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 .
DETAILED ACTION
Response to Amendment and Arguments
The Amendment filed on 12/16/2025 in response to the previous Non-Final Office Action (6/16/2025) is acknowledged and has been entered.
Claims 2, 4-5, 8, and 12-42 have been cancelled.
Claims 1, 3, 6-7, and 9-11 are pending and under consideration for a fusion protein comprising a peptide (elect 8-16 residues and SEQ ID NO: 62), a linker, β2M, and second linker, MHC heavy chain and Avi Tag sequence as a peptide tag.
The following office action contains NEW GROUNDS of rejection-based on the amendment.
Rejections/Objection Withdrawn
The rejection of Claims 1, 3, 6-7, and 9-11 under 35 U.S.C. 103 as being unpatentable over Mitaksov et al (Cell: Chem & Biol 14: 909-922, 2007, IDS #21, filed on 9/30/2021) in view of Fairhead et al (Methods Mol Biol 1266:171-184, 2015) and Li et al (Cellular & Mole Immune, 4: 141-146, 2007) is withdrawn in view of the claim amendment. See New Ground Rejection.
Rejection Maintained and Response to Arguments
Claims 1, 3, 6-7, and 9-11 remain and are rejected under 35 U.S.C. 103 as being
unpatentable over Truscott et al (J Immunoty 178: 6280-6289, 2007) in view of Fairhead et al (Methods Mol Biol 1266:171-184, 2015) and Li et al (Cellular & Mole Immune, 4: 141-146, 2007).
The rejection has been modified to meet the limitation of newly amended claim 1.
The elected MHC heavy chain H2-Kb that was deleted in the presently amended claim 10 is now examined to MHC heavy chain, HLA-A*0101.
Truscott et al (2007) teach engineered MHC class I molecule SCTs (Single Chain Trimers) that have the same structure as claimed (page 6280, right col):
Secretion signal sequence–antigenic peptide– [G4S]3–mature β2-microglobulin (β2m)–[G4S]4–class I H chain ([G4S]n)
Specifically, the antigenic peptide is OVA peptides including OVA257-264 peptide SIINFEKL (the same peptide of instant SEQ ID NO: 62, claim 11) and mature class I H chain H-2K. The structure can be simply written as:
Secretion signal sequence- SIINFEKL-[G4S]3-β2M--[G4S]3-H-2K
Wherein the secretion signal sequence is considered as secretion leader peptide recited in the amended claim 1.
Truscott et al further teach that the DNA construct encoding SCT is expressed in a mammalian cell, a murine embryo fibroblast line derived from 3KO mice (page 6280, right col and 6281 left col). Truscott et al also teach that the SCT structure is transfected into LM1.8 cells (H-2k fibroblast cell, page 6283, right col) that is also a eukaryotic cell line.
Regarding with the new limitation in amended claim 1, the fusion peptide secreted by a eukaryotic cell line can be alternatively explained as, the fusion protein per se seems having the properties of the claimed fusion protein, the courts have held that if the product (fusion protein) in a product-by-process claim is the same as or obvious from a product of the prior art, the claim is unpatentable even though the prior art product was made by a different process. In re Thorpe., 227 USPQ 964, 966 (Fed. Cir. 1985): In re Marosi, 218 USPQ 289, 292-293 (Fed. Cir. 1983). (also see MPEP 2113).
Truscott et al (2007) do not teach C-terminal peptide tag including AviTag sequence (elected) linked to MHC heavy chain C-terminus in the SCT structure.
Fairhead et al teach 15 amino acid AviTag peptide that is specifically biotinylated BirA and can be added at N-or C-terminus of a target protein (abstract). Fairhead et al teach a protocol for biotinylate AviTag on a fusion protein (page 7, section 3.3 an figure1). Fairhead et al teach AviTag peptide being broadly used in the field (page 2).
Li et al also teach a fusion with all the component as Truscott (2007), but slightly different construct, in which Li et al use HLA-A0101 fused to AviTag (BSP (Bir A Substrate Peptide, LHHILDAQKMVWNHR), a peptide tag (p141, right col and 142, right col para 1), which is a substrate biotinylated by BirA, an AviTag sequence set forth in claim 6 (p143, left col).
It would have been prima facie obvious to one of ordinary skill in the art before the effective filing date of the claimed invention was made to combine the methods to produce MHC HLA-A-A0101 monomer fusion protein with MHC heavy chain without transmembrane domain (soluble heavy chain) linked to a peptide tag with expected result. One of ordinary skill in the art before the effective filing date of was made would have been motivated with reasonable expectation of success to apply the teachings of Fairhead and Li et al to the teaching of Truscott et al (2007) in order to benefit of tetramerization, purification, sensitive detection… for MHC monomer fusion protein because Truscott et al (2007) have shown the engineered MHC fusion having SCT structure and Fairhead and Li et al have shown AviTag peptide linked to HLA-A-A0101 chain and shown its advantage and utilities in purification and quantitation broadly used in the fields. Therefore, the references in combination teach every limitation of the claims and the invention as a whole would have been prima facie obvious to one of ordinary skill in the art before the effective filing date of the invention was made, absent unexpected results.
Response to applicant’s arguments:
At page 6, applicant states:
applicant have amended claim 1 to include secretory leader sequence before the peptide recognized by a T cell. Truscott et al teach the same structure as Mitaksov.
Fairhead and Li fail to teach the missing from Truscott….. Fairhead and Li fail to teach that which is missing from Truscott, viz., adding a eukaryortic secretory leader sequence and the removal of the transmembrane domain.
In response, Truscott et al actually teach the secretory leader sequence as set forth in the modified rejection above. One skill in the art would be also to choose a mature or part of the HLA/MHC soluble domain to form a fusion protein with reasonable expectation of success to arrive at current invention. Truscott et al in combination with Fairhead and Li teach each and every limitation of the presently claimed invention as set forth in the rejection.
Claims 1, 3, 6-7, and 9-11 remain and are rejected under 35 U.S.C. 103 as being
unpatentable over Truscott et al (J Biol Chem 283: 7480-91, 2008) in view of Fairhead et al (Methods Mol Biol 1266:171-184, 2015).
MHC heavy chain in the C-terminus is examined to the extent of HLA-A0201.
Truscott et al (2008) teach engineered MHC class I molecule SCT (single chain trimer) having the structure as:
PNG
media_image1.png
130
390
media_image1.png
Greyscale
Ovalbumin257–264- [G4S]3- B2m-[G4S]4-Kb
wherein, the antigenic peptide is OVA peptides including OVA257-264 peptide SIINFEKL (the same peptide of instant SEQ ID NO: 62, claim 11) and A2 of HLA or heavy chain sequence replacement (page 7481-2, figure 1). The secretion signal sequence in the SCT structure is considered as a secretion leader peptide (recited in the present claim 1) linked to the N-terminus of antigenic peptide (The peptide SIINFEKL) that is recognized by a T cell. Truscott et al (2008) teach the DNA construct encoding the SCT expressed in Hela cell, a mammalian cell line (page 7481, left col).
Regarding with new limitation in amended claim 1: the fusion peptide secreted by a eukaryotic cell line can be alternatively explained as: the fusion protein per se seems having the properties of the claimed fusion protein, the courts have held that if the product (fusion protein) in a product-by-process claim is the same as or obvious from a product of the prior art, the claim is unpatentable even though the prior art product was made by a different process. In re Thorpe., 227 USPQ 964, 966 (Fed. Cir. 1985): In re Marosi, 218 USPQ 289, 292-293 (Fed. Cir. 1983). (also see MPEP 2113).
Truscott et al (2008) do not teach C-terminal peptide tag including AviTag sequence (elected) linked to MHC heavy chain C-terminus in the SCT structure.
Fairhead et al teach AviTag peptide with 15 amino acids that is specifically biotinylated BirA and can be added at N-or C-terminus of a target protein (abstract). Fairhead et al teach a protocol for biotinylating AviTag on a fusion protein (page 7, section 3.3 an figure1). Fairhead et al teach AviTag peptide being broadly used in the field (page 2).
It would have been prima facie obvious to one of ordinary skill in the art before the effective filing date of the claimed invention was made to combine the methods to produce MHC engineered fusion protein comprising HLA heavy chain without transmembrane domain linked to a peptide Avi tag with expected result. One of ordinary skill in the art before the effective filing date of was made would have been motivated with reasonable expectation of success to apply the teachings of Fairhead to the teaching of Truscott et al (2008) in order to benefit of tetramerization, purification, sensitive detection… for MHC engineered fusion protein because Truscott et al (2008) have shown the engineered MHC fusion having the SCT structure and Fairhead et al have shown AviTag peptide linked to HLA- chain and shown its utilities in purification and quantitation broadly used in the fields. Therefore, the references in combination teach every limitation of the claims and the invention as a whole would have been prima facie obvious to one of ordinary skill in the art before the effective filing date of the invention was made, absent unexpected results.
Response to applicant’s arguments:
At page 7, Applicant argues:
applicant have amended claim 1 to include secretory leader sequence before the peptide recognized by a T cell. Truscott et al is directed to the addition of disulfide bridges to trap the peptide in MHC peptide hydribs they make are low affinity pMHC. Fairhead and Li fail to teach the missing from Truscott.
In response, first, Truscott et al actually teach the secretory leader sequence as set forth in the modified rejection above and figure shown within the rejection. Truscott et al also teach the constructure is transfected to Hela cells (a eukaryotic cells) for producing the fusion protein.
Regarding with the disulfide bridges taught in the reference, Truscott et al teach basis SCT structure as disclosed in the rejection (top structure of figure 1 in Truscott’s reference) and the same structure with disulfide bridges (bottom structure of the figure). The disulfide bridges could perform additional functions such as disulfide trap that is not a required limitation in the present claims. This rejection is based on the teaching of the top structure in figure 1 which does not include the disulfide bridges.
Improper Markush Grouping
Claims 9-10 and 11 remain rejected on the basis that it contains an improper Markush grouping of alternatives. See In re Harnisch, 631 F.2d 716, 721-22 (CCPA 1980) and Ex parte Hozumi, 3 USPQ2d 1059, 1060 (Bd. Pat. App. & Int. 1984). A Markush grouping is proper if the alternatives defined by the Markush group (i.e., alternatives from which a selection is to be made in the context of a combination or process, or alternative chemical compounds as a whole) share a “single structural similarity” and a common use. A Markush grouping meets these requirements in two situations. First, a Markush grouping is proper if the alternatives are all members of the same recognized physical or chemical class or the same art-recognized class, and are disclosed in the specification or known in the art to be functionally equivalent and have a common use. Second, where a Markush grouping describes alternative chemical compounds, whether by words or chemical formulas, and the alternatives do not belong to a recognized class as set forth above, the members of the Markush grouping may be considered to share a “single structural similarity” and common use where the alternatives share both a substantial structural feature and a common use that flows from the substantial structural feature. See MPEP § 706.03(y).
The Markush groupings of peptides, MHC molecule, and SEQ ID NOs are improper because the alternatives defined by the Markush grouping do not share both a single structural similarity and a common use for the following reasons:
Each of the antigenic peptides listed in claim 9 or each of the SEQ ID NOs listed in claim 11 has unique sequence and function which are not shared by others. The elected peptide with 8-16 or SEQ ID NO: 62 does not share the sequence and functions with the other peptides or SEQ ID NOs.
Each of MHC listed in claim 10 has unique sequence and function which are not shared by other MHCs (polygenicity and polymorphism) on the list. The elected H-2 Kb does not share the sequence and immunological functions with the other MHC molecule on the list.
To overcome this rejection, Applicant may set forth each alternative (or grouping of patentably indistinct alternatives) within an improper Markush grouping in a series of independent or dependent claims and/or present convincing arguments that the group members recited in the alternative within a single claim in fact share a single structural similarity as well as a common use.
Response to Applicant’s argument:
At page 8, applicant argues:
The skilled immunologist will immediately recognize that, in claim 9, all the variants in the Markush are known peptides that are recognized by T cells in the context of MHC. In claim 10, the variant is the MHC backbone, all of which are HLA expressed in humans that present the peptides claimed in claim 9. Finally, claim 11 are peptide sequences claimed herein, again, presented by MHC for recognition by T cells.
what the Office is requesting is that each of the variants be filed as a separate dependent claim, which is against the policy of compact prosecution, would cost a state university an exorbitant amount in claims fees, and makes no scientific or legal sense. For at least these reasons, the variants are all properly in a similar Markush group.
In response, each of the molecules set forth in claims 9, 10 and 11 have different structures and biological functions in live cells, although they may be recognized by T cell. Specifically, the peptide tags listed in claims 9 and 11 do not have same or similarity in their structures. Each of the peptides are the molecules from different origins e.g. examined Ovalbumin is found in egg white that can be major allergen in egg hypersensitivity while EGFR listed in the claim is an endothelial cell expressed receptor in human cells involved in its ligand interaction for a basic biological function in the human cell. Thus. the peptides having 8-16 amino acids listed in claims 9 and 11 are from different sources and have totally different structures/sequences and biological functions. The MHCs listed in claim 10 do not have same or similarity in their structures and functions although they share basic structure in claim I but totally different in their amino acids which land to variation in their ability to bind to and present different peptides to T cell and activate them. For the reasons, the rejection is currently maintained.
The Office does not intend to request applicant filing each of the molecules as separate dependent claims. The related molecules as non-obvious variants listed in the claims might be rejoined for examination once the allowable subject matter established.
NEW GROUNDS of REJECTION
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 of this title, 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:
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, 3, 6-7, and 9-11 are rejected under 35 U.S.C. 103 as being unpatentable over Mitaksov et al (Cell: Chem & Biol 14: 909-922, 2007, IDS #21, filed on 9/30/2021) in view of Li et al (Cellular & Mole Immune, 4: 141-146, 2007) and Truscott et al (J Immunoty 178: 6280-6289, 2007) OR Truscott et al (J Biol Chem 283: 7480-91, 2008).
The elected SEQ ID NO: 62 recited in claim 11 consists of the amino acid sequence SIINFEKL (OVA, Ovalbumin peptide).
The elected MHC heavy chain H2-Kb in the fusion recited in the previous claim 10 has been deleted in the presently amended claim 10, which now is examined to HLA-A*0101 (see amended claim 10).
Mitaksov et al teach a peptide-MHC fusion protein having a SCT (single chain trimer) structure as peptide-linker1st-β2M-linker2nd-MHC heavy chain, wherein the peptide is 8 amino acids peptide SIINFEKL that is from OVA peptide and has identical sequence of elected SEQ ID NO: 62 (elected peptide, claim 11). The first and second linkers are flexible linkers comprising glycine(G) and serine (S), as (Gly4-Ser)4, MHC is class I, and H2-Kb heavy chain with Y84C mutation is soluble and no transmembrane domain (page 916, right col, para 2 and page 910, right col, last two paragraphs). The SCT structure feature in figure 1 as:
PNG
media_image2.png
351
556
media_image2.png
Greyscale
Mitaksov et al do not teach C-terminal peptide tag including AviTag sequence (elected listed in claim 6) linked to the soluble MHC heavy chain C-terminus in the SCT structure and do not teach a secretory leader peptide located as the N-terminus of SCT which is transfected, expressed and secreted from a eukaryotic cell recited in the amended claim 1.
Li et al also teach a fusion with all the component as Mitaksov, but slightly different construct, in which Li et al teach fusing HLA-A0101 chain linked to AviTag (BSP (Bir A Substrate Peptide, LHHILDAQKMVWNHR), a peptide tag (p141, right col and 142, right col para 1), which is a substrate biotinylated by BirA, AviTag sequence, set forth in claim 6 (p143, left col).
Both Truscott et al (2007) and Truscott et al (2008) teach SCT complex comprising the same antigenic peptide, β2M, and MHC heavy chain as well as a secretion leader sequence linked to the antigenic peptide at N-terminus as set forth in the rejections above. Both Truscott et al (2007) and Truscott et al (2008) also teach the SCT complex are transfected, expressed, and produced in a eukaryotic cell line, again as set forth in the rejections above.
Regarding with the limitation in amended claim 1: the fusion protein secreted by a eukaryotic cell line can be alternatively explained as: the fusion protein per se seems having the properties of the claimed fusion protein, the courts have held that if the product (fusion protein) in a product-by-process claim is the same as or obvious from a product of the prior art, the claim is unpatentable even though the prior art product was made by a different process. In re Thorpe., 227 USPQ 964, 966 (Fed. Cir. 1985): In re Marosi, 218 USPQ 289, 292-293 (Fed. Cir. 1983). (also see MPEP 2113).
It would have been prima facie obvious to one of ordinary skill in the art before the effective filing date of the claimed invention was made to combine the methods to produce soluble MHC HLA-A-A0101 monomer fusion protein with a secretion leader sequence at N-terminus and a peptide tag at C-terminus with expected result. One of ordinary skill in the art before the effective filing date of was made would have been motivated with reasonable expectation of success to apply the teachings of Li et al and any one of Truscott’s references to the teaching of Mitaksov et al in order to benefit of tetramerization, purification, sensitive detection… for MHC monomer fusion protein because Mitaksov et al have shown a general method of producing MHC monomer fusion having SCT structure with soluble heavy chain of MHC, Li et al have shown AviTag peptide linked to MHC heavy chain HLA-A-A0101 for substrate biotinylated by BirA, and Truscott et al have shown soluble complex with secretion leader sequence produced in eukaryotic cell lines. Therefore, the references in combination teach every limitation of the claims and the invention as a whole would have been prima facie obvious to one of ordinary skill in the art before the effective filing date of the invention was made, absent unexpected results.
Response to Applicant’s argument:
On page 6, applicant argues:
The art cited (Mitaksov and Li) is directed and limited to the making of the MHC in bacteria, which form inclusion bodies in the bacteria that later require dissolving the inclusion bodies to form a soluble peptide, while Fairhead merely teaches an AviTag. The art fails to render the present claims obvious because it does not include a eukaryotic secretory leader sequence for secretion by eukaryotic cells. Moreover, the addition of a secretory leader sequence is a distinct difference from the prior art be because Mitaksov and Li teach expression in bacteria that form inclusion bodies, while the fusion protein claimed herein is for secretion by eukaryotic cells in its native form. Moreover, bacteria fail to glycosylate proteins, which is a structural different with the bacterially expressed proteins. As such, the combination of Mitaksov, Fairhead and Li fails to teach the present invention as claimed.
In response, applicant’s argument has been considered, but the new rejection with the references in combination above has provided answers which addressed the argument, e.g. one or more reference teaches a secretory leader sequence linked to the antigenic peptide at N-terminus of the SCT fusion complex which is transfected and expressed in a eukaryotic cell. For the reason the rejection with the reference Mitaksoy in combination other references are modified and made again.
Conclusion
No claim is allowed.
Accordingly, THIS ACTION IS MADE FINAL. See MPEP § 706.07(a). Applicant is reminded of the extension of time policy as set forth in 37 CFR 1.136(a).
A shortened statutory period for reply to this final action is set to expire THREE MONTHS from the mailing date of this action. In the event a first reply is filed within TWO MONTHS of the mailing date of this final action and the advisory action is not mailed until after the end of the THREE-MONTH shortened statutory period, then the shortened statutory period will expire on the date the advisory action is mailed, and any extension fee pursuant to 37 CFR 1.136(a) will be calculated from the mailing date of the advisory action. In no event, however, will the statutory period for reply expire later than SIX MONTHS from the mailing date of this final action.
Any inquiry concerning this communication or earlier communications from the examiner should be directed to Lei Yao, whose telephone number is (571) 272-3112. The examiner can normally be reached on 8:00am-6:00pm Monday-Friday.
If attempts to reach the examiner by telephone are unsuccessful, the examiner’s supervisor, Samira Jean-Louis, can be reached on (571) 270-3503. The fax phone number for the organization where this application or proceeding is assigned is 571-273-8300.
Information regarding the status of published or unpublished applications may be obtained from Patent Center. Unpublished application information in Patent Center is available to registered users. To file and manage patent submissions in Patent Center, visit: https://patentcenter.uspto.gov. Visit https://www.uspto.gov/patents/apply/patent-center for more information about Patent Center and https://www.uspto.gov/patents/docx for information about filing in DOCX format. For additional questions, contact the Electronic Business Center (EBC) at 866-217-9197 (toll-free). If you would like assistance from a USPTO Customer Service Representative, call 800-786-9199 (IN USA OR CANADA) or 571-272-1000.
/LEI YAO/ Primary Examiner, Art Unit 1642