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 .
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.
DETAILED ACTION
This action is in response to claim amendments filed 12/4/23. Claims 62-77 are pending and under examination.
Drawings
The drawings submitted 4/29/24 are objected to because:
Figure 10A contains what appear to be letters stacked vertically. However, while some are apparent (LM in column 2 on the left; TVAS in column 2 on the right), many are illegible. For example, column 1 on the left begins with what might be FX, but the remaining letters are too compressed to interpret. The brief description does not provide the missing information.
Figure 10D includes amino acid sequences that meet the requirements for identification by a SEQ ID NO. This identifier may be in the drawing itself or the brief description. Currently, it is in neither. While the description contains two sequence identifiers, these are for the controls and not the listed sequences.
The text in the bar at the bottom of Figure 12B illegible.
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.
Claim Objections
Claim 68 is objected to because of the following informalities: the acronym TEV should be accompanied by the full name of the phrase being abbreviated at the first recitation of the abbreviation. Appropriate correction is required.
Claim Rejections - 35 USC § 112
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.
Claim 67 is 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 67 requires the MHC class I heavy chain to have “one or more mutations in the α3 domain of the heavy chain”. However, a “mutation” is necessarily relative, i.e., it must be compared to something. There is no parent sequence defined by the claim to allow others to determine if a given residue is a mutation or a native residue to that sequence. For example, claim 65 indicates the MHC may be one of five options. The sequence of HLA-B is a native sequence yet any differences when compared to HLA-A or H-2D could be considered a “mutation”. The same is true of the alleles in claim 66: a residue which is native to one sequence is also fairly a “mutation” from another sequence. The specification discloses SEQ ID NO: 38 at p.53 stating that the sequence includes a C94A mutation, but this is only a mutation when compared to a sequence having “C” at position 94, while the sequence of SEQ ID NO: 38 contains zero mutations when compared to itself. The specification does not appear to disclose any examples of a mutation in the α3 domain (paragraph 13) and the specification does not provide a special definition of “mutation”. One of skill in the art is not fairly warned as to when the α3 domain contains a mutation because two skilled artisans could fairly argue that an identical structure is both the native structure (zero mutations) or contains mutations when compared to some other, unclaimed sequence.
Therefore, claim 67 is indefinite.
Claim 71 is 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 71 recites the limitation "the heterodimeric MHC-I/TABPR protein complex". There is insufficient antecedent basis for this limitation in the claim. The claim is an independent claim and does not recite any such complex prior to the use of “the”. Similarly, there is no “an MHC Class I heavy chain” for “the” chain to find antecedent basis.
Therefore, claim 71 is indefinite. While written as an independent claim, the lack of antecedent basis, the use of terminology from previous claims, as well as the claim limitations solely directed at a specific heavy chain residue without reciting any other elements of the complex suggests that this was meant to be a dependent claim. Claim 62 contains a limitation of a heavy chain being glycosylated and so, for the purpose of examination, claim 71 will be treated as depending from claim 62.
Claims 75 and 76 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.
Claims 75 and 76 recites the limitation "the cell line". There is insufficient antecedent basis for this limitation in the claim. The previous claims recite a “host cell” but does not recite a “cell line”.
Therefore, claims 75 and 76 are indefinite. For the purpose of examination, the claim will be treated as stating “where the host cell is a CHO or HEK cell” or “where the host cell is a CHO-K1 cell”, respectively.
Claim 77 is 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 77 recites the limitation "the mammalian host cell of claim 3". There is insufficient antecedent basis for this limitation in the claim. Claim 3 was canceled and so the claim is prima facie indefinite as there are no limitations in claim 3 anymore.
Therefore, claim 77 is indefinite. For the purpose of examination, the claim will be treated as depending from claim 74.
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.
This application currently names joint inventors. In considering patentability of the claims the examiner 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.
Claim(s) 62-66, 71-75, and 77 is/are rejected under 35 U.S.C. 103 as being unpatentable over Jurewicz (IDS 12/4/23 Citation C29) in view of Hermann (IDS 12/4/23 citation C33).
Regarding claim 62, Jurewicz teaches constructs comprising MHC class I heavy chain (HLA-A2), a ß2m, a protease cleavage site (thrombin; T), and both an acidic and basic leucine zipper domain (ZIP; a heterodimerization domain); see e.g., figure 1. Figure 1A discloses these elements as a single construct referred to as an epitope-linked ß2-microglobulin (ELBM)(p.6 section 3.1), thus disclosing all of the above in a single construct including both the HLA and ß2m. The construct was expressed in mammalian cells (Id.). As noted in the instant specification, native glycosylated residues are missing when expressed in E.coli (paragraph 5) but are present when produced in mammalian cells (paragraph 7). Thus, the evidence supports the conclusion that the construct of Jurewicz also contains a native glycosylation position which is glycosylated.
Hermann teaches TAPBPR forms a complex with the MHC class I and ß2m complex (abstract; figure 9A). TAPBPR is beneficial to the MHC/ß2M complex because TAPBPR enhances peptide optimization (abstract) but only functions when brought “into close proximity via a Jun/Fos leucine zipper” (p.2 Results). Hermann teaches a peptide comprising the TAPBPR domain and a C-terminal His-tag (p.3 first paragraph). Hermann teaches the related Tapasin expressed with a linker, thrombin cleavage site, Jun leucine peptide, and HA tag as well as HLA A*02:01 with a C-terminal fos leucine zipper (p.15).
It would have been obvious to a person of ordinary skill in the art at the time of filing to combine the MHC/ß2 protein of Jurewicz with the TAPBPR protein of Hermann because Hermann teaches TAPBPR is beneficial to the MHC I/ß2 complex. Both references teach including leucine zipper domains (heterodimerization domains) at the C-terminus of their respective peptides, with Hermann teaching the use of the domains to bring the TAPBPR into close proximity with the MHC I. Both Jurewicz and Hermann teach the use of thrombin cleavage sites (protease cleavage sites) and Jurewicz teaches this allows release of the peptide at an appropriate time to facilitate improved folding (p.3 bottom paragraph). The art teaches each individual element of the claims, discloses the function each element performs, and one of ordinary skill in the art could have combined these elements in a similar manner for similar reasons resulting in a predictable outcome where each element performs its known function.
With respect to the arrangement, both references teach the heterodimerization domain C-terminally to the protein, making this an obvious arrangement. Jurewicz teaches the protease domain serves the function of releasing the proteins, which would have made it obvious to include between the protein (MHC I/ß2 or TAPBPR) and the heterodimerization domain in order to preserve this benefit. The heterodimerization will form a result in the two polypeptides forming a complex. The MHC-I being N-terminal to ß2M is shown in figure 1 of Jurewicz. Further, the art of record does not criticize or discredit a particular arrangement of the MHC/ß2M peptides. The rearrangement of parts is prima facie obvious (MPEP §2144.04(VI)(C)). There is no evidence of record to suggest that B2M-MHC would successfully complex while MHC-B2M would not. For similar reasons, while the construct of MHC and ß2M might exist as separate peptides, it would have been obvious that they could have been arranged as a single polypeptide because Jurewicz teaches the covalent attachment of these proteins (p.3).
This arrives at every element of the claim arranged in the same way and so the claim would have been obvious.
Regarding claim 63, the construct of Jurewicz includes the biotinylation signal peptide (BSP) element (figure 1). This comprises a lysine and is meant to be biotinylated as evident from the name. This meets the criteria for a multimerization tag (see instant specification paragraphs 55 and 66).
Regarding claim 64, Jurewicz teaches including a his6 tag (figure 1) as does Hermann (p. 15). Hermann teaches the His tag is for purification (p.2) as does Jurewicz (p.4). It would have been obvious to include these tags for the same reason, e.g., to assist in purifying the constructs.
Regarding claims 65 and 66, Jurewicz teaches the MHC-I is HLA-A2 (above) and Hermann specifically teaches HLA A*02:01 (above). Given the teachings above to include an MHC-I, it would have been obvious to use one demonstrated in the art, including HLA A*02:01.
Regarding claim 71, N86 is a native glycosylation site. As it would have been obvious to express the construct in mammalian cells—which will naturally glycosylate MHC—and as it would have been obvious to use HLA-A*0201 (see above), the evidence supports the conclusion that this residue would be glycosylated in the construct resulting from the combination above.
Regarding claim 72, Jurewicz teaches using a leucine zipper as a heterodimerization domain (above) and Hermann teaches the MHC/ß2M/TAPBPR complex functions when brought into close proximity by a leucine zipper (above). This would have made using leucine zippers as the heterodimerization domain obvious.
Regarding claim 73, Hermann teaches methods of expressing the protein via an expression vector (p.2 last paragraph) as does Jurewicz (paragraph spanning p. 4-5), which would have made expression vectors encoding the above polypeptides obvious.
Regarding claim 74, expression in mammalian cells would have been obvious as above.
Regarding claim 75, Jurewicz teaches expression in HEK cells (p.5) as does Hermann (p.2), which would have made the selection of these same cells obvious.
Regarding claim 77, treating the claim as depending from claim 74, the production of the polypeptides above in the known vectors in the mammalian cells taught by the art would have been obvious for the reasons above. Both references recover the expressed proteins, which would have made obvious doing the same.
Therefore, claims 62-66, 71-75, and 77 would have been obvious.
Claim(s) 69-70 is/are rejected under 35 U.S.C. 103 as being unpatentable over Jurewicz (IDS 12/4/23 Citation C29) in view of Hermann (IDS 12/4/23 citation C33) as applied to claims 62-66, 71-75, and 77 above, and further in view of Amin (US 20180319870; IDS 12/4/23 citation A5).
Jurewicz and Hermann are discussed above and incorporated herein. Jurewicz teaches the inclusion of a multimerization tag, including the required biotinylation; however, Jurewicz does not teach the AviTag. Jurewicz does teach multimerization, a biotinylated domain, and a 6x His tag (figure 1). Moreover, the BSP85/6xHis tags are disclosed as “purification tags” (p.6 Section 3.1).
Amin teaches coupling an AviTag with a 6xHis tag for protein purification (paragraph 141).
One means of establishing obviousness is the simple substitution of one known element for another (MPEP §2143(I)(B)). The construct of Jurewicz differs from the construct of claim 69 in that Jurewicz uses a BSP85/6xHis tag for purification, while the instant claims comprise an AviTag. However, AviTag was a known purification tag and was also known to be used in combination with a 6xHis tag. Thus, one of ordinary skill in the art could have substituted the BSP85 of Jurewicz for the AviTag of Amin and reasonably expect that the construct could still be purified, i.e., the results of the substitution would have been predictable. Note that AviTag is a structurally defined biomolecule (GLNDIFEAQKIEWHE; instant specification paragraph 87) and a compound and its properties are inseparable (In re Papesch, 315 F.2d 381, 137 USPQ 43 (CCPA1963); thus, characterization as a “multimerization tag” is inherent to the AviTag structure.
Regarding claim 70, Amin teaches the AviTag is biotinylated at the lysine residue (paragraph 141).
Therefore, claims 62-66, 69-75, and 77 would have been obvious.
Claim(s) 67 is/are rejected under 35 U.S.C. 103 as being unpatentable over Jurewicz (IDS 12/4/23 Citation C29) in view of Hermann (IDS 12/4/23 citation C33) as applied to claims 62-66, 71-75, and 77 above, and further in view of Scholler (US 20100226854; form 892)
Regarding claim 67, as noted in the §112 rejection, any α3 domain contains one or more mutations of the heavy chain when compared to an α3 domain of a different sequence. Additionally, Scholler teaches that the alpha 3 subunit of the MHC I heavy chain is of particular interest because this subunit interacts with CD8. Scholler teaches interaction with “non-specific T cells” can be minimized by introducing mutations into the alpha 3 subunit. It would have been obvious to include these mutations to similarly minimize non-specific interactions.
Therefore, claims 62-67, 71-75, and 77 would have been obvious.
Claim(s) 68 is/are rejected under 35 U.S.C. 103 as being unpatentable over Jurewicz (IDS 12/4/23 Citation C29) in view of Hermann (IDS 12/4/23 citation C33) as applied to claims 62-66, 71-75, and 77 above, and further in view of Seidel (US 20170058015; form 892)
Regarding claim 68, the references render obvious including a protease cleavage site as above, but do not specifically teach TEV.
Seidel also claims MHC polypeptides combined with other domains (claim 1). Like Jurewicz and Hermann, Seidel teaches using protease cleavage domains (paragraphs 202, 204, 207) and names TEV as one such domain (paragraph 207). One of ordinary skill in the art would have found it obvious to use the known TEV protease cleavage domain with predictable results, e.g., the domain will be cleaved by a protease as described in, e.g., Jurewicz.
Therefore, claims 62-66, 68, 71-75, and 77 would have been obvious.
Claim(s) 76 is/are rejected under 35 U.S.C. 103 as being unpatentable over Jurewicz (IDS 12/4/23 Citation C29) in view of Hermann (IDS 12/4/23 citation C33) as applied to claims 62-66, 71-75, and 77 above, and further in view of Deshpande (US20170335341; form 892).
Regarding claim 76, the proteins, vectors encoding the proteins, and expressing the proteins in host cells is discussed above. Both Jurewicz and Hermann use mammalian cell lines as discussed above. Jurewicz and Hermann are silent regarding the use of CHO-K1 for this purpose.
However, CHO-K1 represents a well-known cell line at the time of filing. It would have been obvious to one of ordinary skill in the art, taught to express a protein in a cell as discussed above, to select a known cell line capable of this. Deshpande teaches CHO-K1 cells are a mammalian host cell (claim 66) which may comprise a vector encoding any protein of interest (POI) for expression (claim 60). One could have predictably used the CHO-K1 cell—known to express other proteins—to express the Jurewicz/Hermann proteins with predictable results.
Therefore, claims 62-66 and 71-77 would have been obvious.
Conclusion
Regarding double patenting:
Parent application 17/017685 is abandoned.
Co-pending application 17/790711 does not claim a second polypeptide comprising TABPR. Note that while the issue fee has been paid, no patent number has been assigned as of the writing of this action.
Co-pending application 17/141096 does not claim a second polypeptide comprising TABPR.
Co-pending application 18/840805 claims a TAPBPR protein, but lacks protease cleavage sites, heterodimerization domains, and the complexed MHC.
US 12534510 does not claim a second polypeptide comprising TABPR.
Note that both the instant application and US 12534510 claim priority to, e.g., US 63/076601. US 12534510—based on a similar technology to the instant claims though patentably distinct for the reason above—also claims priority to US 63/011211. The ‘211 provisional is also the basis of US 12512950, which has been considered as the patent is technically a family member of the instant application. However, the provisional 63/011211 and the resulting patent US 12512950 do not appear to claim nor disclose any technology relevant to the instant claims and further do not share an assignee nor inventor.
Regarding §112:
A “multimerization tag” (claim 63) is a class defined solely by its function. However, the specification discloses a structure correlated to this function: any peptide sequence comprising a biotin moiety (paragraph 87). This is sufficient to meet the written description requirement.
Any inquiry concerning this communication or earlier communications from the examiner should be directed to ADAM M WEIDNER whose telephone number is (571)272-3045. The examiner can normally be reached M-T 9-18; W-R 9-15.
Examiner interviews are available via telephone, in-person, and video conferencing using a USPTO supplied web-based collaboration tool. To schedule an interview, applicant is encouraged to use the USPTO Automated Interview Request (AIR) at http://www.uspto.gov/interviewpractice.
If attempts to reach the examiner by telephone are unsuccessful, the examiner’s supervisor, Jeffrey Stucker can be reached at 571-272-0911. 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.
/Adam Weidner/ Primary Examiner, Art Unit 1675
Prosecution Insights