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 .
Application Status
This action is written in response to applicant’s correspondence received on 4/12/2024. Claims 1-23 are pending. All pending claims are currently under examination.
Priority
The priority date of 10/18/2021 established by the Chinese application CHINA 202111208589.0, with access code provided, is acknowledged. However, no English translation of the patent application has been provided, and therefore the application is treated with the earliest priority date of 4/12/2024 (i.e., the present filing date). Receipt is acknowledged of papers submitted under 35 U.S.C. 119(a)-(d), which papers have been placed of record in the file. However, applicant cannot rely on the foreign priority document to overcome any prior art rejections because translation of the foreign priority document has not been made of record in accordance to 37 CFR 1.55.
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 2-15, 17-18, and 21-22 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.
Regarding claim 2, claim 2 recites “the site may be genes such as HPK1…and the like.” Firstly, the phrase “may be genes such as” renders the claim unclear because it is unclear if the genes listed are optional or required by the claim. Furthermore, it is unclear what a gene “such as HPK1” means, if the genes are exemplary, or what other genes may or may not be included in the group of genes “such as” HPK1. Furthermore, the phrase “and the like” is unclear because it is unclear what a gene that is “like” HPK1 encompasses, as this is vague, subjective terminology. Claim 2 further recites that the gene is “preferably” HPK1, and specifically the first exon of HPK1. This claim language is unclear because it is exemplary language, where it is unclear if this limitation is required by the claim language. Additionally, claim 2 recites “particularly HPK1 EXON.” The term “particularly” renders the claim indefinite because it is unclear if the claim is limited by the HPK1 Exon recited, or if this is merely exemplary language.
Regarding claim 3, claim 3 recites “preferably” which renders the claim unclear. The phrase “preferably” is exemplary language, and it is unclear if minicircle DNA or single-stranded DNA is a required component of the claim.
Regarding claim 4, claim 4 recites “the minicircle DNA” which lacks proper antecedent basis because no minicircle DNA is previously recited. Similarly, claim 4 recites “the single-stranded DNA” (step 2), which also lacks proper antecedent basis. Furthermore, the structure of the single-stranded DNA recited in step 2 of claim 4 is unclear for several reasons. For instance, sequence C recites “the sequence A described above pairing to a gRNA non-target region + an overlap region fragment.” It is unclear how the phrase “pairing to a gRNA” is meant to alter the sequence of sequence A as recited in sequence C. Furthermore, recitation of a plus sign (“+”) is unclear in claim 4, as it is unclear if this is meant to be read as “and.” Furthermore, the term “overlap region fragment” is unclear because it is unclear what is meant to be overlapping, or what the region overlaps with. Furthermore, sequence D recites that the DNA may comprise 0 gRNA or non-target guide RNA sequences, and that the overlap fragment region may be 0 basepairs in length. This claim language is unclear because gRNA target and non-target sequences are required in the claim language with respect to the single-stranded DNA; it is therefore unclear how “0” target or non-target regions are possible in the recited structure. Similarly, sequence D is recited to require an overlap fragment but also recites that it can be 0 basepairs in length; this claim language renders an unclear structure because it is unclear how a DNA region which is required in the sequence can also not exist (i..e, be “0” base pairs in length). Finally, claim 4 further recites “preferably” which is exemplary language which renders the claim indefinite because it is unclear if the recited preference is required by the claim.
Claims 6-11 depend from claim 4 and do not resolve these 112(b) issues and are therefore also rejected.
Regarding claim 5, claim 5 recites “preferably” which is exemplary language which renders the claim indefinite because it is unclear if the recited preference is required by the claim.
Regarding claim 6, claim 6 recites “the TSF comprises” which lacks clarity and proper antecedent basis because two separate TSFs are recited in claim 4 from which claim 6 depends. It is therefore unclear as to which TSF is being referred to by “the TSF.”
Regarding claim 7, claim 7 recites “the gRNA target region” which lacks clarity and proper antecedent basis because multiple gRNA target regions are recited in claim 4 from which claim 6 depends. It is therefore unclear as to which gRNA target region is being referred to by “the gRNA target region.” Claim 7 recites “preferably” which is exemplary language which renders the claim indefinite because it is unclear if the recited preference is required by the claim.
Regarding claim 8, claim 8 recites “the gRNA non-target region” which lacks clarity and proper antecedent basis because multiple gRNA non-target regions are recited in claim 4 from which claim 6 depends. It is therefore unclear as to which gRNA non-target region is being referred to by “the gRNA target region.” Claim 8 recites “preferably” which is exemplary language which renders the claim indefinite because it is unclear if the recited preference is required by the claim.
Regarding claim 9, claim 9 recites “the left homology arm and the right homology arm” which lacks clarity and proper antecedent basis because multiple left and right homology arms are recited in claim 4 from which claim 6 depends. It is therefore unclear as to which homology arms are being referred to by “the left homology and the right homology arm.” Claim 9 recites “preferably” which is exemplary language which renders the claim indefinite because it is unclear if the recited preference is required by the claim.
Regarding claim 10, claim 10 recites “preferably” which is exemplary language which renders the claim indefinite because it is unclear if the recited preference is required by the claim. Claim 10 recites “and the like;” it is unclear what promoters are like a CMV promoter, or what promoters would be encompassed by this claim language because “and the like” is subjective terminology.
Regarding claim 11, claim 11 recites “preferably” which is exemplary language which renders the claim indefinite because it is unclear if the recited preference is required by the claim.
Regarding claim 12, claim 12 recites “preferably” which is exemplary language which renders the claim indefinite because it is unclear if the recited preference is required by the claim. Claims 13-15 depend from claim 12 and do not resolve this issue and are also rejected.
Regarding claim 13, claim 13 recites “preferably” which is exemplary language which renders the claim indefinite because it is unclear if the recited preference is required by the claim.
Regarding claim 14, claim 14 recites “preferably” which is exemplary language which renders the claim indefinite because it is unclear if the recited preference is required by the claim.
Regarding claim 15, claim 15 recites “may also comprise,” which inherently renders the claim unclear because it is unclear if the elements are required by the claim. Claim 15 recites “preferably” which is exemplary language which renders the claim indefinite because it is unclear if the recited preference is required by the claim.
Regarding claim 17, claim 17 recites “and the like” and “preferably” which render the claim unclear for reasons set forth in the rejections above.
Regarding claim 18, claim 18 recites “preferably” which is exemplary language which renders the claim indefinite because it is unclear if the recited preference is required by the claim.
Regarding claim 21, claim 21 is a “use” claim, and is therefore rejected because it is unclear how or in what way the “use” is carried out or performed. Claim 21 lacks properly defined metes and bounds because it is unclear how the method or immune cell will be used. Claim 22 depends from claim 21 and does not resolve this issue and is therefore also rejected.
Regarding claim 22, claim 22 recites “disease requiring gene therapy are selected from.” However, this list is in no way connected to the “use” claim of 21, from which claim 22 depends. Claim 22 is simply a list of diseases which is not connected to an element of claim 21. Claim 22 is therefore not construed properly as a claim, and instead is simply a list of diseases without context to the claims. The metes and bounds and the required limitations imposed by claim 22 are therefore unclear.
Claim Rejections - 35 USC § 101
35 U.S.C. 101 reads as follows:
Whoever invents or discovers any new and useful process, machine, manufacture, or composition of matter, or any new and useful improvement thereof, may obtain a patent therefor, subject to the conditions and requirements of this title.
Claim 20 is rejected under 35 U.S.C. 101 because the claimed invention is directed to a product of nature without significantly more.
Regarding claim 20, claim 20 recites an immune cell prepared using the method of claim 1. Claim 1 recites a method comprising introducing a vector comprising a donor template and introducing a gene editing system into an immune cell. Claim 20 therefore recites a product/composition. Claim 20 can broadly be interpreted to be simply the immune cell itself, because the vector and gene editing system themselves are not required to be permanent components of the cell, nor are any repair or donor template replacement required in the claim. Claim 20 therefore recites a product of nature (Step 2A, prong 1). Furthermore, the claim does not recite additional elements which integrate the claim into a practical application (Step 2A, prong 2). Additionally, such a cell broadly reads on an immune cell lacking any markedly different characteristics when compared with simply a wildtype immune cell, where claim 20 therefore does not recite limitations which transform the claim into significantly more than the judicial exception of an immune cell (Step 2B). Claim 20 is therefore not subject matter eligible.
Furthermore, claim 20 is rejected for the following additional 101 rationale:
Regarding claim 20, claim 20 is rejected under 35 U.S.C. 101 and section 33(a) of the America Invents Act as being directed to or encompassing a human organism. See also Animals - Patentability, 1077 Off. Gaz. Pat. Office 24 (April 21, 1987) (indicating that human organisms are excluded from the scope of patentable subject matter under 35 U.S.C. 101. Specifically, claim 20 recites “an immune cell.” While claims immediately considered on merits recite a composition, the specification describes methods of treating a subject where the claimed cell comprising administering the cell to treat a disease in a subject which can be human (e.g., page 10 final two paragraphs, page 11 seventh paragraph). Furthermore, claims 21-23 recite a method of treatment or use in gene medicine. Accordingly, when the claimed cell compositions are delivered to a human subject, cells of the subject will comprise the composition claimed. Therefore, the claims would encompass cells in a human organism and the human organism itself.
Amending the claim to an isolated host cell or a host cell in vitro will be remedial.
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 (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 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.
Claims 1-3, 5, and 12-23 are rejected under 35 U.S.C. 102(a)(1) as being anticipated by Liao (WO 2019/057102 A1, published 3/28/2020).
Regarding claim 1, Liao teaches site specific integration of a target gene into an immune cell (paragraph 2). Liao teaches that donor sequences (homologous recombination repair templates) can be used to introduce and edit the immune cells at specific sites to introduce a target gene (page 3, first paragraph). Liao teaches that the components of their systems and methods are encoded in vectors (paragraph 10). Liao teaches that gene editing systems, such as CRISPR/Cas are introduced with the vector (e.g, paragraph 58 and throughout).
Regarding claim 2, Liao teaches that the specific site is HPK1 (Abstract, paragraph 2, and throughout the document).
Regarding claim 3, Liao teaches that the vector is an adeno-associated vector (paragraph 10).
Regarding claim 5, Liao teaches that the target gene is a CAR (page 3, first paragraph).
Regarding claim 12, Liao teaches that the gene editing system is CRISPR (e.g., paragraph 8 and throughout).
Regarding claim 13, Liao teaches that the CRISPR system is SpCas9 (S. pyogenes Cas9, paragraph 9).
Regarding claim 14, Liao teaches that the gRNA can be complementary to SEQ ID NO: 1, which is 100% identical to instant SEQ ID NO: 1 (paragraphs 109-110, and see alignment, below):
GACCTGGTGGCACTGAAGA – SEQ ID NO: 1, instant
GACCTGGTGGCACTGAAGA – SEQ ID NO: 1, Liao (paragraph 110)
Regarding claim 15, Liao teaches that the gRNA can comprise chemical modifications (paragraph 107).
Regarding claim 16, Liao teaches that the gene editing system is a gRNA and Cas nuclease (paragraph 107).
Regarding claim 17, Liao teaches that the vectors/nucleic acids can be delivered by methods such as transfection and electroporation (paragraph 120).
Regarding claim 18, Liao teaches that the immune cell is a T cell (Abstract, paragraph 2).
Regarding claim 19, Liao teaches that the immune cell is autologous or allogenic (paragraph 71).
Regarding claim 20, Liao teaches that the methods generate immune cells (Abstract, paragraph 71, and throughout).
Regarding claims 21-23, Liao teaches a method of treating a disease by administering immune cells generated by their method, where the disease is associated with a NOD SCID mouse model of human lymphoma/malignant tumor model (Liao Example, pages 86-89 ). A method of treatment of a tumor model (claim 22) can broadly be interpreted to be a “use” of the immune cells of claim 1 in preparing gene therapy medicine (claims 21-22).
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.
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 4 and 9 are rejected under 35 U.S.C. 103 as being unpatentable over Liao (WO 2019/057102 A1, published 3/28/2020) in view of Cannon (WO 2014/182700 A1).
A discussion of the teachings of Liao as they relate to claims 1-3, 5, and 12-23 is given above in the 102 rejection and incorporated herein. Liao teaches the immune cells of claim 1, and teaches the introduction of a vector comprising a homologous recombination donor template (paragraphs 2-3, 10, 58).
Liao does not teach that the homologous recombination donor template is a mini circle DNA.
Cannon is a patent document which focuses on compositions for nuclease-mediated genome engineering comprising donor templates to target site specific integration of target genes (Title, Abstract, and throughout). Liao and Cannon therefore directly overlap is subject matter and field of endeavor because they both teach targeted gene engineering and methods of accomplishing such goals. Cannon teaches that:
“DNA minicircles (MCs) are supercoiled DNA molecules that can be
used for non- viral gene transfer that have neither an origin of replication or a
antibiotic selection marker. These DNAs are devoid of bacterial DNA, and thus lack the unmethylated CpG motifs found in bacterial DNA. These CpG motifs have been shown to active the innate immune response in mammals by binding to the Toll-like receptor 9 receptors on antigen presenting cells. Thus, use of DNAs for gene therapy that contain bacterially derived DNA sequence may be more inflammatory that those DNAs lacking bacterial sequences. MCs are smaller than standard plasmids used in some gene therapy applications, and are more efficiently transfected into both cell lines than standard plasmids,” (Paragraph 5).
Thus, Cannon teaches that mini circle DNAs are known to have several advantages compared with traditional plasmids for targeted gene therapy and genome engineering, as such delivery mechanisms reduce innate immune responses and are furthermore more efficiently transfected into cells owing to their smaller size (paragraph 5). Cannon teaches that the mini circle DNA comprise, in the 5’ to 3’ direction, left homology arms, promoter, target gene, polyA, and right homology arms (Figure 1).
Regarding the limitation of a “target sequence” recited in claim 4, this region is not specifically defined by any sequence restraints, as any sequence can be a “target region.” Thus, the homology arms taught by Cannon, or any segment of such a homology arm, reads on the target sequences presently recited in claim 4.
It would have been obvious to a person of ordinary skill in the art before the effective filing date to modify the donor repair templates taught by Liao to include mini circle DNA templates as taught by Cannon because such a combination is the simple combination of known prior art elements with predictable success. Furthermore, the combination is not simply a combination of known prior art elements; to the contrary, the practitioner would be motivated to incorporate the teachings of Cannon with those of Liao because Cannon has taught that mini circle DNAs offer known advantages over other delivery vectors such as improved transfection.
Regarding claim 9, Cannon teaches that the homology arms can be 500 bae pairs (paragraph 28).
Claims 6-8 are rejected under 35 U.S.C. 103 as being unpatentable over Liao (WO 2019/057102 A1, published 3/28/2020) in view of Cannon (WO 2014/182700 A1) and NCBI NM_001042600 (hereafter ‘600, NCBI BLAST Accession number for human HPK1 gene, published 5/31/2018).
A discussion of the teachings of Liao as they relate to claims 1-3, 5, and 12-23 is given above in the 102 rejection and incorporated herein. Liao teaches the immune cells of claim 1, and teaches the introduction of a vector comprising a homologous recombination donor template (paragraphs 2-3, 10, 58).
Regarding claim 6, Liao further teaches that the specific target site is HPK1, and specifically the first or second exon (page 2 final paragraph into page 3, first paragraph). Additionally, Liao teaches that SpCas9 has an “NGG” PAM site recognition (paragraph 113).
Liao does not specifically teach SEQ ID NO: 7 (claim 6), SEQ ID NO: 9 (claim 7), or SEQ ID NO: 10 (claim 8).
With respect to SEQ ID NO: 7, instant SEQ ID NO: 7 is shown in alignment below with residues 178-200 of ‘600, the human HPK1 gene (see page 3, line 13, which identifies the gene as HPK1):
PNG
media_image1.png
333
1229
media_image1.png
Greyscale
As shown above, residues 178-200 are 100% complimentary to residues 178-200 of ‘600, the HPK1 gene taught by Liao. Thus, the target sequence of SEQ ID NO: 7 can broadly be interpreted to simply be encompassed by the left homology arms of Cannon, as target sequence of SEQ ID NO: 7 is a sequence that is 100% complimentary to the target taught by Liao (i.e., exon 1 of the HPK1 gene). Furthermore, ‘600 teaches that residues 178-200 are within Exon 1 of HPK1, which is the region which Liao teaches to target the HPK1 gene for integration (see page 3, line 19 of ‘600, and Liao, page 2 final paragraph to page 3).
It would have been obvious to a person of ordinary skill in the art before the effective filing date of the claimed invention to modify the donor templates taught by Liao to include homology arms comprising target sequences including SEQ ID NO: 7, as taught by Cannon and ‘600 because Liao has already taught both the target gene (HPK1) and also where to target the gene for integration (Exon 1). SEQ ID NO: 7, and a homology arm/target sequence comprising SEQ ID NO: 7 are therefore obvious, where the practitioner is motivated to target this region directly by the teachings of Liao.
Regarding claim 7, Cannon teaches that the donor repair template can be single stranded (paragraph 120). Claim 7 recites SEQ ID NO: 9 as a gRNA target sequence. SEQ ID NO: 9 is the reverse compliment of SEQ ID NO: 7, and reads as the reverse compliment of residues 178-200 of ‘600 (see alignment, below):
PNG
media_image2.png
148
729
media_image2.png
Greyscale
Furthermore, residues 176-177 are “GG” residues (see ‘600, page 6, which lists the sequence). Thus, the gRNA target site comprises “NGG” PAM motifs within Exon 1 of the HPK1 gene, where each of these components are taught by Liao (i.e., targeting Exon 1 of the HPK1 gene, and furthermore gRNAs which target NGG motifs). Furthermore, residues 198-200 of ‘600 comprise the NGG motif (TGG).
It would have been obvious to a person of ordinary skill in the art before the effective filing date to modify the donor templates taught by Liao and Cannon to include SEQ ID NO: 9 because such a region is simply a known prior art component combined with another component to yield predictable results. In the present case, SEQ ID NO: 9 is simply 100% complimentary to a region of Exon 1 of the HPK1 gene taught by Liao, as taught by ‘600, and furthermore comprise an NGG and NGG adjacent motif, which Liao teaches is the gRNA PAM motif of the Cas enzymes they also teach.
Regarding claim 8, Cannon teaches that the donor template can be single stranded (paragraph 120). Furthermore, SEQ ID NO: 7, as recited in claim 6, is 100% identical in sequence and length compared with SEQ ID NO: 10 as recited in claim 8 (see below):
PNG
media_image3.png
192
688
media_image3.png
Greyscale
Thus, claim 8 is rejected for the same reasons given in the rejection of claim 6.
Claims 10-11 are rejected under 35 U.S.C. 103 as being unpatentable over Liao (WO 2019/057102 A1, published 3/28/2020) and Cannon (WO 2014/182700 A1), as applied to claims 4 and 9, above, and further in view of Gao (WO 2016/131009 A1).
Regarding claims 4 and 9, a discussion of the teachings of Liao and Cannon are given above and incorporated here. Cannon teaches that the vectors and expression constructs comprise polyA regions and promoters (e.g., Figure 1).
The combination of Liao and Cannon does not teach that the promoter is the CMV promoter (claim 10) or that the polyA region is BGHpA (claim 11).
Gao is a patent document which teaches the methods for the delivery of nuclease constructs and associated vectors (Title, Abstract, and throughout). Gao, Liao, and Cannon therefore directly overlap in subject matter and field of endeavor because they are both directed to the delivery of nuclease constructs and vectors, where Gao also teaches overlapping components such as Cas9 and gRNA (Gao, page 8 first and last paragraphs). Furthermore, for the purposes of the construction of such constructs, Gao teaches that such constructs including both the CMV promoter and BGHpA polyA region are known to function for the delivery of a transgene (see Figure 1). Gao therefore teaches that the BGHpA polyA tract and the CMV promoter are known elements for delivery and expression of transgenes used in CRISPR Cas systems, and therefore teaches that such elements are useful embodiments to deliver a desired gene. Furthermore, the specification indicates that SEQ ID NO: 20 is the sequence of BHGpA (page 4, third paragraph). By teaching the polA element BGHpA, Gao inherently teaches its sequence (SEQ ID NO: 20).
It would have been obvious to a person of ordinary skill in the art before the effective filing date to modify the polA and promoter regions of the combination of Liao/Cannon to include the BGHpA and CMV promoters because such a combination is the simple substitution of known prior art elements for known elements with predictable success. In the present case, the practitioner would simply substitute the polyA region and promoters taught by Cannon to be the BGHpA polyA region and CMV promoter, as taught by Gao, who teaches that such expression elements are known and furthermore useful for expressing a target gene or transgene. The results are predictable because Gao, Liao, and Cannon are directed to similar expression constructs and use similar components in their systems.
Claim Rejections - 35 USC § 112
Claims 21-23 are rejected under 35 U.S.C. 112(a) or 35 U.S.C. 112 (pre-AIA ), first paragraph, because the specification, while being enabling for a method of treating NOD SCID mouse models of human lymphoma using engineered T cells, as described in the prior art Liao (WO 2019/057102), does not reasonably provide enablement for a method of treating diseases in general. The specification does not enable any person skilled in the art to which it pertains, or with which it is most nearly connected, to use the invention commensurate in scope with these claims.
Factors to be considered in determining whether a disclosure meets the enablement requirement of 35 U.S.C. 112, first paragraph, have been described by the court in In re Wands, 8 USPQ2d 1400 (Fed. Cir. 1988). Wands states, on page 1404:
Factors to be considered in determining whether a disclosure would require undue experimentation have been summarized by the board in Ex parte Forman. They include (1) the quantity of experimentation necessary, (2) the amount of direction or guidance presented, (3) the presence or absence of working examples, (4) the nature of the invention, (5) the state of the prior art, (6) the relative skill of these in the art, (7) the predictability or unpredictability of the art, and (8) the breadth of the claims.
Claim Interpretation
As an initial matter, claims 21-22 are use claims, which are indefinite per the 112(b) rejection in this office action, above. Claims 21-22 can broadly be interpreted to include any use, such as in a use of treating a disease. Thus, claims 21-22 are included in this rejection as broadly including the limitations of claim 23.
Nature of the Invention/Breadth of Claims
Regarding claims 21-23, these claims are broadly drawn to methods/uses of treating a disease using immune cells generated by introducing a repair template vector into an immune cell and a gene editing cassette (i.e., the cells of claims 1 and 20). This claim language is problematic because 1) the claim includes any repair template and gene cassette, and is therefore not limited in a donor repair target, target gene, or target region, 2) the claims are not limited to immune cell type, and 3) the claims are not limited by disease type. Furthermore, as discussed below, it is known in the art that a high degree of unpredictability exists when using engineered immune cells to treat diseases, where furthermore there is a high degree of unpredictability and lack of likelihood that non-specific repair templates and target genes would be useful in treating any diseases.
Guidance in the Specification
Regarding the guidance provided in the specification, the Applicant offers examples 1-4. Example 1 concerns the construction of a mini circle DNA harboring a target CAR gene. Example 2 describes the construction of a single stranded DNA repair donor comprising a target CAR gene. Example 3 describes a gRNA which targets HPK1. Example 4 describes construction of CAR-T cells using the components of Examples 1-3. Example 4 details an in vitro tumor killing assay using the CAR-T cells. Thus, the Applicants have made a CAR-T cell and tested its abilities to neutralize one type of tumor cell in vitro. The Applicant has not tested additional target genes, made any other additional immune cell types/reduced to practice such cells to show tumor killing potential, or performed any in vivo testing or treated any diseases using the limited cells they have made.
State of the Art
With regards to the state of the art, it is known in the art that unpredictability exists when trying to treat diseases in vivo using engineered T cells. For example, Lyon (Lyon JG et al. Adv Drug Deliv Rev. 2017 May 15;114:19-32) is a research article which focuses on known challenges when using engineered T cells to treat tumors in vivo, specifically brain tumors. Lyon teaches that:
“While some of the advances in immunotherapy clinical trials for brain cancers are promising, many hurdles remain before those immunotherapies can be standard of care for difficult to treat brain tumors such as GBM. Some of these challenges are broadly applicable to all cancer immunotherapies throughout the body. For example, the heterogeneity posed by individualized immune systems makes patient-agnostic immunotherapies among large populations difficult. Also, as mentioned above, depending on the domain or epitope recognized by immune cells, these immunotherapies could potentially target healthy cells that share tumor-associated antigens,” (page 12, final paragraph to 13).
Thus, Lyon teaches that several hurdle still exist when treating brain cancers, which are broadly applicable to all cancer therapies throughout the body including the heterogeneity of patient populations and the potential of immune cells to target health cells (above). Specifically in the context of brain tumors, Lyon teaches that known problems exist such as crossing the blood-brain barrier and uncharacterized antigens within the brain (page 13-14). Thus, Lyon teaches not only that cancer cellular immunotherapies face challenges when adapting them to treatment, but that each cancer type (e.g., brain cancer) poses its own unique set of obstacles when adopting an immune cell treatment. The Applicant has not addressed or solved any of these known issues in treating disease such as cancer, nor have they offered any additional target genes or tested other immune cells aside from T cells (e.g., macrophages, where they have identified no repair template constructs or target repair regions within such cells).
Undue Experimental Burden
Owing to the high degree of unpredictability and known lack of success and challenges associated with adopting engineered immune cell therapies across diverse disease (e.g., the diverse and tissue specific nature of cancer), the practitioner faces undue experimental burden when using the recited method. For instance, the practitioner would be required to solve known challenges which have existed within the field for decades (e.g., tissue targeting to the brain to deliver and treat brain cancer), where no guidance or reduction to practice within the specification is offered to the practitioner.
Conclusion
Any inquiry concerning this communication or earlier communications from the examiner should be directed to DOUGLAS CHARLES RYAN whose telephone number is (571)272-8406. The examiner can normally be reached M-F 8AM - 5PM.
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If attempts to reach the examiner by telephone are unsuccessful, the examiner’s supervisor, Ram Shukla can be reached at (571)-272-0735. The fax phone number for the organization where this application or proceeding is assigned is 571-273-8300.
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/D.C.R./Examiner, Art Unit 1635
/RAM R SHUKLA/Supervisory Patent Examiner, Art Unit 1635
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