulfide trap pMHC tetramers bind T cells specific for the native complex” (pg. 6288, col. 2, par. 1). The pMHC tetramers are the multimers of claim 13.
Regarding claim 14, Truscott teaches a method of making the peptide-MHC complex of claim 1 comprising forming a covalent bond between the MHC heavy chain and the C terminal amino acid anchor residue of the peptide. Specifically, Truscott teaches substituting an amino acid residue in the F pocket of the MHC I and the C terminal amino acid anchor residue of the peptide with cysteine residues, and expressing the engineered complex peptide-MHC as a single-chain trimer, wherein “the engineered SCT molecules oxidized properly in the endoplasmic reticulum (ER) and were recognized at the cell surface by both Abs and T cells specific” (pg. 6281, col. 1, par. 2).
Regarding claim 15, Truscott teaches T cell recognition of the disulfide linked SCT molecules. Specifically, cells expressing dtSCT constructs were strongly recognized by OT-1 in cytolytic assays (pg. 6283, col. 2, last par.), wherein OT-1 are Kb/OVA-reactive T cells that bind to the dtSCT complex.
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 set forth in Graham v. John Deere Co., 383 U.S. 1, 148 USPQ 459 (1966), that are applied for establishing a background for determining obviousness under 35 U.S.C. 103 are summarized as follows:
Determining the scope and contents of the prior art.
Ascertaining the differences between the prior art and the claims at issue.
Resolving the level of ordinary skill in the pertinent art.
Considering objective evidence present in the application indicating obviousness or nonobviousness.
This application currently names joint inventors. In considering patentability of the claims the examiner presumes that the subject matter of the various claims presumes that the subject matter of the various claims was commonly owned as of the effective filing date of the claimed invention(s) absent any evidence to the contrary. Applicant is advised of the obligation under 37 CFR 1.56 to point out the inventor and effective filing dates of each claim that was not commonly owned as of the effective filing date of the later invention in order for the examiner to consider the applicability of 35 U.S.C. 102(b)(2)(C) for any potential 35 U.S.C. 102(a)(2) prior art against the later invention.
Claims 4 and 6 are rejected under 35 U.S.C. 103 as being unpatentable over Truscott and as evidenced by Nguyen, as applied to claims 1-3 above.
Regarding claims 4 and 6, Truscott teaches the substituted amino acid residue in the F pocket of the MHC is at position 80 or 84, and the substitution is cysteine (T80C or Y84C; Table I). Truscott fails to teach specifically the substituted amino acid residue is at position 116 or 147. However, Nguyen provides evidence that the F pocket contains only 8 residues, including claimed 116 and 147 positions; and all 8 residues surround the C terminal peptide residue (PΩ in Fig. 1F).
It would have been obvious to one having ordinary skill in the art before the effective filing date of the claimed invention to substitute residues in the F pocket of MHC with cysteine residues as taught by Truscott, in order to provide cysteine at position 116 or 147, as an "obvious to try" approach of choosing from a finite number of identified, predictable solutions, with a reasonable expectation of success.
The total number of residues in the F pocket is eight. The remaining six residues can be readily modified to cysteines – the finite number of identified, predictable solutions. All eight residues are responsible for interacting with the same C terminal peptide residue and Truscott teaches that two residues at position 80 or 84 can be successfully substituted. Therefore, one would have a reasonable expectation of success that the other six residues would be able to form a disulfide bond with the C terminal peptide residue. Cysteine side chain allows for 360o rotation of the sulfhydryl group so it can be positioned at a proper distance for successful formation of a disulfide bond.
Claims 7-9 are rejected under 35 U.S.C. 103 as being unpatentable over Truscott and as evidenced by Nguyen, as applied to claims 1-3 above, in view of Mitaksov et al. (IDS; Chem Biol. 2007 Aug;14(8):909-22) and Perez et el. (PGPub 20140112976).
The teachings of Truscott have been set forth above.
Regarding claims 7-9, Truscott fails to teach the amino acid substituted for the C-terminal anchor residue of the peptide is a non-natural amino acid; an analogue of homocysteine that has an extended carbon side chain; and 2-amino-5-sulfanyl-pentanoic acid or 2-amino-6-sulfanylhexanoic acid.
Regarding claims 7-9, Mitaksov teaches structural engineering of pMHC reagents for T cell vaccines and diagnostics (Title) using disulfide-trapped peptides (Summary). Additionally, Mitaksov teaches pMHC complexes with a synthetic peptide disulfide-trapped to the peptide-binding groove (pg. 916, col. 2, par. 1) and a specific synthetic SIINFEKLGC peptide with cysteine as a C-terminal anchor residue (pg. 919, col. 2, par. 3).
Truscott and Mitaksov fail to teach the amino acid substituted for the C-terminal anchor residue of the peptide is a non-natural amino acid; is an analogue of homocysteine that has an extended carbon side chain; and the analogue of homocysteine is 2-amino-5-sulfanyl-pentanoic acid or 2-amino-6-sulfanylhexanoic acid.
Regarding claims 7-9, Perez teaches cyclic peptides bearing antitumor and antiangiogenic properties (Title) comprising a non-natural amino acid with a sulfhydryl group ([0044]).
Specifically, Perez teaches peptides comprising a C terminal (X4) non-natural amino acid with a sulfhydryl group ([0044]) which forms a covalent disulfide bridge with the sulfhydryl groups of other residues of the peptide ([0047]). The reference also teaches that the non-natural amino acid is 2-amino-5-sulfanyl-pentanoic acid ([0053]) meeting the limitations of claims 7-9.
It would have been obvious to one having ordinary skill in the art before the effective filing date of the claimed invention to modify the teachings of Truscott for the pMHC complexes with disulfide-trapped peptides (pg. 6281, col. 1, par. 2) with the synthetic disulfide-trapped peptides as taught by Mitaksov (pg. 916, col. 2, par. 1), in order to provide a stabilized peptide-MHC complex. One having ordinary skill in the art would have been motivated to use the synthetic disulfide-trapped peptides because it would eliminate the need for a linker connecting the peptide to the MHC heavy chain – “covalent attachment of synthetic peptide through a disulfide bond would preclude the need for stabilizing linkers involving b2m” (id.) and simplify the peptide-MHC complex. This combination would have been desirable to those of ordinary skill in the art for the reasons mentioned above.
One having ordinary skill in the art would have had a reasonable expectation of success in combining the prior art references because both prior art references are similarly drawn to stabilizing peptide-MHC complexes using disulfide traps, and Mitaksov successfully demonstrates synthetic disulfide-trapped peptides in peptide-MHC complexes.
It would have been obvious to one having ordinary skill in the art before the effective filing date of the claimed invention to modify the teachings of Truscott and Mitaksov for the synthetic disulfide-trapped peptides in peptide-MHC complexes with a non-natural amino acid 2-amino-5-sulfanyl-pentanoic acid as taught by Perez, in order to stabilize peptide-MHC complex, as an obvious matter of simple substitution of one known element (2-amino-5-sulfanyl-pentanoic acid of Perez) for another (cysteine residue of Truscott and Mitaksov) to obtain predictable results.
One having ordinary skill in the art would have had a reasonable expectation of success in combining the prior art references because the prior art references are similarly drawn to forming disulfide bonds between amino acid residues with sulfhydryl groups, and Perez teaches that 2-amino-5-sulfanyl-pentanoic acid incorporated at the C terminus of a peptide can form a disulfide bond with another of side chain comprising the sulfhydryl group. Cysteine and 2-amino-5-sulfanyl-pentanoic acid are functional analogs: both are amino acids that can be incorporated into synthetic peptides and both comprise sulfhydryl groups capable of forming a disulfide bond.
Claim 11 is rejected under 35 U.S.C. 103 as being unpatentable over Truscott and as evidenced by Nguyen, as applied to claim 1 above, in view of Mitaksov.
The teachings of Truscott have been set forth above.
Regarding claim 11, Truscott fails to teach the MHC includes a biotin tag.
Regarding claim 11, Mitaksov teaches structural engineering of pMHC reagents for T cell vaccines and diagnostics (Title) using disulfide-trapped peptides (Summary). Mitaksov also teaches the MHC includes a biotin tag.
Specifically, Mitaksov teaches pMHC tetramers for staining purposes. The tetramers are constructed by including a C-terminal biotinylation sequence into MHC heavy chain (pg. 916, col. 2, par. 2). During expression in vivo the C-terminal biotinylation sequence gets modified with biotin. For tetramerization, fluorochrome-conjugated streptavidin is mixed with biotinylated MHC (pg. 919, col. 2, par. 3). The biotin tag is a required component for interaction with streptavidin.
It would have been obvious to one having ordinary skill in the art before the effective filing date of the claimed invention to modify the teachings of Truscott for the pMHC tetramers (pg. 6288, col. 2, par. 1) with the biotin tag attached to the C-terminal biotinylation sequence as taught by Mitaksov, in order to assemble the pMHC complexes into the tetramers. One having ordinary skill in the art would have been motivated to include the biotin tag because it is required for assembly of the pMHC tetramers. This combination would have been desirable to those of ordinary skill in the art for the reasons mentioned above.
One having ordinary skill in the art would have had a reasonable expectation of success in combining the prior art references because Truscott teaches using the pMHC tetramers, but fails to teach explicitly the biotin tag, and Mitaksov teaches the biotin tag as a missing detail of the tetramer assembly.
Claim 12 is rejected under 35 U.S.C. 103 as being unpatentable over Truscott and as evidenced by Nguyen, as applied to claim 1 above, in view of Crew et al. (Mol Immunol. 2005 Jun;42(10):1205-14).
The teachings of Truscott have been set forth above.
Regarding claim 12, Truscott fails to teach the MHC is HLA-E.
Regarding claim 12, Crew teaches an HLA-E single chain trimer and its use for inhibiting human NK cell reactivity towards porcine cells (Title).
Specifically, Crew teaches that HLA-E expressed on porcine cells might be the most potent inhibitor of human NK cell lysis and alleviate human natural killer cell-mediated rejection of porcine xenografts (pg. 1206, col. 2, par. 1).
It would have been obvious to one having ordinary skill in the art before the effective filing date of the claimed invention to apply the teachings of Truscott for the single chain trimer stabilized by a disulfide bond to HLA-E MHC class I as taught by Crew, in order to provide a stabilized HLA-E complex, as an obvious matter of using of known technique (disulfide bond of Truscott) to improve similar product (single chain trimer of Crew) in the same way.
One having ordinary skill in the art would have had a reasonable expectation of success in combining the prior art references because the prior art references are similarly drawn to single chain trimer of pMHC complex and stabilization of the pMHC complex with a disulfide bond improves complex stability at least 100-fold (Mitaksov, pg. 915, col. 1, par. 1).
Conclusion
Any inquiry concerning this communication or earlier communications from the examiner should be directed to Alexander Volkov whose telephone number is (571) 272-1899. The examiner can normally be reached M-F 9:00AM-5:00PM (EST).
If attempts to reach the examiner by telephone are unsuccessful, the examiner’s supervisor, Bao-Thuy Nguyen can be reached on (571) 272-0824. The fax phone number for the organization where this application or proceeding is assigned is 571-273-8300.
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/ALEXANDER ALEXANDROVIC VOLKOV/
Examiner, Art Unit 1677
/REBECCA M GIERE/Primary Examiner, Art Unit 1677