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 .
The examiner of your application in the PTO has changed. To aid in correlating any papers for this application, all further correspondence regarding this application should be directed to Brian Whiteman, Art Unit 1636.
Election/Restrictions
Applicant’s election without traverse of group I (claims 1, 3, 8-10, 12, 15-18, 20, 22, 40, 43, 46, 49, 51, 53, 58, 59, 62-64, 66, and 68-69 and species (Trp439*; 1316 G>A; MGMT inhibitor; O6BG; RNA-guided DNA binding domain, nickase variant; a cytidine deaminase domain; EpoR gene) in the reply filed on 7/2/26 is acknowledged.
Claims 23, 24, 29-31, and 36 are withdrawn from further consideration pursuant to 37 CFR 1.142(b) as being drawn to a nonelected invention, there being no allowable generic or linking claim. Election was made without traverse in the reply filed on 7/2/26.
The non-elected species in claims 3 (items (i)-(iv) and non-elected species in item (v)), 8 (non-elected modifications in table 1), 18 (Loneguatrib), 43 (items (i) and (ii)), 49 (adenosine deaminase), and 66 (item (ii) EpoR mRNA transcript) and claims 20 and 69 are withdrawn from further consideration pursuant to 37 CFR 1.142(b) as being drawn to a nonelected species, there being no allowable generic or linking claim. Election was made without traverse in the reply filed on 7/2/26.
Information Disclosure Statement
The information disclosure statement filed 2/2/24 fails to comply with 37 CFR 1.98(a)(2), which requires a legible copy of each cited foreign patent document; each non-patent literature publication or that portion which caused it to be listed; and all other information or that portion which caused it to be listed. It has been placed in the application file, but the information referred to therein has not been considered. Items no. B1-B9 are WO documents and do not appear to have been filed with the IDS and there is no evidence of them in the record.
Specification
The use of the term TALEN and GENBANK, which is a trade name or a mark used in commerce, has been noted in this application. The term should be accompanied by the generic terminology; furthermore the term should be capitalized wherever it appears or, where appropriate, include a proper symbol indicating use in commerce such as ™, SM , or ® following the term.
Although the use of trade names and marks used in commerce (i.e., trademarks, service marks, certification marks, and collective marks) are permissible in patent applications, the proprietary nature of the marks should be respected and every effort made to prevent their use in any manner which might adversely affect their validity as commercial marks.
Claim Objections
Claim 17 is objected to because of the following informalities: Suggest adding the term O⁶-methylguanine-DNA methyltransferase before the abbreviation MGMT polypeptide so one of skill in the art does think the term MGMT is amino acid sequence and understands the abbreviation.
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.
Claims 8, 15-18, and 43 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 15-18 recite the limitation "the nucleic acid" in line 2(3). There is insufficient antecedent basis for this limitation in the claim. The claims depend from 1 and claim does not recite a nucleic acid ending the editing enzyme
Claim 8 recites “a nucleic acid modification selected from Table 1” and is rejected as indefinite and the claim is not complete. "Where possible, claims are to be complete in themselves. Incorporation by reference to a specific figure or table '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. Incorporation by reference is a necessity doctrine, not for applicant’s convenience.' Ex parte Fressola, 27 USPQ2d 1608, 1609 (Bd. Pat. App. & Inter. 1993)" (MPEP 2173.05(s)).
Claim 43 contains the trademark/trade name TALEN in TALEN domain. Where a trademark or trade name is used in a claim as a limitation to identify or describe a particular material or product, the claim does not comply with the requirements of 35 U.S.C. 112(b) or 35 U.S.C. 112 (pre-AIA ), second paragraph. See Ex parte Simpson, 218 USPQ 1020 (Bd. App. 1982). The claim scope is uncertain since the trademark or trade name cannot be used properly to identify any particular material or product. A trademark or trade name is used to identify a source of goods, and not the goods themselves. Thus, a trademark or trade name does not identify or describe the goods associated with the trademark or trade name. In the present case, the trademark/trade name is used to identify/describe a DNA binding domain and, accordingly, the identification/description is indefinite.
Claim Rejections - 35 USC § 103
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 (i.e., changing from AIA to pre-AIA ) 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 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.
Claims 1, 3, 8, 9, 10, 12, 22, 40, 43, 46, 49, 58, 59, 63, 64, and 66 are rejected under 35 U.S.C. 103 as being unpatentable over Vinanica et al. (WO 2020044239, published 3/5/20 and EFD 8/29/18) taken with Bowen et al. (WO 2020139783, published 7/2/20, EFD 12/27/18).
The instant application claims priority to an international application (PCT/US22/23738) and a written opinion in the international application was filed on 10/15/23. NOTE: instant claims 1, 3, 8-10, 12, 15-18, 22, 40, 43, 46, 49, 51, 53, 58-59, 62-64, 66, and 68 and claims 1, 3, 8-10, 12, 15-18, 22, 40, 43, 46, 49, 51, 53, 58-59, 62-64, 66, and 68 from the international application appear to embrace the overlapping subject matter. There does not appear to be any arguments and/or amendments in the international application to address the lack of novelty of claims 1 and 3 by WO 2020/004239, cited on an IDS. The reasons set forth on pages 4-7 of the written opinion are incorporated herein.
NOTE: any limitation after the term “optional” or “optional” is not required to be taught or made obvious by the prior art of record because there is no active step requiring the limitations after the terms.
‘239 discloses making transgenic mammalian host cell comprising a vector encoding a wildtype or truncated form of erythropoietin receptor (EpoR) to promote T cell survival and proliferation. See abstract and pages 2-10, 13-15, 18-20 and 23-33. The Epo receptor can have 90% sequence identity to any of SEQ ID NOs: 2, 4, 6, and 8 (paragraph 8). SEQ ID NO: 4 is 100% identical to instant SEQ ID NO: 1 in claim 8. The truncated EpoR can be formed by mutations, including frameshifts, insertions and deletions. Those lacking the C-terminal negative regulatory domain exhibit hypersensitivity to Epo stimulation in red cells. One example is an EpoR has a nonsense mutation within exon 8 of the Epo receptor gene that encode premature stop codons. One EpoR mutant has a mutation at nucleotide 6002 so that codon 439 encoded a stop codon (TAG) instead of tryptophan (TGG). See Figure 5 that shows the alteration of for amino acid 439 Trp to a stop codon. The truncated form of EpoR can be expressed at higher levels than EpoR. Various viral vectors are known in the prior art for gene delivery, including viral vectors selected from lentiviral, retroviral, adenoviral, adeno-associated viral. CRISPR-based system can be used to introduce the nucleic acid encoding wildtype or truncated forms of EpoR into mammalian host cells (page 17).
‘239 does not specifically teach modifying an endogenous EpoR nucleic acid in one or more cells of a mammal comprising administering an editing enzyme (CRISPR-based system) to the mammal to produce a modified EpoR-encoding nucleic acid that has a signaling-enhanced EpoR polypeptide, wherein the contacting occurs in vivo, in vitro or ex vivo.
However, ‘783 discloses that genome editing using CRISPR-based systems (crRNAs and/or tracrRNAs), RNA-guided nuclease, DNA-binding polypeptide deaminases fusions, deaminases (cytosine deaminase or adenosine deaminase) can successfully be used by one of ordinary in the art for gene editing a target polynucleotide sequence in a mammalian cell. For example, see pages 1-36 and 135-145. In certain embodiments, the RNA-guided nuclease functions as a nickase. The genome editing can be delivered using a viral or a non-viral vector, including liposomes. The targeted polynucleotide sequence can be in a mammalian cell, including hematopoietic stem cells (HSCs).
It would have been prima facie obvious to a person of ordinary skill in the art before the time of the effective filing date to combine the teaching of ‘239 taken with ‘783 as a simple substitution to use any known gene editing technique (CRISPR-Cas system) in place of the method taught by ‘239 to produce a modified EpoR encoding nucleic acid in a cell of a mammal. See MPEP 2143(I)B. One of ordinary skill in the art would have been motivated to combine the teaching to genetically modify an endogenous EpoR encoding nucleic acid in a mammal to produce a modified EpoR-encoding nucleic encoding a signaling-enhanced EpoR polypeptide, wherein the genetically modifying step can be in vivo, ex vivo or in vitro with a reasonable expectation of success. ‘239 teaches Trp439 in an EpoR polypeptide. When one of ordinary skill in the art edits Trp439 in the EpoR amino acid sequence encoding by the nucleotide sequence set forth in SEQ ID NO: 4 (instant SEQ ID NO: 1), they would target nucleotide 1316 resulting in a G>A.. See MPEP 2144(II)C. The limitation recited in instant claim 22 is a ‘wherein’ clause and does not add any structural limitations to the modified EpoR-encoding nucleic acid used in the method step made obvious by ’239 and ‘783, thus, the limitation is an inherent function of the method step made obvious by ‘239 and ‘783. ‘783 teaches that a deaminase can be used in a nucleotide sequence editing method. It would have been a simple substitution to use any editing agent in the method, including deaminase (cytosine deaminase or adenosine deaminase), an RNA-guided DNA binding domain (a nickase variant) to make the modified EpoR-encoding nucleic acid. One of ordinary skill in the art would have been motivated to use a viral vector (adenoviral) comprising a nucleic acid encoding the gene editing agent or a non-viral vector (liposome) to assist in delivery of the gene editing agent to mammalian cells. It would have been obvious to use any route known in the art to successfully deliver a nucleic to mammalian cells, including the routes listed in instant claim 12. ‘783 teaches a vector also comprising a selectable marker gene for selection of transformed cells. It would have been obvious to add this marker sequence (payload) to the vector to identify which cells have the gene editing agent.
Therefore the invention as a whole would have been prima facie obvious to one ordinary skill in the art before the effective filing date of the claimed invention to a person having ordinary skill in the art to which the claimed invention pertains.
Claims 17 and 18 are rejected under 35 U.S.C. 103 as being unpatentable over Vinanica et al. (‘239) taken with Bowen et al. (WO 2020139783 as applied to claims 1, 3, 8, 9, 10, 12, 22, 40, 43, 46, 49, 58, 59, 63, 64, and 66 above, and further in view of Phaltane et al. (Human Gene Therapy 25: 144-155, 2014) and Lokitonava et al. (Biochemical Pharmacology 58: 237-244, 1999).
‘239 and ‘783 do not specifically teach using a nucleic acid encoding the editing enzyme and a transgene encoding an inhibitor-resistant MGMT polypeptide in the method, and then administering O6-Benzylguanine (O6BG) after administering the MGMT the nucleic acid to the subject
However, Phaltane et al. disclose that HSC gene therapy has been applied with considerable success to a number of disorders. Phaltane studied efficiency and safety of O6-methylguanine DNA methyltransferase (MGMTP140K)-mediated in vivo selection in a humanized mouse model.
Lokitonava discloses the usefulness of drug resistant MGMT enzymes (O6BG) and their use in editing methods and in therapy. In addition, a person of ordinary skill in the art would possess the knowledge that Cas9 nuclease is directed to DNA by a guide RNA and introduces double stranded breaks (DSB) mammalian cells prefer to repair DSBs by NHEJ (non-homologous end joining) rather than HDR (homology-directed repair) and this limits the potential of CRISPR-Cas system for precise editing. One of ordinary skill in the art would look for methods to enhance the efficiency of HDR from donor templates.
It would have been prima facie obvious to a person of ordinary skill in the art before the time of the effective filing date to combine the teaching of ‘239 and ‘783 taken with Phaltane and Lokitonava to use the claimed nucleic acid and O6BG in the method, namely to study safe and efficient enrichment of mammalian cells having the nucleic acid without overt abnormalities when using viral vectors.
Therefore the invention as a whole would have been prima facie obvious to one ordinary skill in the art before the effective filing date of the claimed invention to a person having ordinary skill in the art to which the claimed invention pertains.
Claims 51 and 53 are rejected under 35 U.S.C. 103 as being unpatentable over Vinanica et al. (‘239) taken with Bowen et al. (‘783) as applied to claims 1, 3, 8, 9, 10, 12, 22, 40, 43, 46, 49, 58, 59, 63, 64, and 66 above, and further in view of Liu et al.(WO 2020191249/US20220356469, NOTE: WO ‘249 is a 102(a)(1) reference, however, in the time allotted, the examiner does not have access to any tool to download and attach this WO document into the office action because it is over 1100 pages and the Office has limited the length of foreign patent documents that can be attached to an office action. The examiner cannot break up the WO document into smaller documents and attach to the office action because there is no box on a PTO-892 to indicate that a WO document was provided in multiple documents. The Office is providing the U.S. pre-grant publication ‘469 (102(a)(2) reference) corresponding to the ‘249 publication. If the applicant would like the WO publication, they can request the publication from the Examiner and they will try to figure out a solution to supply the WO document to the applicant or the applicant can obtain the WO document via the Patentscope Website).
‘239 and ‘783 do not specifically teach using a Cas9 fused to an MLV reverse transcriptase domain in the method.
However ‘249 teaches a composition for editing nucleotide sequences, wherein the composition comprises a fusion protein comprising an MLV reverse transcriptase fused to nickase Cas9 (Figure 14). This composition showed improved gene editing efficiency in mammalian cells (Figure 39A-D).
It would have been prima facie obvious to a person of ordinary skill in the art before the time of the effective filing date to combine the teaching of ‘239 and ‘783 taken with ’249 as a simple substitution to use a DNA binding domain (nickase Cas9) and an MLV reverse transcriptase domain in the method, namely to arrive at the claimed invention.
Therefore the invention as a whole would have been prima facie obvious to one ordinary skill in the art before the effective filing date of the claimed invention to a person having ordinary skill in the art to which the claimed invention pertains.
Claims 15, 16, and 62 are rejected under 35 U.S.C. 103 as being unpatentable over Vinanica et al. (‘239) taken with Bowen et al. (‘783) as applied to claims 1, 3, 8, 9, 10, 12, 22, 40, 43, 46, 49, 58, 59, 63, 64, and 66 above, and further in view of Kiem et al. (WO2021003432, published 1/7/21 and EFD 7/2/19).
‘239 and ‘783 do not teach using a helper depend adenoviral (HdAd vector) for delivering the nucleotide sequence encoding the editing enzyme to the mammalian cells.
However, Kiem et al. teach recombinant Ad35 vectors for in vivo gene editing of hematopoietic stem cells and related gene therapy improvements (paragraph 8). Kiem et al. also teach mobilization strategies of hematopoietic stem cells (HSPC). (paragraphs 9 and 661). Kiem et al. further teaches delivering a payload to the cells (paragraph 503). Ad35 viral vectors can be administered with one or more immunosuppression agents or regiments to alleviate potential side effects of treatments (paragraph 686).
It would have been prima facie obvious to a person of ordinary skill in the art before the time of the effective filing date to combine the teaching of ‘239 and ‘783 taken with Kiem et al., to use a HdAd (Ad35) vector in the method since it was well known in the prior art to successfully delivery a nucleic acid encoding a protein to a mammalian cell. It would have been obvious for one of ordinary skill in the art to add a payload to the adenoviral vector to also deliver the payload to the cells. In view of the teaching of Kiem et al., a person of ordinary skill in the art would have been motivated to use a method step comprising mobilization of HSPC of the subject prior to administration of the nucleic acid encoding the editing enzyme to increase the number of HPSC circulating in the blood stream of the mammalian subject. It would have been prima facie obvious to a person of ordinary skill in the art before the time of the effective filing date to combine the teaching of ‘239 and ‘783 taken with Kiem et al. to administer an immunosuppressant agent to the subject to reduce the immune response to the editing enzyme or nucleic acid encoding the editing enzyme.
Therefore, the invention as a whole would have been prima facie obvious to one ordinary skill in the art before the effective filing date of the claimed invention to a person having ordinary skill in the art to which the claimed invention pertains.
Conclusion
See attached PTO-326 for disposition of claims.
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/BRIAN WHITEMAN/ Primary Examiner, Art Unit 1636
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